{"gene":"ARMH2","run_date":"2026-06-09T22:02:44","timeline":{"discoveries":[{"year":2025,"finding":"ARMH2 is a cytosolic component of the CatSper sperm calcium channel complex, forming a ternary subcomplex with EFCAB9 and CATSPERζ that contributes to stable linear arrangement of CatSper nanodomains along the sperm tail and regulates pH and Ca2+ sensitivity of the channel. Loss of ARMH2 compromises physiological CatSper activation, leading to asthenozoospermia and severe subfertility.","method":"Cryo-EM structural determination, mass spectrometry, AlphaFold structure prediction, coevolutionary analysis, and loss-of-function mouse model with sperm motility and fertility phenotypic readout","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (cryo-EM, MS, structural prediction, loss-of-function in vivo) in a single rigorous study establishing complex membership, subcomplex composition, and functional consequence","pmids":["41271765"],"is_preprint":false}],"current_model":"ARMH2 is a cytosolic auxiliary subunit of the CatSper sperm calcium channel that forms a ternary subcomplex with EFCAB9 and CATSPERζ, stabilizes the linear nanodomain architecture along the sperm tail, and regulates the pH and Ca2+ sensitivity of CatSper; its loss impairs channel activation, causing asthenozoospermia and subfertility."},"narrative":{"mechanistic_narrative":"ARMH2 is a cytosolic auxiliary component of the CatSper sperm calcium channel complex, where it assembles into a ternary subcomplex with EFCAB9 and CATSPERζ that supports the stable linear arrangement of CatSper nanodomains along the sperm tail and tunes the pH and Ca2+ sensitivity of the channel [PMID:41271765]. Loss of ARMH2 compromises physiological CatSper activation, producing asthenozoospermia and severe subfertility [PMID:41271765]. Beyond this single integrated study, no further mechanistic detail for ARMH2 has been characterized in the available corpus.","teleology":[{"year":2025,"claim":"Whether ARMH2 has any defined molecular role was unknown; this work established it as a bona fide cytosolic subunit of the CatSper channel that forms a ternary subcomplex with EFCAB9 and CATSPERζ and is required for proper channel activation and male fertility.","evidence":"Cryo-EM, mass spectrometry, AlphaFold prediction and coevolutionary analysis defining complex membership, combined with a loss-of-function mouse model scored for sperm motility and fertility","pmids":["41271765"],"confidence":"High","gaps":["The atomic mechanism by which ARMH2 sets pH and Ca2+ sensitivity of CatSper is not resolved","Direct binding interfaces within the EFCAB9–CATSPERζ–ARMH2 subcomplex are not biochemically dissected","Whether ARMH2 has any function outside sperm or the CatSper complex is unaddressed"]},{"year":null,"claim":"How ARMH2 is recruited and assembled into the CatSper nanodomain architecture, and the structural basis for its regulation of channel gating, remain open.","evidence":"Not addressed in the available corpus","pmids":[],"confidence":"High","gaps":["No reconstitution defining the minimal ARMH2-containing subcomplex","No structure of ARMH2 engaged with the gating apparatus","Human relevance of the mouse fertility phenotype not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]}],"localization":[{"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","CATSPERZ"],"other_free_text":[]}},"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":2,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":3312,"output_tokens":413,"usd":0.008065,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6681,"output_tokens":1005,"usd":0.029265,"stage2_stop_reason":"end_turn"},"total_usd":0.03733,"stage1_batch_id":"msgbatch_0179Z2pxRYBsXi2xADneafRw","stage2_batch_id":"msgbatch_01LaY9ZaVdgjWArcZo9eqQE5","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 sperm calcium channel complex, forming a ternary subcomplex with EFCAB9 and CATSPERζ that contributes to stable linear arrangement of CatSper nanodomains along the sperm tail and regulates pH and Ca2+ sensitivity of the channel. Loss of ARMH2 compromises physiological CatSper activation, leading to asthenozoospermia and severe subfertility.\",\n      \"method\": \"Cryo-EM structural determination, mass spectrometry, AlphaFold structure prediction, coevolutionary analysis, and loss-of-function mouse model with sperm motility and fertility phenotypic readout\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (cryo-EM, MS, structural prediction, loss-of-function in vivo) in a single rigorous study establishing complex membership, subcomplex composition, and functional consequence\",\n      \"pmids\": [\"41271765\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ARMH2 is a cytosolic auxiliary subunit of the CatSper sperm calcium channel that forms a ternary subcomplex with EFCAB9 and CATSPERζ, stabilizes the linear nanodomain architecture along the sperm tail, and regulates the pH and Ca2+ sensitivity of CatSper; its loss impairs channel activation, causing asthenozoospermia and subfertility.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ARMH2 is a cytosolic auxiliary component of the CatSper sperm calcium channel complex, where it assembles into a ternary subcomplex with EFCAB9 and CATSPERζ that supports the stable linear arrangement of CatSper nanodomains along the sperm tail and tunes the pH and Ca2+ sensitivity of the channel [#0]. Loss of ARMH2 compromises physiological CatSper activation, producing asthenozoospermia and severe subfertility [#0]. Beyond this single integrated study, no further mechanistic detail for ARMH2 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2025,\n      \"claim\": \"Whether ARMH2 has any defined molecular role was unknown; this work established it as a bona fide cytosolic subunit of the CatSper channel that forms a ternary subcomplex with EFCAB9 and CATSPERζ and is required for proper channel activation and male fertility.\",\n      \"evidence\": \"Cryo-EM, mass spectrometry, AlphaFold prediction and coevolutionary analysis defining complex membership, combined with a loss-of-function mouse model scored for sperm motility and fertility\",\n      \"pmids\": [\"41271765\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The atomic mechanism by which ARMH2 sets pH and Ca2+ sensitivity of CatSper is not resolved\",\n        \"Direct binding interfaces within the EFCAB9–CATSPERζ–ARMH2 subcomplex are not biochemically dissected\",\n        \"Whether ARMH2 has any function outside sperm or the CatSper complex is unaddressed\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ARMH2 is recruited and assembled into the CatSper nanodomain architecture, and the structural basis for its regulation of channel gating, remain open.\",\n      \"evidence\": \"Not addressed in the available corpus\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No reconstitution defining the minimal ARMH2-containing subcomplex\",\n        \"No structure of ARMH2 engaged with the gating apparatus\",\n        \"Human relevance of the mouse fertility phenotype not established\"\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: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\", \"CATSPERZ\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":2,"faith_total":2,"faith_pct":100.0}}