{"gene":"CFAP58","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2020,"finding":"Bi-allelic loss-of-function variants in CFAP58 cause axonemal and mitochondrial sheath malformations in human sperm flagella. CFAP58 localizes to the entire flagellum of control sperm, concentrated in the mid-piece. Loss of CFAP58 reduces abundance of axoneme ultrastructure markers SPAG6 and SPEF2 and mitochondrial sheath protein HSP60. Cfap58-knockout mice generated by CRISPR/Cas9 are male-infertile with severe flagellar defects, establishing CFAP58 as essential for sperm flagellogenesis.","method":"Whole-exome sequencing, immunofluorescence, immunoblotting, transmission electron microscopy, CRISPR/Cas9 knockout mice","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal human genetic + KO mouse model with TEM ultrastructural phenotype, IF localization, and protein-level readouts; replicated across multiple patients and in mouse model","pmids":["32791035"],"is_preprint":false},{"year":2020,"finding":"CFAP58 is identified as a testis-enriched protein that co-localizes with Odf2/Cenexin at the sperm midpiece and primary cilia. Cfap58 knockdown in astrocytes impairs primary cilium elongation and sperm midpiece formation via modulation of the Notch signaling pathway. Cfap58 was identified as an interactor of Odf2/Cenexin by mass spectrometry interactome analysis.","method":"Mass spectrometry interactome analysis, siRNA knockdown, immunofluorescence, drug administration studies (Notch pathway modulation)","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — pulldown/MS identification plus knockdown with pathway modulation, single lab, moderate orthogonal methods but Notch pathway link relies on pharmacological evidence","pmids":["31904090"],"is_preprint":false},{"year":2024,"finding":"CFAP58 (FAP58/CCDC147) forms a heterodimer with MBO2/CCDC146 that is part of a conserved L-shaped structure in the Chlamydomonas axoneme, varying between doublet microtubules. This structure interconnects inner dynein arms with multiple regulatory complexes and is required for normal ciliary waveform. Loss of FAP58 disrupts inner arm dynein b assembly. Comparative proteomics revealed overlapping protein defects with other motility mutants.","method":"Cryo-electron tomography, comparative proteomics, epitope tagging, Chlamydomonas mbo mutant analysis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Moderate — cryo-ET structural determination combined with proteomics and genetic mutant analysis in Chlamydomonas ortholog; multiple orthogonal methods in single study","pmids":["38568782"],"is_preprint":false},{"year":2024,"finding":"CFAP58 loss in mice causes not only sperm tail defects but also disrupts the manchette structure, leading to abnormal sperm head shaping and increased spermatozoa apoptosis. CFAP58 physically interacts with IFT88 and CCDC42, and may act as a cargo protein stabilizing CCDC42 in the intra-manchette transport/intra-flagellar transport (IMT/IFT) pathway.","method":"Gene knockout mice, co-immunoprecipitation (CFAP58-IFT88 and CFAP58-CCDC42 interaction), immunofluorescence, TEM","journal":"Development (Cambridge, England)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mouse with defined manchette/head phenotype plus co-IP identification of IFT88 and CCDC42 as binding partners; single lab, multiple orthogonal methods","pmids":["38602507"],"is_preprint":false},{"year":2025,"finding":"A homozygous nonsense mutation in CFAP58 (c.562C>T, p.R188*) disrupts central pair (CP) microtubule assembly in the sperm flagellar axoneme. Cfap58 mutant mice mimicking the patient mutation recapitulate the MMAF phenotype, and TEM shows absence of the central pair of microtubules, demonstrating CFAP58 is required for CP assembly during spermiogenesis.","method":"Whole-exome sequencing (human patients), Cfap58 knock-in mutant mouse model, transmission electron microscopy, immunofluorescence","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mutant mouse model with TEM ultrastructural readout showing CP loss; single lab, mechanistic detail beyond prior reports but not yet replicated","pmids":["40675161"],"is_preprint":false}],"current_model":"CFAP58 is a testis-enriched cilia- and flagella-associated protein that localizes to the sperm flagellum (concentrated in the mid-piece) and forms a heterodimer with MBO2/CCDC146 to create an L-shaped axonemal structure interconnecting inner dynein arms with regulatory complexes; loss of CFAP58 disrupts central pair microtubule assembly, reduces axonemal (SPAG6, SPEF2) and mitochondrial sheath (HSP60) proteins, impairs manchette-dependent sperm head shaping via interaction with IFT88 and CCDC42 in the IFT/IMT pathway, and modulates Notch signaling during ciliogenesis — collectively establishing CFAP58 as essential for sperm flagellar axoneme assembly, midpiece integrity, and normal ciliary waveform."