{"gene":"EFCAB5","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2025,"finding":"EFCAB5 was identified as a sperm-specific component in proximity to the radial spoke protein CFAP91 via BioID2-based proximity labeling in mature spermatozoa, establishing it as a sperm-specialized axonemal factor. Efcab5 knockout male mice exhibit reduced sperm motility and fertility, demonstrating that EFCAB5 is required for normal sperm flagellar movement.","method":"BioID2 proximity labeling in transgenic mice expressing FLAG/BioID2-tagged CFAP91 in mature spermatozoa; Efcab5 knockout mouse model with sperm motility and fertility assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype (reduced motility/fertility) plus proximity labeling; single study, single lab","pmids":["40931011"],"is_preprint":false}],"current_model":"EFCAB5 is a sperm-specific axonemal protein identified as a proximal component of the radial spoke scaffold protein CFAP91; loss of EFCAB5 in mice reduces sperm motility and male fertility, indicating a role as a sperm-specialized movement regulator of the flagellum."},"narrative":{"teleology":[{"year":2025,"claim":"The identity and functional requirement of EFCAB5 in sperm were unknown; BioID2 proximity labeling of CFAP91 in transgenic mouse spermatozoa identified EFCAB5 as a sperm-specific axonemal factor, and knockout of Efcab5 revealed that it is required for normal sperm motility and male fertility.","evidence":"BioID2 proximity labeling in CFAP91-tagged transgenic mouse spermatozoa; Efcab5 knockout mouse model with motility and fertility phenotyping","pmids":["40931011"],"confidence":"Medium","gaps":["Single study from one laboratory; independent replication is lacking","Direct physical interaction with CFAP91 or other radial spoke subunits has not been confirmed by reciprocal pull-down or structural methods","Whether EFCAB5 calcium-binding EF-hand domains are functionally required for motility regulation is untested"]},{"year":null,"claim":"It remains unknown whether EFCAB5 acts as a calcium sensor within the radial spoke complex to modulate flagellar waveform, and whether its function is conserved beyond mice.","evidence":"","pmids":[],"confidence":"Low","gaps":["No calcium-binding assays or EF-hand mutagenesis studies have been reported","No structural or cryo-EM data positioning EFCAB5 within the axoneme","Relevance to human male infertility has not been investigated"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0]}],"complexes":[],"partners":["CFAP91"],"other_free_text":[]},"mechanistic_narrative":"EFCAB5 is a sperm-specific axonemal protein that localizes in proximity to the radial spoke scaffold protein CFAP91 in mature spermatozoa [PMID:40931011]. Loss of EFCAB5 in knockout mice reduces sperm motility and male fertility, establishing it as a structural or regulatory component required for normal flagellar beating [PMID:40931011]."},"prefetch_data":{"uniprot":{"accession":"A4FU69","full_name":"EF-hand calcium-binding domain-containing protein 5","aliases":[],"length_aa":1503,"mass_kda":173.4,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/A4FU69/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/EFCAB5","classification":"Not Classified","n_dependent_lines":6,"n_total_lines":1208,"dependency_fraction":0.004966887417218543},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/EFCAB5","total_profiled":1310},"omim":[{"mim_id":"602463","title":"DIHYDROPYRIMIDINASE-LIKE 2; DPYSL2","url":"https://www.omim.org/entry/602463"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nuclear bodies","reliability":"Approved"},{"location":"Mitochondria","reliability":"Additional"}],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"testis","ntpm":8.0}],"url":"https://www.proteinatlas.org/search/EFCAB5"},"hgnc":{"alias_symbol":["FLJ46247"],"prev_symbol":[]},"alphafold":{"accession":"A4FU69","domains":[{"cath_id":"-","chopping":"168-197_208-244","consensus_level":"medium","plddt":71.4436,"start":168,"end":244},{"cath_id":"-","chopping":"772-805_851-882_885-965","consensus_level":"medium","plddt":82.8235,"start":772,"end":965},{"cath_id":"3.30.450.40","chopping":"970-1158","consensus_level":"medium","plddt":89.7979,"start":970,"end":1158},{"cath_id":"1.20.920","chopping":"1311-1358_1368-1503","consensus_level":"medium","plddt":75.4052,"start":1311,"end":1503}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/A4FU69","model_url":"https://alphafold.ebi.ac.uk/files/AF-A4FU69-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-A4FU69-F1-predicted_aligned_error_v6.png","plddt_mean":67.