{"gene":"PF3D7_1460900","run_date":"2026-09-08T14:19:07","timeline":{"discoveries":[{"year":2015,"finding":"A nonsynonymous polymorphism in ARPS10 (PF3D7_1460900) showed strong genome-wide association with artemisinin resistance in a large multicenter study across Southeast Asia, and was identified as a marker of a genetic background on which kelch13 mutations are particularly likely to arise, indicating ARPS10 variants predispose parasites to acquiring artemisinin resistance-causing mutations.","method":"Genome-wide association study (GWAS) across 15 Southeast Asian locations with fine population structure analysis","journal":"Nature genetics","confidence":"Medium","confidence_rationale":"Tier 4 / Strong — large-scale GWAS with population structure analysis, replicated across 15 sites, but no direct biochemical or genetic epistasis experiment; association only","pmids":["25599401"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"finding":"Introducing the ARPS10-V127M variant (together with FD-D193Y) into a kelch13-C580Y-containing P. falciparum 3D7 parasite, but not into wild-type kelch13 parasites, significantly increased parasite survival in the 0–3 h ring survival assay (RSA0–3h), demonstrating that ARPS10-V127M is a modifier of artemisinin susceptibility that acts epistatically with the kelch13-C580Y allele.","method":"Transgenic parasite generation by allelic replacement mutagenesis; ring survival assay (RSA0–3h); genetic epistasis analysis","journal":"Malaria journal","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct allelic replacement mutagenesis in live parasites combined with functional RSA phenotypic assay and epistasis analysis; single lab but two orthogonal approaches (genetic manipulation + functional assay)","pmids":["36303209"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":2019,"finding":"Strong selection against alleles from an artemisinin-resistant parent at the chromosome 14 locus containing ARPS10 was observed across multiple asexual blood stage cycles in experimental genetic crosses (selection coefficient s ≤ 0.18/asexual cycle), indicating that the ARPS10 locus harbors alleles that incur a fitness cost in blood stage parasites when inherited from the resistant parent.","method":"Experimental genetic crosses using humanized mice; selective whole genome amplification and pooled sequencing to track allele frequencies across lifecycle stages","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic cross with genome-wide allele frequency tracking; functional fitness inference but no direct biochemical characterization of ARPS10 protein","pmids":["31609965"],"is_preprint":false,"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"current_model":"ARPS10 (PF3D7_1460900) encodes an apicoplast ribosomal protein S10 in P. falciparum; the V127M variant acts as an epistatic modifier of artemisinin susceptibility specifically in a kelch13-C580Y background (demonstrated by allelic replacement and ring survival assay), and population genomic evidence indicates that ARPS10 variants mark a predisposing genetic background on which kelch13 resistance mutations preferentially arise, with blood-stage fitness costs associated with resistance-background ARPS10 alleles observed in experimental crosses."},"narrative":{"mechanistic_narrative":"ARPS10 (PF3D7_1460900) is annotated as an apicoplast ribosomal protein S10, but the available corpus characterizes it not through any biochemical or ribosomal function but as a genetic modifier of artemisinin susceptibility in Plasmodium falciparum. A nonsynonymous polymorphism in ARPS10 shows strong genome-wide association with artemisinin resistance across Southeast Asia and marks a permissive genetic background on which kelch13 resistance mutations preferentially arise [PMID:25599401]. This modifier role is causally demonstrated: introducing the ARPS10-V127M variant into a kelch13-C580Y parasite, but not into a wild-type kelch13 parasite, increases ring-stage survival in the RSA0–3h assay, establishing that ARPS10-V127M acts epistatically with the kelch13 resistance allele rather than conferring resistance on its own [PMID:36303209]. The resistance-associated ARPS10 locus also carries a blood-stage fitness cost, as alleles inherited from an artemisinin-resistant parent are strongly selected against over successive asexual cycles in experimental crosses [PMID:31609965]. Beyond this population-genetic and epistatic role, no direct biochemical, structural, or ribosome-associated function of the ARPS10 protein has been characterized in the available corpus.","teleology":[{"year":2015,"claim":"Before this work it was unknown what genetic features distinguished parasites prone to acquiring artemisinin resistance; associating an ARPS10 polymorphism with resistance established it as a marker of a predisposing genetic background.","evidence":"Genome-wide association study across 15 Southeast Asian sites with population structure analysis in P. falciparum","pmids":["25599401"],"confidence":"Medium","gaps":["Association only; no causal or biochemical test of the ARPS10 variant","Does not establish whether ARPS10 affects the ribosome or a separate pathway","Does not distinguish ARPS10 causation from linkage to other chromosome 14 loci"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2019,"claim":"It was unknown whether resistance-associated ARPS10 alleles carry a fitness penalty; experimental crosses showed strong selection against the resistant-parent allele at this locus across asexual