},"narrative":{"mechanistic_narrative":"CFAP58 is a testis-enriched cilia- and flagella-associated protein essential for sperm flagellar axoneme assembly and midpiece integrity, with bi-allelic loss-of-function variants causing multiple morphological abnormalities of the sperm flagella (MMAF) and male infertility in humans and recapitulated in knockout and knock-in mice [PMID:32791035, PMID:40675161]. The protein localizes throughout the sperm flagellum, concentrating at the mid-piece, and its loss reduces axonemal markers (SPAG6, SPEF2) and the mitochondrial sheath protein HSP60 while disrupting central pair microtubule assembly [PMID:32791035, PMID:40675161]. Structurally, CFAP58 forms a heterodimer with CCDC146/MBO2 within a conserved L-shaped axonemal element that interconnects inner dynein arms with regulatory complexes and is required for normal ciliary waveform [PMID:38568782]. Beyond the axoneme, CFAP58 acts in the intra-manchette/intra-flagellar transport pathway through physical interactions with IFT88 and CCDC42, stabilizing CCDC42 to support manchette-dependent sperm head shaping [PMID:38602507]. CFAP58 co-localizes with ODF2/Cenexin and modulates Notch signaling during primary cilium elongation, extending its role to ciliogenesis beyond the male germline [PMID:31904090].","teleology":[{"year":2020,"claim":"Establishing whether CFAP58 has an essential in vivo function addressed the unknown of its requirement for sperm formation, demonstrating it is causally linked to human male infertility via flagellar and mitochondrial sheath defects.","evidence":"Whole-exome sequencing of patients plus CRISPR/Cas9 knockout mice with TEM, IF, and immunoblotting","pmids":["32791035"],"confidence":"High","gaps":["Did not resolve the molecular structure CFAP58 builds within the axoneme","Direct binding partners not yet defined"]},{"year":2020,"claim":"Identifying CFAP58 as an ODF2/Cenexin interactor and a Notch-pathway modulator addressed where it acts beyond the flagellum, linking it to primary cilium elongation and ciliogenesis.","evidence":"Mass spectrometry interactome, siRNA knockdown in astrocytes with Notch pharmacological modulation and IF","pmids":["31904090"],"confidence":"Medium","gaps":["Notch link rests on pharmacological evidence only","Direct ODF2 binding interface not mapped","Single-lab, knockdown-based"]},{"year":2024,"claim":"Cryo-ET of the Chlamydomonas ortholog answered the structural question of how CFAP58 is organized in the axoneme, showing it heterodimerizes with CCDC146/MBO2 in an L-shaped element coupling inner dynein arms to regulatory complexes.","evidence":"Cryo-electron tomography, comparative proteomics, epitope tagging, and mbo mutant analysis in Chlamydomonas","pmids":["38568782"],"confidence":"High","gaps":["Conservation of the L-shaped structure in mammalian sperm not directly demonstrated","Mechanism of waveform regulation not resolved"]},{"year":2024,"claim":"Defining CFAP58 interactions with IFT88 and CCDC42 addressed how its loss affects sperm head morphology, implicating it in the intra-manchette/intra-flagellar transport pathway as a stabilizer of CCDC42.","evidence":"Knockout mice with co-immunoprecipitation, IF, and TEM","pmids":["38602507"],"confidence":"Medium","gaps":["Cargo role for CCDC42 inferred, not directly demonstrated","Co-IP without reciprocal/structural validation of interaction interfaces"]},{"year":2025,"claim":"A knock-in mouse modeling a patient nonsense mutation answered which axonemal substructure depends on CFAP58, showing it is required for central pair microtubule assembly during spermiogenesis.","evidence":"Whole-exome sequencing of patients and Cfap58 knock-in mutant mice with TEM and IF","pmids":["40675161"],"confidence":"Medium","gaps":["Mechanistic link between CFAP58 and central pair nucleation unresolved","Not yet independently replicated"]},{"year":null,"claim":"How CFAP58's axonemal structural role, IFT/IMT transport function, and Notch modulation are mechanistically integrated remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of the mammalian CFAP58 complex","Direct binding interfaces with IFT88/CCDC42/CCDC146 not mapped","Mechanism connecting CFAP58 to central pair assembly unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,4]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2,4]}],"pathway":[{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,4]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[2]}],"complexes":["CFAP58-CCDC146/MBO2 heterodimer","axonemal L-shaped structure"],"partners":["CCDC146","IFT88","CCDC42","ODF2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q5T655","full_name":"Cilia- and flagella-associated protein 58","aliases":["Coiled-coil domain-containing protein 147"],"length_aa":872,"mass_kda":103.4,"function":"Has an essential role in the assembly and organization of the sperm flagellar axoneme (PubMed:32791035). Required for the elongation of the primary cilium and sperm flagellar midpiece via modulation of the Notch signaling pathway (By similarity)","subcellular_location":"Cell