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=EFCAB5","jax_strain_url":"https://www.jax.org/strain/search?query=EFCAB5"},"sequence":{"accession":"A4FU69","fasta_url":"https://rest.uniprot.org/uniprotkb/A4FU69.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/A4FU69/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/A4FU69"}},"corpus_meta":[{"pmid":"28516910","id":"PMC_28516910","title":"Genetic architecture of epigenetic and neuronal ageing rates in human brain regions.","date":"2017","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/28516910","citation_count":84,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"38967597","id":"PMC_38967597","title":"Whole-exome sequencing reveals novel cancer genes and actionable targets in biliary tract cancers in primary sclerosing cholangitis.","date":"2024","source":"Hepatology communications","url":"https://pubmed.ncbi.nlm.nih.gov/38967597","citation_count":4,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35049806","id":"PMC_35049806","title":"Gene-Set Enrichment Analysis for Identifying Genes and Biological Activities Associated with Growth Traits in Dromedaries.","date":"2022","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/35049806","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40931011","id":"PMC_40931011","title":"Proximity labeling of axonemal protein CFAP91 identifies EFCAB5 that regulates sperm motility.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40931011","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39987414","id":"PMC_39987414","title":"Clinical implications and molecular mechanism of long noncoding RNA LINC00518 and protein-coding genes in skin cutaneous melanoma by genome‑wide investigation.","date":"2025","source":"Archives of dermatological research","url":"https://pubmed.ncbi.nlm.nih.gov/39987414","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA 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associated with habitual coffee consumption.","date":"2014","source":"Molecular psychiatry","url":"https://pubmed.ncbi.nlm.nih.gov/25288136","citation_count":205,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"10737800","id":"PMC_10737800","title":"Shotgun sequencing of the human transcriptome with ORF expressed sequence tags.","date":"2000","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/10737800","citation_count":135,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30021884","id":"PMC_30021884","title":"Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei.","date":"2018","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/30021884","citation_count":101,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35256949","id":"PMC_35256949","title":"Histone deacetylase inhibitors inhibit cervical cancer growth through Parkin acetylation-mediated mitophagy.","date":"2021","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/35256949","citation_count":66,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35575683","id":"PMC_35575683","title":"In-Depth In Vivo Crosslinking in Minutes by a Compact, Membrane-Permeable, and Alkynyl-Enrichable Crosslinker.","date":"2022","source":"Analytical chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35575683","citation_count":38,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"36243803","id":"PMC_36243803","title":"USP7 targets XIAP for cancer progression: Establishment of a p53-independent therapeutic avenue for glioma.","date":"2022","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/36243803","citation_count":28,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"37223481","id":"PMC_37223481","title":"SERBP1 Promotes Stress Granule Clearance by Regulating 26S Proteasome Activity and G3BP1 Ubiquitination and Protects Male Germ Cells from Thermostimuli Damage.","date":"2023","source":"Research (Washington, D.C.)","url":"https://pubmed.ncbi.nlm.nih.gov/37223481","citation_count":21,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21509594","id":"PMC_21509594","title":"Differential expression of a set of genes in follicular and classic variants of papillary thyroid carcinoma.","date":"2011","source":"Endocrine pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21509594","citation_count":19,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32129710","id":"PMC_32129710","title":"Wnt regulation: exploring Axin-Disheveled interactions and defining mechanisms by which the SCF E3 ubiquitin ligase is recruited to the destruction complex.","date":"2020","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/32129710","citation_count":19,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31615875","id":"PMC_31615875","title":"Regulation of ETAA1-mediated ATR activation couples DNA replication fidelity and genome stability.","date":"2019","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31615875","citation_count":17,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"37249651","id":"PMC_37249651","title":"TRIM21 ameliorates hepatic glucose and lipid metabolic disorders in type 2 diabetes mellitus by ubiquitination of PEPCK1 and FASN.","date":"2023","source":"Cellular and molecular life sciences : CMLS","url":"https://pubmed.ncbi.nlm.nih.gov/37249651","citation_count":17,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"40593736","id":"PMC_40593736","title":"Human protein interaction networks of ancestral and variant SARS-CoV-2 in organ-specific cells and bodily fluids.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40593736","citation_count":2,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":4075,"output_tokens":343,"usd":0.008685},"stage2":{"model":"claude-opus-4-6","input_tokens":3489,"output_tokens":692,"usd":0.052117},"total_usd":0.135448,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":11029,"output_tokens":725,"usd":0.021981},"round2_rules_fired":"R3","round2_stage2":{"model":"claude-opus-4-6","input_tokens":3747,"output_tokens":655,"usd":0.052665}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"EFCAB5 was identified as a sperm-specific component proximal to the radial spoke protein CFAP91 in mature spermatozoa via BioID2-based proximity labeling. Knockout of Efcab5 in male mice results in reduced sperm motility and fertility, establishing EFCAB5 as a sperm-specialized axonemal movement regulator.\",\n      \"method\": \"Proximity labeling (BioID2-tagged CFAP91 transgenic rescue model), immunoprecipitation, Efcab5 knockout mouse with sperm motility and fertility phenotyping\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal proximity labeling + clean KO with defined cellular and organismal phenotype in a single rigorous study\",\n      \"pmids\": [\"40931011\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EFCAB5 is a sperm-specific axonemal protein that localizes proximal to the radial spoke 3 scaffold protein CFAP91 in mature spermatozoa and is required for normal sperm motility and male fertility, as demonstrated by reduced motility and subfertility in Efcab5 knockout male mice.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\nI'll classify each paper first, then extract discoveries from KEEP papers only.\n\n**Classification:**\n\nRetrieved papers:\n1. PMID:28516910 — GWAS/eQTL association for EFCAB5 expression. No mechanistic finding. EXCLUDE (expression/eQTL association only).\n2. PMID:38967597 — Whole-exome sequencing identifying EFCAB5 as candidate cancer gene. EXCLUDE (genomic association, no mechanism).\n3. PMID:35049806 — GWAS in dromedaries, EFCAB5 listed as candidate gene. EXCLUDE (GWAS association, non-mammalian model with no mechanistic data).\n4. PMID:40931011 — Proximity labeling identifies EFCAB5 as CFAP91-proximal sperm component; Efcab5 KO shows reduced sperm motility and fertility. KEEP.\n5. PMID:39987414 — lncRNA LINC00518 study; EFCAB5 mentioned only as prognostically significant PCG. EXCLUDE (expression/prognostic correlation only).\n\nGene2pubmed papers: All 15 papers are about unrelated genes/topics (MGC cDNA sequencing, histone interactions, Wnt signaling, ATR kinase, TRIM21, SERBP1, SARS-CoV-2 PPIs, coffee GWAS, etc.). None describe EFCAB5 mechanistically. EXCLUDE all.\n\n**Only PMID:40931011 is KEEP.**\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2025,\n      \"finding\": \"EFCAB5 was identified as a sperm-specific component in proximity to the radial spoke protein CFAP91 via BioID2-based proximity labeling in mature spermatozoa, establishing it as a sperm-specialized axonemal factor. Efcab5 knockout male mice exhibit reduced sperm motility and fertility, demonstrating that EFCAB5 is required for normal sperm flagellar movement.