cycles, revealing a blood-stage fitness cost.","evidence":"Experimental genetic crosses in humanized mice with selective whole-genome amplification and pooled allele-frequency tracking in P. falciparum","pmids":["31609965"],"confidence":"Medium","gaps":["Selection was measured at the locus, not attributed to the ARPS10 coding variant specifically","Mechanism of the fitness cost was not defined","No biochemical characterization of ARPS10 protein"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]},{"year":2022,"claim":"The GWAS association left open whether ARPS10-V127M is causally involved; allelic replacement showed it increases ring survival only in a kelch13-C580Y background, establishing it as an epistatic modifier rather than an independent resistance determinant.","evidence":"Allelic replacement mutagenesis in P. falciparum 3D7 combined with RSA0–3h ring survival assay and epistasis analysis","pmids":["36303209"],"confidence":"High","gaps":["The variant was introduced together with FD-D193Y, leaving the independent contribution of ARPS10-V127M alone undefined","The molecular mechanism by which the variant modifies kelch13-mediated survival is unknown","Single-lab result"],"attribution":[{"species":"Plasmodium falciparum","strain":"3D7"}]},{"year":null,"claim":"The biochemical function of the ARPS10 protein and the mechanism linking its variant to artemisinin susceptibility remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No experimental confirmation of apicoplast ribosome association for the ARPS10 protein in the corpus","No mechanistic connection between ARPS10-V127M and kelch13 pathway function","Independent effect of ARPS10-V127M separate from co-introduced variants not established"],"attribution":[{"species":"Plasmodium falciparum","strain":""}]}],"mechanism_profile":{"molecular_activity":[],"localization":[],"pathway":[],"complexes":[],"partners":["KELCH13 (C580Y ALLELE; EPISTATIC INTERACTION)"],"other_free_text":["ARPS10 is annotated as apicoplast ribosomal protein S10, but the corpus establishes no direct biochemical or ribosomal function for the protein.","ARPS10-V127M acts as an epistatic modifier of artemisinin susceptibility in a kelch13-C580Y background [#1].","An ARPS10 polymorphism marks a permissive genetic background for the emergence of kelch13 artemisinin-resistance mutations [#0].","The resistance-associated ARPS10 locus carries a blood-stage fitness cost in experimental crosses [#2]."]}},"prefetch_data":{},"corpus_meta":[{"pmid":"25599401","id":"PMC_25599401","title":"Genetic architecture of artemisinin-resistant Plasmodium falciparum.","date":"2015","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25599401","citation_count":471,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ARPS10","S10"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"31609965","id":"PMC_31609965","title":"Genetic mapping of fitness determinants across the malaria parasite Plasmodium falciparum life cycle.","date":"2019","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31609965","citation_count":43,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ARPS10"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"31718631","id":"PMC_31718631","title":"A comprehensive analysis of drug resistance molecular markers and Plasmodium falciparum genetic diversity in two malaria endemic sites in Mali.","date":"2019","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/31718631","citation_count":30,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfARPS10"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"28068997","id":"PMC_28068997","title":"Absence of in vivo selection for K13 mutations after artemether-lumefantrine treatment in Uganda.","date":"2017","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/28068997","citation_count":28,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["S10"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"32817665","id":"PMC_32817665","title":"Antimalarial drug resistance molecular makers of Plasmodium falciparum isolates from Sudan during 2015-2017.","date":"2020","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/32817665","citation_count":26,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfARPS10"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"28806957","id":"PMC_28806957","title":"Clinical and molecular surveillance of artemisinin resistant falciparum malaria in Myanmar (2009-2013).","date":"2017","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/28806957","citation_count":25,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfARPS10"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"28249583","id":"PMC_28249583","title":"Molecular surveillance of artemisinin resistance falciparum malaria among migrant goldmine workers in Myanmar.","date":"2017","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/28249583","citation_count":15,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfARPS10"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"32070355","id":"PMC_32070355","title":"Assessment of Plasmodium falciparum drug resistance molecular markers from the Blue Nile State, Southeast Sudan.","date":"2020","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/32070355","citation_count":13,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfARPS10"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"35511795","id":"PMC_35511795","title":"Prevalence of arps10, fd, pfmdr-2, pfcrt and pfkelch13 gene mutations in Plasmodium falciparum parasite population in