{"gene":"CFAP119","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2019,"finding":"A splice donor variant in CCDC189 (CFAP119) disrupts the canonical 5' splice site, activating a cryptic splice site that causes a frameshift and premature termination, truncating the protein by more than 40% and lacking the flagellar C1a complex subunit C1a-32, resulting in asthenospermia (loss of progressive sperm motility) in homozygous bulls.","method":"Whole genome sequencing, transcription/splicing analysis, autozygosity mapping, loss-of-function genetic analysis in cattle","journal":"BMC genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function variant with defined molecular consequence (frameshift, truncation of C1a-32 domain) and phenotypic readout, single study with two orthogonal methods (sequencing + transcription analysis)","pmids":["30975085"],"is_preprint":false},{"year":2023,"finding":"CCDC189 (CFAP119) protein localizes to the radial spoke of the first peripheral microtubule doublet in the sperm axoneme, as determined by immunoelectron microscopy.","method":"Immunoelectron microscopy on mouse sperm axoneme","journal":"National science review","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization by immunoelectron microscopy, single lab, single method","pmids":["37601242"],"is_preprint":false},{"year":2023,"finding":"CCDC189 (CFAP119) physically interacts with CABCOCO1 (ciliary-associated calcium-binding coiled-coil protein 1), identified by co-immunoprecipitation and mass spectrometry; inactivation of CCDC189 causes downregulation of CABCOCO1 protein expression.","method":"Co-immunoprecipitation, mass spectrometry, knockout mouse model with protein expression analysis","journal":"National science review","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus MS plus KO phenotype, single lab, multiple orthogonal methods","pmids":["37601242"],"is_preprint":false},{"year":2023,"finding":"Both CCDC189 (CFAP119) and CABCOCO1 interact with the radial-spoke-specific protein RSPH1 and with intraflagellar transport proteins, placing CCDC189 in a radial-spoke-associated complex involved in sperm flagellum formation.","method":"Co-immunoprecipitation, knockout mouse model","journal":"National science review","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP interactions validated in KO context, single lab, two orthogonal approaches","pmids":["37601242"],"is_preprint":false},{"year":2023,"finding":"Ccdc189 knockout in mice causes male infertility with multiple morphological abnormalities of the sperm flagella (MMAF), including coiled, curved, or short flagella, establishing CCDC189 as required for sperm flagellum formation.","method":"Knockout mouse model, histological analysis, immunofluorescence","journal":"National science review","confidence":"High","confidence_rationale":"Tier 2 / Strong — replicated KO phenotype across two independent studies (PMID 37601242 and 39018224) with defined morphological and ultrastructural readouts","pmids":["37601242","39018224"],"is_preprint":false},{"year":2024,"finding":"CCDC189 (CFAP119) is specifically expressed in spermatocytes, round spermatids, and elongating spermatids in mouse testis, and its deletion causes oligo-astheno-teratozoospermia with disordered/missing peripheral microtubule doublets, outer dense fibers, and consistent absence of central pairs in sperm flagella.","method":"Knockout mouse model, electron microscopy, immunofluorescence localization in seminiferous tubules","journal":"Biology of reproduction","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO with ultrastructural phenotype by electron microscopy, replicates findings from prior independent study, multiple readouts","pmids":["39018224"],"is_preprint":false},{"year":2024,"finding":"CCDC189 (CFAP119) interacts with poly(A)-binding proteins PABPC1 and PABPC2 in spermatogenic cells, suggesting a role in regulating mRNA translational activity; identified as interacting proteins by co-immunoprecipitation.","method":"Co-immunoprecipitation, knockout mouse model","journal":"Biology of reproduction","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP identification without functional validation of the interaction's consequence, single lab","pmids":["39018224"],"is_preprint":false},{"year":2025,"finding":"Biallelic missense variants in CFAP119 in a human patient with asthenoteratozoospermia impair protein expression and cause severely malformed sperm tails with defects in the '9+2' microtubule composition, establishing pathogenicity of CFAP119 loss-of-function in human male infertility.","method":"Whole exome sequencing, immunofluorescence, western blotting, ultrastructural