\",\n      \"method\": \"BioID2 proximity labeling in transgenic mice expressing FLAG/BioID2-tagged CFAP91 in mature spermatozoa; Efcab5 knockout mouse model with sperm motility and fertility assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype (reduced motility/fertility) plus proximity labeling; single study, single lab\",\n      \"pmids\": [\"40931011\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"EFCAB5 is a sperm-specific axonemal protein identified as a proximal component of the radial spoke scaffold protein CFAP91; loss of EFCAB5 in mice reduces sperm motility and male fertility, indicating a role as a sperm-specialized movement regulator of the flagellum.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"EFCAB5 is a sperm-specific axonemal protein that localizes proximal to the radial spoke 3 scaffold protein CFAP91 in mature spermatozoa [PMID:40931011]. Knockout of Efcab5 in male mice causes reduced sperm motility and subfertility, establishing EFCAB5 as a specialized regulator of flagellar movement required for normal male fertility [PMID:40931011].\",\n  \"teleology\": [\n    {\n      \"year\": 2025,\n      \"claim\": \"The identity and function of EFCAB5 were unknown; proximity labeling from CFAP91 in spermatozoa revealed EFCAB5 as a sperm-specific axonemal component, and its knockout demonstrated a requirement for normal sperm motility and male fertility.\",\n      \"evidence\": \"BioID2-based proximity labeling from transgenic CFAP91 rescue model, immunoprecipitation, and Efcab5 knockout mouse with motility and fertility phenotyping\",\n      \"pmids\": [\"40931011\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct binding partner(s) of EFCAB5 within the axoneme have not been mapped beyond proximity to CFAP91\",\n        \"The calcium-binding capacity of EFCAB5's EF-hand domains and its relevance to motility regulation have not been tested\",\n        \"No structural model of EFCAB5 within the radial spoke or axonemal repeat is available\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how EFCAB5 mechanistically contributes to flagellar beat regulation — whether it acts as a calcium sensor, a structural scaffold, or a signaling adaptor within the radial spoke complex.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Biochemical activity of EFCAB5 (e.g., calcium binding, protein–protein interaction surfaces) is uncharacterized\",\n        \"Precise localization within the 96-nm axonemal repeat has not been resolved by cryo-ET or expansion microscopy\",\n        \"Whether EFCAB5 loss affects radial spoke assembly or only signaling output is undetermined\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CFAP91\"],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"EFCAB5 is a sperm-specific axonemal protein that localizes in proximity to the radial spoke scaffold protein CFAP91 in mature spermatozoa [PMID:40931011]. Loss of EFCAB5 in knockout mice reduces sperm motility and male fertility, establishing it as a structural or regulatory component required for normal flagellar beating [PMID:40931011].\",\n  \"teleology\": [\n    {\n      \"year\": 2025,\n      \"claim\": \"The identity and functional requirement of EFCAB5 in sperm were unknown; BioID2 proximity labeling of CFAP91 in transgenic mouse spermatozoa identified EFCAB5 as a sperm-specific axonemal factor, and knockout of Efcab5 revealed that it is required for normal sperm motility and male fertility.\",\n      \"evidence\": \"BioID2 proximity labeling in CFAP91-tagged transgenic mouse spermatozoa; Efcab5 knockout mouse model with motility and fertility phenotyping\",\n      \"pmids\": [\"40931011\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single study from one laboratory; independent replication is lacking\",\n        \"Direct physical interaction with CFAP91 or other radial spoke subunits has not been confirmed by reciprocal pull-down or structural methods\",\n        \"Whether EFCAB5 calcium-binding EF-hand domains are functionally required for motility regulation is untested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown whether EFCAB5 acts as a calcium sensor within the radial spoke complex to modulate flagellar waveform, and whether its function is conserved beyond mice.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No calcium-binding assays or EF-hand mutagenesis studies have been reported\",\n        \"No structural or cryo-EM data positioning EFCAB5 within the axoneme\",\n        \"Relevance to human male infertility has not been investigated\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"CFAP91\"],\n    \"other_free_text\": []\n  }\n}\n```"}