projection, cilium; Cell projection, cilium, flagellum; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q5T655/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CFAP58","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CFAP58","total_profiled":1310},"omim":[{"mim_id":"619144","title":"SPERMATOGENIC FAILURE 49; SPGF49","url":"https://www.omim.org/entry/619144"},{"mim_id":"619129","title":"CILIA- AND FLAGELLA-ASSOCIATED PROTEIN 58; CFAP58","url":"https://www.omim.org/entry/619129"},{"mim_id":"258150","title":"SPERMATOGENIC FAILURE 1; SPGF1","url":"https://www.omim.org/entry/258150"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Principal piece","reliability":"Supported"},{"location":"Calyx","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"fallopian tube","ntpm":7.9},{"tissue":"testis","ntpm":12.8}],"url":"https://www.proteinatlas.org/search/CFAP58"},"hgnc":{"alias_symbol":["FLJ35908","bA554P13.1"],"prev_symbol":["C10orf80","CCDC147"]},"alphafold":{"accession":"Q5T655","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T655","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T655-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q5T655-F1-predicted_aligned_error_v6.png","plddt_mean":79.56},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CFAP58","jax_strain_url":"https://www.jax.org/strain/search?query=CFAP58"},"sequence":{"accession":"Q5T655","fasta_url":"https://rest.uniprot.org/uniprotkb/Q5T655.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q5T655/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q5T655"}},"corpus_meta":[{"pmid":"32791035","id":"PMC_32791035","title":"Bi-allelic Loss-of-function Variants in CFAP58 Cause Flagellar Axoneme and Mitochondrial Sheath Defects and Asthenoteratozoospermia in Humans and Mice.","date":"2020","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32791035","citation_count":90,"is_preprint":false},{"pmid":"34089056","id":"PMC_34089056","title":"Exome sequencing reveals variants in known and novel candidate genes for severe sperm motility disorders.","date":"2021","source":"Human reproduction (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/34089056","citation_count":51,"is_preprint":false},{"pmid":"34173924","id":"PMC_34173924","title":"Immunogenomic profiling and pathological response results from a clinical trial of docetaxel and carboplatin in triple-negative breast cancer.","date":"2021","source":"Breast cancer research and treatment","url":"https://pubmed.ncbi.nlm.nih.gov/34173924","citation_count":32,"is_preprint":false},{"pmid":"26762739","id":"PMC_26762739","title":"Focused Analysis of Exome Sequencing Data for Rare Germline Mutations in Familial and Sporadic Lung Cancer.","date":"2016","source":"Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/26762739","citation_count":27,"is_preprint":false},{"pmid":"33314088","id":"PMC_33314088","title":"Biallelic mutations of CFAP58 are associated with multiple morphological abnormalities of the sperm flagella.","date":"2020","source":"Clinical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33314088","citation_count":21,"is_preprint":false},{"pmid":"33955803","id":"PMC_33955803","title":"Prediction of bladder cancer outcome by identifying and validating a mutation-derived genomic instability-associated long noncoding RNA (lncRNA) signature.","date":"2021","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/33955803","citation_count":21,"is_preprint":false},{"pmid":"31904090","id":"PMC_31904090","title":"The novel testicular enrichment protein Cfap58 is required for Notch-associated ciliogenesis.","date":"2020","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/31904090","citation_count":12,"is_preprint":false},{"pmid":"38602507","id":"PMC_38602507","title":"CFAP58 is involved in the sperm head shaping and flagellogenesis of cattle and mice.","date":"2024","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/38602507","citation_count":8,"is_preprint":false},{"pmid":"38568782","id":"PMC_38568782","title":"The MBO2/FAP58 heterodimer stabilizes assembly of inner arm dynein b and reveals axoneme asymmetries involved in ciliary waveform.","date":"2024","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/38568782","citation_count":6,"is_preprint":false},{"pmid":"40317966","id":"PMC_40317966","title":"Clinicopathological and molecular characterization of KRAS wild-type pancreatic ductal adenocarcinomas reveals precursor lesions with oncogenic mutations and fusions in RAS pathway genes.","date":"2025","source":"The Journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/40317966","citation_count":3,"is_preprint":false},{"pmid":"40675161","id":"PMC_40675161","title":"A novel mutation in CFAP58 leads to MMAF in humans and mice by disrupting CP assembly.","date":"2025","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40675161","citation_count":1,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8643,"output_tokens":1602,"usd":0.02498,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":8383,"output_tokens":2185,"usd":0.04827,"stage2_stop_reason":"end_turn"},"total_usd":0.07325,"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\": 2020,\n      \"finding\": \"Bi-allelic loss-of-function variants in CFAP58 cause axonemal and mitochondrial sheath malformations in human sperm flagella. CFAP58 localizes to the entire flagellum of control sperm, concentrated in the mid-piece. Loss of CFAP58 reduces abundance of axoneme ultrastructure markers SPAG6 and SPEF2 and mitochondrial sheath protein HSP60. Cfap58-knockout mice generated by CRISPR/Cas9 are male-infertile with severe flagellar defects, establishing CFAP58 as essential for sperm flagellogenesis.