electron microscopy of sperm","journal":"The world journal of men's health","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (WES, IF, WB, EM) in single lab, single patient case","pmids":["40759592"],"is_preprint":false},{"year":2025,"finding":"CFAP119 physically interacts with flagellum development-related proteins CFAP74 and CFAP221, as predicted by in silico analysis and validated by co-immunoprecipitation.","method":"Co-immunoprecipitation, in silico interaction prediction","journal":"The world journal of men's health","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP validation supported only by in silico prediction, single study, single patient context","pmids":["40759592"],"is_preprint":false}],"current_model":"CFAP119 (CCDC189) is a coiled-coil domain-containing protein expressed in spermatogenic cells that localizes to the radial spoke of the first peripheral microtubule doublet of the sperm axoneme, where it interacts with CABCOCO1, RSPH1, intraflagellar transport proteins, CFAP74, and CFAP221 to support sperm flagellum formation; loss of CFAP119 in mice and humans causes multiple morphological abnormalities of the sperm flagella (MMAF) with disrupted microtubule doublets and absent central pairs, resulting in male infertility."},"narrative":{"mechanistic_narrative":"CFAP119 (CCDC189) is a coiled-coil protein expressed specifically in spermatogenic cells—spermatocytes, round spermatids, and elongating spermatids—that is required for sperm flagellum formation [PMID:37601242, PMID:39018224]. It localizes to the radial spoke of the first peripheral microtubule doublet of the sperm axoneme [PMID:37601242], where it assembles into a radial-spoke-associated complex through physical interaction with CABCOCO1, the radial-spoke protein RSPH1, and intraflagellar transport proteins; loss of CFAP119 destabilizes CABCOCO1, indicating an interdependent assembly relationship [PMID:37601242]. Genetic loss of function produces a consistent flagellar phenotype across species: a splice variant truncating the C1a-32 domain causes asthenospermia in bulls [PMID:30975085], knockout in mice causes multiple morphological abnormalities of the sperm flagella with disordered or missing peripheral microtubule doublets and absent central pairs [PMID:37601242, PMID:39018224], and biallelic variants in a human patient cause asthenoteratozoospermia with disrupted '9+2' axonemal architecture, establishing CFAP119 loss-of-function as a cause of male infertility [PMID:40759592]. Beyond its role in radial-spoke/axoneme assembly, the corpus characterizes no enzymatic activity for CFAP119.","teleology":[{"year":2019,"claim":"Before any cellular role was defined, it was unknown whether CCDC189 loss had reproductive consequences; a natural truncating variant linked the gene to sperm motility.","evidence":"Whole genome sequencing, splicing analysis, and autozygosity mapping of asthenospermic bulls","pmids":["30975085"],"confidence":"Medium","gaps":["Did not establish subcellular localization or molecular partners","Mechanism linking C1a-32 truncation to motility loss not resolved"]},{"year":2023,"claim":"It was unknown where in the axoneme CCDC189 acts; immunoEM placed it at the radial spoke of the first peripheral doublet, defining a structural locus of action.","evidence":"Immunoelectron microscopy on mouse sperm axoneme","pmids":["37601242"],"confidence":"Medium","gaps":["Single method, single lab","Does not establish how the protein is targeted to this doublet"]},{"year":2023,"claim":"To define molecular function, the relevant question was which partners CCDC189 engages; Co-IP/MS identified CABCOCO1 and showed CCDC189 stabilizes its expression, and placed both in a complex with RSPH1 and IFT proteins.","evidence":"Co-immunoprecipitation, mass spectrometry, and protein-expression analysis in knockout mice","pmids":["37601242"],"confidence":"Medium","gaps":["Direct vs. indirect nature of RSPH1/IFT interactions not dissected","Stoichiometry and assembly order of the complex unknown"]},{"year":2023,"claim":"Whether CCDC189 is genuinely required for flagellum formation was untested in a controlled model; knockout mice established a causal requirement via an MMAF phenotype, later replicated.","evidence":"Knockout mouse model with histology and immunofluorescence, replicated across two studies","pmids":["37601242","39018224"],"confidence":"High","gaps":["Does not separate assembly defect from maintenance defect"]},{"year":2024,"claim":"The cellular expression window and ultrastructural consequence were undefined; KO ultrastructural analysis showed stage-specific expression and consistent loss of central pairs and disordered