{"gene":"ARMH2","run_date":"2026-04-28T17:12:37","timeline":{"discoveries":[{"year":2025,"finding":"ARMH2 is a cytosolic component of the CatSper calcium channel complex in sperm, forming a ternary subcomplex with EFCAB9 and CATSPERζ that contributes to stable assembly of linear CatSper nanodomains along the sperm tail and regulates pH and Ca2+ sensitivity of the channel.","method":"Cryo-EM structural determination, mass spectrometry, AlphaFold structure prediction, coevolutionary analysis, and loss-of-function mouse models with phenotypic readout (asthenozoospermia, subfertility, compromised CatSper activation)","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including cryo-EM structure, MS, and in vivo KO with defined molecular and physiological phenotypes in a single study","pmids":["41271765"],"is_preprint":false}],"current_model":"ARMH2 is a cytosolic subunit of the sperm-specific CatSper Ca2+ channel that forms a ternary subcomplex with EFCAB9 and CATSPERζ, stabilizes the linear nanodomain arrangement of CatSper along the sperm tail, and regulates the channel's pH and Ca2+ sensitivity; its loss causes defective CatSper activation, asthenozoospermia, and subfertility."},"narrative":{"teleology":[{"year":2025,"claim":"Resolving the molecular identity and structural role of ARMH2 within the CatSper complex established it as a cytosolic subunit that forms a ternary subcomplex with EFCAB9 and CATSPERζ, stabilizes CatSper nanodomain architecture, and tunes channel gating — filling the gap in understanding how accessory subunits regulate sperm Ca²⁺ signaling.","evidence":"Cryo-EM structure, mass spectrometry, AlphaFold prediction, coevolutionary analysis, and Armh2-knockout mouse phenotyping in sperm","pmids":["41271765"],"confidence":"High","gaps":["Atomic-resolution details of the ARMH2–EFCAB9–CATSPERζ interface and how conformational changes transmit pH/Ca²⁺ signals to the pore remain unresolved","Whether ARMH2 has any function outside sperm or the CatSper complex is unknown","Human genetic validation linking ARMH2 mutations to male infertility has not been reported"]},{"year":null,"claim":"The precise allosteric mechanism by which ARMH2 modulates CatSper pH and Ca²⁺ sensitivity, and whether ARMH2 loss-of-function variants contribute to human male infertility, remain open questions.","evidence":"","pmids":[],"confidence":"High","gaps":["No reconstituted electrophysiology of the ARMH2-containing subcomplex to dissect gating contributions","No human patient cohort data linking ARMH2 variants to asthenozoospermia or infertility"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0]}],"complexes":["CatSper channel complex"],"partners":["EFCAB9","CATSPERΖ"],"other_free_text":[]},"mechanistic_narrative":"ARMH2 is a cytosolic subunit of the sperm-specific CatSper Ca²⁺ channel complex, where it forms a ternary subcomplex with EFCAB9 and CATSPERζ that stabilizes the linear nanodomain arrangement of CatSper along the sperm flagellum [PMID:41271765]. ARMH2 regulates the pH and Ca²⁺ sensitivity of CatSper channel activation, and its genetic ablation in mice causes defective CatSper activation, asthenozoospermia, and subfertility [PMID:41271765]."},"prefetch_data":{"uniprot":{"accession":"H3BNL8","full_name":"Armadillo-like helical domain-containing protein 2","aliases":[],"length_aa":230,"mass_kda":26.5,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/H3BNL8/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ARMH2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ARMH2","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"testis","ntpm":12.5}],"url":"https://www.proteinatlas.org/search/ARMH2"},"hgnc":{"alias_symbol":[],"prev_symbol":["C6orf229"]},"alphafold":{"accession":"H3BNL8","domains":[{"cath_id":"1.25.10.10","chopping":"50-226","consensus_level":"medium","plddt":94.4589,"start":50,"end":226}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/H3BNL8","model_url":"https://alphafold.ebi.ac.uk/files/AF-H3BNL8-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-H3BNL8-F1-predicted_aligned_error_v6.png","plddt_mean":89.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ARMH2","jax_strain_url":"https://www.jax.org/strain/search?query=ARMH2"},"sequence":{"accession":"H3BNL8","fasta_url":"https://rest.uniprot.org/uniprotkb/H3BNL8.