\",\n      \"method\": \"Whole-exome sequencing, immunofluorescence, immunoblotting, transmission electron microscopy, CRISPR/Cas9 knockout mice\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal human genetic + KO mouse model with TEM ultrastructural phenotype, IF localization, and protein-level readouts; replicated across multiple patients and in mouse model\",\n      \"pmids\": [\"32791035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CFAP58 is identified as a testis-enriched protein that co-localizes with Odf2/Cenexin at the sperm midpiece and primary cilia. Cfap58 knockdown in astrocytes impairs primary cilium elongation and sperm midpiece formation via modulation of the Notch signaling pathway. Cfap58 was identified as an interactor of Odf2/Cenexin by mass spectrometry interactome analysis.\",\n      \"method\": \"Mass spectrometry interactome analysis, siRNA knockdown, immunofluorescence, drug administration studies (Notch pathway modulation)\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — pulldown/MS identification plus knockdown with pathway modulation, single lab, moderate orthogonal methods but Notch pathway link relies on pharmacological evidence\",\n      \"pmids\": [\"31904090\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CFAP58 (FAP58/CCDC147) forms a heterodimer with MBO2/CCDC146 that is part of a conserved L-shaped structure in the Chlamydomonas axoneme, varying between doublet microtubules. This structure interconnects inner dynein arms with multiple regulatory complexes and is required for normal ciliary waveform. Loss of FAP58 disrupts inner arm dynein b assembly. Comparative proteomics revealed overlapping protein defects with other motility mutants.\",\n      \"method\": \"Cryo-electron tomography, comparative proteomics, epitope tagging, Chlamydomonas mbo mutant analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cryo-ET structural determination combined with proteomics and genetic mutant analysis in Chlamydomonas ortholog; multiple orthogonal methods in single study\",\n      \"pmids\": [\"38568782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"CFAP58 loss in mice causes not only sperm tail defects but also disrupts the manchette structure, leading to abnormal sperm head shaping and increased spermatozoa apoptosis. CFAP58 physically interacts with IFT88 and CCDC42, and may act as a cargo protein stabilizing CCDC42 in the intra-manchette transport/intra-flagellar transport (IMT/IFT) pathway.\",\n      \"method\": \"Gene knockout mice, co-immunoprecipitation (CFAP58-IFT88 and CFAP58-CCDC42 interaction), immunofluorescence, TEM\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mouse with defined manchette/head phenotype plus co-IP identification of IFT88 and CCDC42 as binding partners; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38602507\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A homozygous nonsense mutation in CFAP58 (c.562C>T, p.R188*) disrupts central pair (CP) microtubule assembly in the sperm flagellar axoneme. Cfap58 mutant mice mimicking the patient mutation recapitulate the MMAF phenotype, and TEM shows absence of the central pair of microtubules, demonstrating CFAP58 is required for CP assembly during spermiogenesis.\",\n      \"method\": \"Whole-exome sequencing (human patients), Cfap58 knock-in mutant mouse model, transmission electron microscopy, immunofluorescence\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutant mouse model with TEM ultrastructural readout showing CP loss; single lab, mechanistic detail beyond prior reports but not yet replicated\",\n      \"pmids\": [\"40675161\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CFAP58 is a testis-enriched cilia- and flagella-associated protein that localizes to the sperm flagellum (concentrated in the mid-piece) and forms a heterodimer with MBO2/CCDC146 to create an L-shaped axonemal structure interconnecting inner dynein arms with regulatory complexes; loss of CFAP58 disrupts central pair microtubule assembly, reduces axonemal (SPAG6, SPEF2) and mitochondrial sheath (HSP60) proteins, impairs manchette-dependent sperm head shaping via interaction with IFT88 and CCDC42 in the IFT/IMT pathway, and modulates Notch signaling during ciliogenesis — collectively establishing CFAP58 as essential for sperm flagellar axoneme assembly, midpiece integrity, and normal ciliary waveform.