doublets.","evidence":"Knockout mouse model with electron microscopy and seminiferous-tubule immunofluorescence","pmids":["39018224"],"confidence":"High","gaps":["Mechanism by which radial-spoke loss leads to central-pair absence unresolved"]},{"year":2024,"claim":"A possible non-structural role was raised by identification of poly(A)-binding protein interactions, hinting at translational regulation in spermatogenic cells.","evidence":"Co-immunoprecipitation in knockout mouse context","pmids":["39018224"],"confidence":"Low","gaps":["Single Co-IP without functional validation of consequence","No demonstrated effect on translation of any transcript"]},{"year":2025,"claim":"Human relevance was unconfirmed; biallelic missense variants in a patient impaired protein expression and disrupted the 9+2 axoneme, establishing pathogenicity in human infertility.","evidence":"Whole exome sequencing, immunofluorescence, western blotting, and electron microscopy of patient sperm","pmids":["40759592"],"confidence":"Medium","gaps":["Single patient case","No rescue experiment"]},{"year":2025,"claim":"The partner network was extended to additional flagellar proteins CFAP74 and CFAP221 by Co-IP.","evidence":"Co-immunoprecipitation validated against in silico interaction prediction","pmids":["40759592"],"confidence":"Low","gaps":["Single Co-IP supported only by in silico prediction","Direct vs. indirect interaction not established"]},{"year":null,"claim":"It remains unknown what biochemical activity CFAP119 contributes within the radial spoke and how its loss mechanistically causes central-pair absence and doublet disorganization.","evidence":"","pmids":[],"confidence":"Low","gaps":["No defined enzymatic or biophysical activity","No structural model of the CFAP119-containing complex","Mechanism coupling radial-spoke defect to central-pair loss unresolved"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[1,4,5]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,5]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[4,5,7]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[4,5]}],"complexes":["radial spoke"],"partners":["CABCOCO1","RSPH1","CFAP74","CFAP221","PABPC1","PABPC2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"A1A4V9","full_name":"Cilia- and flagella-associated protein 119","aliases":["Coiled-coil domain-containing protein 189"],"length_aa":331,"mass_kda":37.9,"function":"","subcellular_location":"Cell projection, cilium, flagellum; Cytoplasmic vesicle, secretory vesicle, acrosome; Cytoplasm","url":"https://www.uniprot.org/uniprotkb/A1A4V9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CFAP119","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CFAP119","total_profiled":1310},"omim":[{"mim_id":"618318","title":"CILIA- AND FLAGELLA-ASSOCIATED PROTEIN 119; CFAP119","url":"https://www.omim.org/entry/618318"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Mid piece","reliability":"Approved"},{"location":"Principal piece","reliability":"Approved"},{"location":"End piece","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"choroid plexus","ntpm":36.5},{"tissue":"testis","ntpm":22.1}],"url":"https://www.proteinatlas.org/search/CFAP119"},"hgnc":{"alias_symbol":["MGC104706"],"prev_symbol":["C16orf93","CCDC189"]},"alphafold":{"accession":"A1A4V9","domains":[{"cath_id":"-","chopping":"85-217","consensus_level":"medium","plddt":93.5489,"start":85,"end":217}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/A1A4V9","model_url":"https://alphafold.ebi.ac.uk/files/AF-A1A4V9-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-A1A4V9-F1-predicted_aligned_error_v6.png","plddt_mean":73.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CFAP119","jax_strain_url":"https://www.jax.org/strain/search?query=CFAP119"},"sequence":{"accession":"A1A4V9","fasta_url":"https://rest.uniprot.org/uniprotkb/A1A4V9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/A1A4V9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/A1A4V9"}},"corpus_meta":[{"pmid":"30975085","id":"PMC_30975085","title":"A splice donor variant in CCDC189 is associated with asthenospermia in Nordic Red dairy cattle.","date":"2019","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/30975085","citation_count":25,"is_preprint":false},{"pmid":"36177513","id":"PMC_36177513","title":"Mendelian Randomization Study Using Dopaminergic Neuron-Specific eQTL Nominates Potential Causal Genes for Parkinson's Disease.","date":"2022","source":"Movement disorders : official journal of the Movement Disorder Society","url":"https://pubmed.ncbi.nlm.nih.gov/36177513","citation_count":17,"is_preprint":false},{"pmid":"37601242","id":"PMC_37601242","title":"CCDC189 