Uganda.","date":"2022","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/35511795","citation_count":11,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ARPS10","S10"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"31251952","id":"PMC_31251952","title":"Plasmodium berghei sporozoite specific genes- PbS10 and PbS23/SSP3 are required for the development of exo-erythrocytic forms.","date":"2019","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/31251952","citation_count":9,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PbS10"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"36303209","id":"PMC_36303209","title":"Apicoplast ribosomal protein S10-V127M enhances artemisinin resistance of a Kelch13 transgenic Plasmodium falciparum.","date":"2022","source":"Malaria journal","url":"https://pubmed.ncbi.nlm.nih.gov/36303209","citation_count":7,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["ARPS10","S10"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"38456076","id":"PMC_38456076","title":"Putative molecular markers of Plasmodium falciparum resistance to antimalarial drugs in malaria parasites from Ghana.","date":"2024","source":"Frontiers in epidemiology","url":"https://pubmed.ncbi.nlm.nih.gov/38456076","citation_count":4,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["S10","PfARPS10"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false},{"pmid":"40666336","id":"PMC_40666336","title":"A Novel Plasmodium falciparum Kelch13 A675T Mutation and High Levels of Chloroquine and Sulfadoxine-Pyrimethamine Resistance in Burundi.","date":"2025","source":"medRxiv : the preprint server for health sciences","url":"https://pubmed.ncbi.nlm.nih.gov/40666336","citation_count":1,"is_preprint":false,"source_species":["Pf"],"role":"primary","match_terms":["PfARPS10"],"competing_organism_flag":false,"competing_organism_match":"","competing_organism_only":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":11804,"output_tokens":988,"usd":0.025116,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":5827,"output_tokens":1950,"usd":0.038942,"stage2_stop_reason":"end_turn"},"total_usd":0.064058,"stage1_batch_id":"msgbatch_011BPjN2BL33F8cJXD1r7V7T","stage2_batch_id":"msgbatch_01Qwg6vP7qxkpL6Gsc7tajsb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"A nonsynonymous polymorphism in ARPS10 (PF3D7_1460900) showed strong genome-wide association with artemisinin resistance in a large multicenter study across Southeast Asia, and was identified as a marker of a genetic background on which kelch13 mutations are particularly likely to arise, indicating ARPS10 variants predispose parasites to acquiring artemisinin resistance-causing mutations.\",\n      \"method\": \"Genome-wide association study (GWAS) across 15 Southeast Asian locations with fine population structure analysis\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 4 / Strong — large-scale GWAS with population structure analysis, replicated across 15 sites, but no direct biochemical or genetic epistasis experiment; association only\",\n      \"pmids\": [\"25599401\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Introducing the ARPS10-V127M variant (together with FD-D193Y) into a kelch13-C580Y-containing P. falciparum 3D7 parasite, but not into wild-type kelch13 parasites, significantly increased parasite survival in the 0–3 h ring survival assay (RSA0–3h), demonstrating that ARPS10-V127M is a modifier of artemisinin susceptibility that acts epistatically with the kelch13-C580Y allele.\",\n      \"method\": \"Transgenic parasite generation by allelic replacement mutagenesis; ring survival assay (RSA0–3h); genetic epistasis analysis\",\n      \"journal\": \"Malaria journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct allelic replacement mutagenesis in live parasites combined with functional RSA phenotypic assay and epistasis analysis; single lab but two orthogonal approaches (genetic manipulation + functional assay)\",\n      \"pmids\": [\"36303209\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Strong selection against alleles from an artemisinin-resistant parent at the chromosome 14 locus containing ARPS10 was observed across multiple asexual blood stage cycles in experimental genetic crosses (selection coefficient s ≤ 0.18/asexual cycle), indicating that the ARPS10 locus harbors alleles that incur a fitness cost in blood stage parasites when inherited from the resistant parent.\",\n      \"method\": \"Experimental genetic crosses using humanized mice; selective whole genome amplification and pooled sequencing to track allele frequencies across lifecycle stages\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic cross with genome-wide allele frequency tracking; functional fitness inference but no direct biochemical characterization of ARPS10 protein\",\n      \"pmids\": [\"31609965\"],\n      \"is_preprint\": false,\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"current_model\": \"ARPS10 (PF3D7_1460900) encodes an apicoplast ribosomal protein S10 in P. falciparum; the V127M variant acts as an epistatic modifier of artemisinin susceptibility specifically in a kelch13-C580Y background (demonstrated by allelic replacement and ring survival assay), and population genomic evidence indicates that ARPS10 variants mark a predisposing genetic background on which kelch13 resistance mutations preferentially arise, with blood-stage fitness costs associated with resistance-background ARPS10 alleles observed in experimental crosses.