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CFAP58 is a testis-enriched cilia- and flagella-associated protein essential for sperm flagellar axoneme assembly and midpiece integrity, with bi-allelic loss-of-function variants causing multiple morphological abnormalities of the sperm flagella (MMAF) and male infertility in humans and recapitulated in knockout and knock-in mice [#0, #4]. The protein localizes throughout the sperm flagellum, concentrating at the mid-piece, and its loss reduces axonemal markers (SPAG6, SPEF2) and the mitochondrial sheath protein HSP60 while disrupting central pair microtubule assembly [#0, #4]. Structurally, CFAP58 forms a heterodimer with CCDC146/MBO2 within a conserved L-shaped axonemal element that interconnects inner dynein arms with regulatory complexes and is required for normal ciliary waveform [#2]. Beyond the axoneme, CFAP58 acts in the intra-manchette/intra-flagellar transport pathway through physical interactions with IFT88 and CCDC42, stabilizing CCDC42 to support manchette-dependent sperm head shaping [#3]. CFAP58 co-localizes with ODF2/Cenexin and modulates Notch signaling during primary cilium elongation, extending its role to ciliogenesis beyond the male germline [#1].\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Establishing whether CFAP58 has an essential in vivo function addressed the unknown of its requirement for sperm formation, demonstrating it is causally linked to human male infertility via flagellar and mitochondrial sheath defects.\",\n      \"evidence\": \"Whole-exome sequencing of patients plus CRISPR/Cas9 knockout mice with TEM, IF, and immunoblotting\",\n      \"pmids\": [\"32791035\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the molecular structure CFAP58 builds within the axoneme\", \"Direct binding partners not yet defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identifying CFAP58 as an ODF2/Cenexin interactor and a Notch-pathway modulator addressed where it acts beyond the flagellum, linking it to primary cilium elongation and ciliogenesis.\",\n      \"evidence\": \"Mass spectrometry interactome, siRNA knockdown in astrocytes with Notch pharmacological modulation and IF\",\n      \"pmids\": [\"31904090\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Notch link rests on pharmacological evidence only\", \"Direct ODF2 binding interface not mapped\", \"Single-lab, knockdown-based\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Cryo-ET of the Chlamydomonas ortholog answered the structural question of how CFAP58 is organized in the axoneme, showing it heterodimerizes with CCDC146/MBO2 in an L-shaped element coupling inner dynein arms to regulatory complexes.\",\n      \"evidence\": \"Cryo-electron tomography, comparative proteomics, epitope tagging, and mbo mutant analysis in Chlamydomonas\",\n      \"pmids\": [\"38568782\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conservation of the L-shaped structure in mammalian sperm not directly demonstrated\", \"Mechanism of waveform regulation not resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defining CFAP58 interactions with IFT88 and CCDC42 addressed how its loss affects sperm head morphology, implicating it in the intra-manchette/intra-flagellar transport pathway as a stabilizer of CCDC42.\",\n      \"evidence\": \"Knockout mice with co-immunoprecipitation, IF, and TEM\",\n      \"pmids\": [\"38602507\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cargo role for CCDC42 inferred, not directly demonstrated\", \"Co-IP without reciprocal/structural validation of interaction interfaces\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A knock-in mouse modeling a patient nonsense mutation answered which axonemal substructure depends on CFAP58, showing it is required for central pair microtubule assembly during spermiogenesis.\",\n      \"evidence\": \"Whole-exome sequencing of patients and Cfap58 knock-in mutant mice with TEM and IF\",\n      \"pmids\": [\"40675161\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between CFAP58 and central pair nucleation unresolved\", \"Not yet independently replicated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CFAP58's axonemal structural role, IFT/IMT transport function, and Notch modulation are mechanistically integrated remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of the mammalian CFAP58 complex\", \"Direct binding interfaces with IFT88/CCDC42/CCDC146 not mapped\", \"Mechanism connecting CFAP58 to central pair assembly unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0, 4]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"complexes\": [\"CFAP58-CCDC146/MBO2 heterodimer\", \"axonemal L-shaped structure\"],\n    \"partners\": [\"CCDC146\", \"IFT88\", \"CCDC42\", \"ODF2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}