affects sperm flagellum formation by interacting with CABCOCO1.","date":"2023","source":"National science review","url":"https://pubmed.ncbi.nlm.nih.gov/37601242","citation_count":15,"is_preprint":false},{"pmid":"39018224","id":"PMC_39018224","title":"CCDC189 depletion leads to oligo-astheno-teratozoospermia and male infertility in mice†.","date":"2024","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/39018224","citation_count":5,"is_preprint":false},{"pmid":"39821281","id":"PMC_39821281","title":"Gene pseudogenization in fertility-associated genes in cheetah (Acinonyx jubatus), a species with long-term low effective population size.","date":"2025","source":"Evolution; international journal of organic evolution","url":"https://pubmed.ncbi.nlm.nih.gov/39821281","citation_count":2,"is_preprint":false},{"pmid":"37248840","id":"PMC_37248840","title":"[Preparation and identification of rabbit anti-mouse coiled-coil domain containing 189(Ccdc189)polyclonal antibody].","date":"2023","source":"Xi bao yu fen zi mian yi xue za zhi = Chinese journal of cellular and molecular immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37248840","citation_count":1,"is_preprint":false},{"pmid":"40759592","id":"PMC_40759592","title":"Identification of a Novel Biallelic CFAP119 Variant in an Infertile Man with Asthenoteratozoospermia.","date":"2025","source":"The world journal of men's health","url":"https://pubmed.ncbi.nlm.nih.gov/40759592","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":5549,"output_tokens":1958,"usd":0.023009,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8846,"output_tokens":2442,"usd":0.05264,"stage2_stop_reason":"end_turn"},"total_usd":0.075649,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2019,\n      \"finding\": \"A splice donor variant in CCDC189 (CFAP119) disrupts the canonical 5' splice site, activating a cryptic splice site that causes a frameshift and premature termination, truncating the protein by more than 40% and lacking the flagellar C1a complex subunit C1a-32, resulting in asthenospermia (loss of progressive sperm motility) in homozygous bulls.\",\n      \"method\": \"Whole genome sequencing, transcription/splicing analysis, autozygosity mapping, loss-of-function genetic analysis in cattle\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function variant with defined molecular consequence (frameshift, truncation of C1a-32 domain) and phenotypic readout, single study with two orthogonal methods (sequencing + transcription analysis)\",\n      \"pmids\": [\"30975085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CCDC189 (CFAP119) protein localizes to the radial spoke of the first peripheral microtubule doublet in the sperm axoneme, as determined by immunoelectron microscopy.\",\n      \"method\": \"Immunoelectron microscopy on mouse sperm axoneme\",\n      \"journal\": \"National science review\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization by immunoelectron microscopy, single lab, single method\",\n      \"pmids\": [\"37601242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CCDC189 (CFAP119) physically interacts with CABCOCO1 (ciliary-associated calcium-binding coiled-coil protein 1), identified by co-immunoprecipitation and mass spectrometry; inactivation of CCDC189 causes downregulation of CABCOCO1 protein expression.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, knockout mouse model with protein expression analysis\",\n      \"journal\": \"National science review\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus MS plus KO phenotype, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"37601242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Both CCDC189 (CFAP119) and CABCOCO1 interact with the radial-spoke-specific protein RSPH1 and with intraflagellar transport proteins, placing CCDC189 in a radial-spoke-associated complex involved in sperm flagellum formation.\",\n      \"method\": \"Co-immunoprecipitation, knockout mouse model\",\n      \"journal\": \"National science review\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP interactions validated in KO context, single lab, two orthogonal approaches\",\n      \"pmids\": [\"37601242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Ccdc189 knockout in mice causes male infertility with multiple morphological abnormalities of the sperm flagella (MMAF), including coiled, curved, or short flagella, establishing CCDC189 as required for sperm flagellum formation.