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/H3BNL8/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/H3BNL8"}},"corpus_meta":[{"pmid":"35606283","id":"PMC_35606283","title":"A genome-wide association study on frequent exacerbation of asthma depending on smoking status.","date":"2022","source":"Respiratory medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35606283","citation_count":10,"is_preprint":false},{"pmid":"41271765","id":"PMC_41271765","title":"ARMH2 is a cytosolic component of CatSper crucial for sperm function.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/41271765","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":2553,"output_tokens":392,"usd":0.00677},"stage2":{"model":"claude-opus-4-6","input_tokens":3542,"output_tokens":818,"usd":0.05724},"total_usd":0.06401,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"ARMH2 is a cytosolic component of the CatSper calcium channel complex in sperm, forming a ternary subcomplex with EFCAB9 and CATSPERζ that contributes to stable assembly of linear CatSper nanodomains along the sperm tail and regulates pH and Ca2+ sensitivity of the channel.\",\n      \"method\": \"Cryo-EM structural determination, mass spectrometry, AlphaFold structure prediction, coevolutionary analysis, and loss-of-function mouse models with phenotypic readout (asthenozoospermia, subfertility, compromised CatSper activation)\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including cryo-EM structure, MS, and in vivo KO with defined molecular and physiological phenotypes in a single study\",\n      \"pmids\": [\"41271765\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ARMH2 is a cytosolic subunit of the sperm-specific CatSper Ca2+ channel that forms a ternary subcomplex with EFCAB9 and CATSPERζ, stabilizes the linear nanodomain arrangement of CatSper along the sperm tail, and regulates the channel's pH and Ca2+ sensitivity; its loss causes defective CatSper activation, asthenozoospermia, and subfertility.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ARMH2 is a cytosolic subunit of the sperm-specific CatSper Ca²⁺ channel complex, where it forms a ternary subcomplex with EFCAB9 and CATSPERζ that stabilizes the linear nanodomain arrangement of CatSper along the sperm flagellum [PMID:41271765]. ARMH2 regulates the pH and Ca²⁺ sensitivity of CatSper channel activation, and its genetic ablation in mice causes defective CatSper activation, asthenozoospermia, and subfertility [PMID:41271765].\",\n  \"teleology\": [\n    {\n      \"year\": 2025,\n      \"claim\": \"Resolving the molecular identity and structural role of ARMH2 within the CatSper complex established it as a cytosolic subunit that forms a ternary subcomplex with EFCAB9 and CATSPERζ, stabilizes CatSper nanodomain architecture, and tunes channel gating — filling the gap in understanding how accessory subunits regulate sperm Ca²⁺ signaling.\",\n      \"evidence\": \"Cryo-EM structure, mass spectrometry, AlphaFold prediction, coevolutionary analysis, and Armh2-knockout mouse phenotyping in sperm\",\n      \"pmids\": [\"41271765\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Atomic-resolution details of the ARMH2–EFCAB9–CATSPERζ interface and how conformational changes transmit pH/Ca²⁺ signals to the pore remain unresolved\",\n        \"Whether ARMH2 has any function outside sperm or the CatSper complex is unknown\",\n        \"Human genetic validation linking ARMH2 mutations to male infertility has not been reported\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The precise allosteric mechanism by which ARMH2 modulates CatSper pH and Ca²⁺ sensitivity, and whether ARMH2 loss-of-function variants contribute to human male infertility, remain open questions.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No reconstituted electrophysiology of the ARMH2-containing subcomplex to dissect gating contributions\",\n        \"No human patient cohort data linking ARMH2 variants to asthenozoospermia or infertility\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [\"CatSper channel complex\"],\n    \"partners\": [\"EFCAB9\", \"CATSPERζ\"],\n    \"other_free_text\": []\n  }\n}\n```"}