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ARPS10 (PF3D7_1460900) is annotated as an apicoplast ribosomal protein S10, but the available corpus characterizes it not through any biochemical or ribosomal function but as a genetic modifier of artemisinin susceptibility in Plasmodium falciparum. A nonsynonymous polymorphism in ARPS10 shows strong genome-wide association with artemisinin resistance across Southeast Asia and marks a permissive genetic background on which kelch13 resistance mutations preferentially arise [#0]. This modifier role is causally demonstrated: introducing the ARPS10-V127M variant into a kelch13-C580Y parasite, but not into a wild-type kelch13 parasite, increases ring-stage survival in the RSA0\\u20133h assay, establishing that ARPS10-V127M acts epistatically with the kelch13 resistance allele rather than conferring resistance on its own [#1]. The resistance-associated ARPS10 locus also carries a blood-stage fitness cost, as alleles inherited from an artemisinin-resistant parent are strongly selected against over successive asexual cycles in experimental crosses [#2]. Beyond this population-genetic and epistatic role, no direct biochemical, structural, or ribosome-associated function of the ARPS10 protein has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Before this work it was unknown what genetic features distinguished parasites prone to acquiring artemisinin resistance; associating an ARPS10 polymorphism with resistance established it as a marker of a predisposing genetic background.\",\n      \"evidence\": \"Genome-wide association study across 15 Southeast Asian sites with population structure analysis in P. falciparum\",\n      \"pmids\": [\"25599401\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Association only; no causal or biochemical test of the ARPS10 variant\",\n        \"Does not establish whether ARPS10 affects the ribosome or a separate pathway\",\n        \"Does not distinguish ARPS10 causation from linkage to other chromosome 14 loci\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"It was unknown whether resistance-associated ARPS10 alleles carry a fitness penalty; experimental crosses showed strong selection against the resistant-parent allele at this locus across asexual cycles, revealing a blood-stage fitness cost.\",\n      \"evidence\": \"Experimental genetic crosses in humanized mice with selective whole-genome amplification and pooled allele-frequency tracking in P. falciparum\",\n      \"pmids\": [\"31609965\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Selection was measured at the locus, not attributed to the ARPS10 coding variant specifically\",\n        \"Mechanism of the fitness cost was not defined\",\n        \"No biochemical characterization of ARPS10 protein\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"The GWAS association left open whether ARPS10-V127M is causally involved; allelic replacement showed it increases ring survival only in a kelch13-C580Y background, establishing it as an epistatic modifier rather than an independent resistance determinant.\",\n      \"evidence\": \"Allelic replacement mutagenesis in P. falciparum 3D7 combined with RSA0\\u20133h ring survival assay and epistasis analysis\",\n      \"pmids\": [\"36303209\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The variant was introduced together with FD-D193Y, leaving the independent contribution of ARPS10-V127M alone undefined\",\n        \"The molecular mechanism by which the variant modifies kelch13-mediated survival is unknown\",\n        \"Single-lab result\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"3D7\"}]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The biochemical function of the ARPS10 protein and the mechanism linking its variant to artemisinin susceptibility remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No experimental confirmation of apicoplast ribosome association for the ARPS10 protein in the corpus\",\n        \"No mechanistic connection between ARPS10-V127M and kelch13 pathway function\",\n        \"Independent effect of ARPS10-V127M separate from co-introduced variants not established\"\n      ],\n      \"attribution\": [{\"species\": \"Plasmodium falciparum\", \"strain\": \"\"}]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [],\n    \"pathway\": [],\n    \"complexes\": [],\n    \"partners\": [\"kelch13 (C580Y allele; epistatic interaction)\"],\n    \"other_free_text\": [\n      \"ARPS10 is annotated as apicoplast ribosomal protein S10, but the corpus establishes no direct biochemical or ribosomal function for the protein.\",\n      \"ARPS10-V127M acts as an epistatic modifier of artemisinin susceptibility in a kelch13-C580Y background [#1].\",\n      \"An ARPS10 polymorphism marks a permissive genetic background for the emergence of kelch13 artemisinin-resistance mutations [#0].\",\n      \"The resistance-associated ARPS10 locus carries a blood-stage fitness cost in experimental crosses [#2].\"\n    ]\n  }\n}","audit_flag":null,"strains":[{"strain":"Pf3D7","gene_id":"PF3D7_1460900","name":null,"product":"ribosomal protein S10, apicoplast, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PbANKA","gene_id":"PBANKA_1324600","name":null,"product":"ribosomal protein S10, apicoplast, putative","uniprot_acc":null,"chromosome":null,"start_pos":null},{"strain":"PkH","gene_id":"PKNH_1220800","name":null,"product":"ribosomal protein S10, apicoplast, putative","uniprot_acc":null,"chromosome":null,"start_pos":null}],"gene_symbol":"ARPS10","evaluation":null}