\",\n      \"method\": \"Knockout mouse model, histological analysis, immunofluorescence\",\n      \"journal\": \"National science review\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — replicated KO phenotype across two independent studies (PMID 37601242 and 39018224) with defined morphological and ultrastructural readouts\",\n      \"pmids\": [\"37601242\", \"39018224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCDC189 (CFAP119) is specifically expressed in spermatocytes, round spermatids, and elongating spermatids in mouse testis, and its deletion causes oligo-astheno-teratozoospermia with disordered/missing peripheral microtubule doublets, outer dense fibers, and consistent absence of central pairs in sperm flagella.\",\n      \"method\": \"Knockout mouse model, electron microscopy, immunofluorescence localization in seminiferous tubules\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO with ultrastructural phenotype by electron microscopy, replicates findings from prior independent study, multiple readouts\",\n      \"pmids\": [\"39018224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CCDC189 (CFAP119) interacts with poly(A)-binding proteins PABPC1 and PABPC2 in spermatogenic cells, suggesting a role in regulating mRNA translational activity; identified as interacting proteins by co-immunoprecipitation.\",\n      \"method\": \"Co-immunoprecipitation, knockout mouse model\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP identification without functional validation of the interaction's consequence, single lab\",\n      \"pmids\": [\"39018224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Biallelic missense variants in CFAP119 in a human patient with asthenoteratozoospermia impair protein expression and cause severely malformed sperm tails with defects in the '9+2' microtubule composition, establishing pathogenicity of CFAP119 loss-of-function in human male infertility.\",\n      \"method\": \"Whole exome sequencing, immunofluorescence, western blotting, ultrastructural electron microscopy of sperm\",\n      \"journal\": \"The world journal of men's health\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (WES, IF, WB, EM) in single lab, single patient case\",\n      \"pmids\": [\"40759592\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CFAP119 physically interacts with flagellum development-related proteins CFAP74 and CFAP221, as predicted by in silico analysis and validated by co-immunoprecipitation.\",\n      \"method\": \"Co-immunoprecipitation, in silico interaction prediction\",\n      \"journal\": \"The world journal of men's health\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP validation supported only by in silico prediction, single study, single patient context\",\n      \"pmids\": [\"40759592\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CFAP119 (CCDC189) is a coiled-coil domain-containing protein expressed in spermatogenic cells that localizes to the radial spoke of the first peripheral microtubule doublet of the sperm axoneme, where it interacts with CABCOCO1, RSPH1, intraflagellar transport proteins, CFAP74, and CFAP221 to support sperm flagellum formation; loss of CFAP119 in mice and humans causes multiple morphological abnormalities of the sperm flagella (MMAF) with disrupted microtubule doublets and absent central pairs, resulting in male infertility.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CFAP119 (CCDC189) is a coiled-coil protein expressed specifically in spermatogenic cells—spermatocytes, round spermatids, and elongating spermatids—that is required for sperm flagellum formation [#4, #5]. It localizes to the radial spoke of the first peripheral microtubule doublet of the sperm axoneme [#1], where it assembles into a radial-spoke-associated complex through physical interaction with CABCOCO1, the radial-spoke protein RSPH1, and intraflagellar transport proteins; loss of CFAP119 destabilizes CABCOCO1, indicating an interdependent assembly relationship [#2, #3]. Genetic loss of function produces a consistent flagellar phenotype across species: a splice variant truncating the C1a-32 domain causes asthenospermia in bulls [#0], knockout in mice causes multiple morphological abnormalities of the sperm flagella with disordered or missing peripheral microtubule doublets and absent central pairs [#4, #5], and biallelic variants in a human patient cause asthenoteratozoospermia with disrupted '9+2' axonemal architecture, establishing CFAP119 loss-of-function as a cause of male infertility [#7]. Beyond its role in radial-spoke/axoneme assembly, the corpus characterizes no enzymatic activity for CFAP119.\",\n  \"teleology\": [\n    {\n      \"year\": 2019,\n      \"claim\": \"Before any cellular role was defined, it was unknown whether CCDC189 loss had reproductive consequences; a natural truncating variant linked the gene to sperm motility.\",\n      \"evidence\": \"Whole genome sequencing, splicing analysis, and autozygosity mapping of asthenospermic bulls\",\n      \"pmids\": [\"30975085\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Did not establish subcellular localization or molecular partners\", \"Mechanism linking C1a-32 truncation to motility loss not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"It was unknown where in the axoneme CCDC189 acts; immunoEM placed it at the radial spoke of the first peripheral doublet, defining a structural locus of action.\",\n      \"evidence\": \"Immunoelectron microscopy on mouse sperm axoneme\",\n      \"pmids\": [\"37601242\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single method, single lab\", \"Does not establish how the protein is targeted to this doublet\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"To define molecular function, the relevant question was which partners CCDC189 engages; Co-IP/MS identified CABCOCO1 and showed CCDC189 stabilizes its expression, and placed both in a complex with RSPH1 and IFT proteins.\",\n      \"evidence\": \"Co-immunoprecipitation, mass spectrometry, and protein-expression analysis in knockout mice\",\n      \"pmids\": [\"37601242\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect nature of RSPH1/IFT interactions not dissected\", \"Stoichiometry and assembly order of the complex unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Whether CCDC189 is genuinely required for flagellum formation was untested in a controlled model; knockout mice established a causal requirement via an MMAF phenotype, later replicated.\",\n      \"evidence\": \"Knockout mouse model with histology and immunofluorescence, replicated across two studies\",\n      \"pmids\": [\"37601242\", \"39018224\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not separate assembly defect from maintenance defect\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"The cellular expression window and ultrastructural consequence were undefined; KO ultrastructural analysis showed stage-specific expression and consistent loss of central pairs and disordered doublets.\",\n      \"evidence\": \"Knockout mouse model with electron microscopy and seminiferous-tubule immunofluorescence\",\n      \"pmids\": [\"39018224\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which radial-spoke loss leads to central-pair absence unresolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"A possible non-structural role was raised by identification of poly(A)-binding protein interactions, hinting at translational regulation in spermatogenic cells.\",\n      \"evidence\": \"Co-immunoprecipitation in knockout mouse context\",\n      \"pmids\": [\"39018224\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP without functional validation of consequence\", \"No demonstrated effect on translation of any transcript\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Human relevance was unconfirmed; biallelic missense variants in a patient impaired protein expression and disrupted the 9+2 axoneme, establishing pathogenicity in human infertility.\",\n      \"evidence\": \"Whole exome sequencing, immunofluorescence, western blotting, and electron microscopy of patient sperm\",\n      \"pmids\": [\"40759592\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single patient case\", \"No rescue experiment\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The partner network was extended to additional flagellar proteins CFAP74 and CFAP221 by Co-IP.\",\n      \"evidence\": \"Co-immunoprecipitation validated against in silico interaction prediction\",\n      \"pmids\": [\"40759592\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Single Co-IP supported only by in silico prediction\", \"Direct vs. indirect interaction not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown what biochemical activity CFAP119 contributes within the radial spoke and how its loss mechanistically causes central-pair absence and doublet disorganization.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No defined enzymatic or biophysical activity\", \"No structural model of the CFAP119-containing complex\", \"Mechanism coupling radial-spoke defect to central-pair loss unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [1, 4, 5]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [4, 5, 7]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [4, 5]}\n    ],\n    \"complexes\": [\"radial spoke\"],\n    \"partners\": [\"CABCOCO1\", \"RSPH1\", \"CFAP74\", \"CFAP221\", \"PABPC1\", \"PABPC2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":3,"faith_total":3,"faith_pct":100.0}}