{"gene":"CFAP206","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2020,"finding":"CFAP206 protein localizes to the basal body and to the axoneme of motile cilia in mouse and Xenopus, and is transcriptionally regulated downstream of FOXJ1. Loss of Cfap206 in Xenopus crispants enhanced ciliary beat frequency of skin multiciliated cells while reducing bead transport across the epidermal mucociliary epithelium. Electron tomography of immotile Cfap206 knockout mouse sperm flagella indicated a role in radial spoke formation, consistent with FAP206 function in Tetrahymena.","method":"CRISPR crispant Xenopus larvae (ciliary beat frequency, bead transport assay), Cfap206 knockout mice (electron tomography of sperm flagella), immunofluorescence localization to basal body and axoneme","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (KO mouse ultrastructure, Xenopus crispant functional assay, direct protein localization) in a single rigorous study","pmids":["32376681"],"is_preprint":false},{"year":2021,"finding":"Bi-allelic loss-of-function variants in CFAP206 cause male infertility with multiple morphological abnormalities of the flagella (MMAF) phenotype. CFAP206 functions as a microtubule-docking adapter for radial spoke and inner dynein arm components; its absence leads to loss of WDR66 and RSPH1 proteins, indicating severe radial spoke and calmodulin/spoke-associated complex (CASA complex) defects. Cfap206 knockout mice generated by CRISPR-Cas9 recapitulate male infertility with structural and ultrastructural sperm flagellum defects and very low ICSI embryo development rates.","method":"Exome sequencing identifying homozygous frameshift variant in patient; immunostaining of patient sperm for WDR66 and RSPH1; CRISPR-Cas9 Cfap206 KO mouse with sperm motility/morphology/ultrastructure analysis and ICSI embryo development assay","journal":"Human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — human genetic evidence corroborated by KO mouse model with multiple orthogonal readouts (immunostaining, ultrastructure, functional ICSI assay)","pmids":["34255152"],"is_preprint":false},{"year":2022,"finding":"In Tetrahymena, CFAP206 (FAP206) is an RS2-associated protein whose stable docking at the axoneme depends on Cfap91. Loss of Cfap91 significantly reduces the level of RS2-associated Cfap206, indicating that Cfap91 is required upstream of CFAP206 for radial spoke RS2 positioning and stability.","method":"Proteomic and localization studies in Tetrahymena CFAP91-KO cells; immunofluorescence quantification of Cfap206 levels; genetic and microscopic approaches","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — proteomic and localization data in Tetrahymena KO, single lab, two orthogonal methods","pmids":["36552811"],"is_preprint":false}],"current_model":"CFAP206 is a conserved axonemal protein that localizes to the basal body and axoneme of motile cilia and flagella, where it functions as a microtubule-docking adapter required for radial spoke (particularly RS2) and inner dynein arm assembly; its loss disrupts radial spoke integrity (including WDR66 and RSPH1 localization), impairs ciliary/flagellar beat, and causes male infertility and mucociliary clearance defects in mammals, while its axonemal stability is itself dependent on Cfap91."},"narrative":{"mechanistic_narrative":"CFAP206 is a conserved axonemal protein of motile cilia and flagella that functions as a microtubule-docking adapter required for radial spoke and inner dynein arm assembly [PMID:32376681, PMID:34255152]. It localizes to the basal body and the ciliary axoneme, and its expression is controlled downstream of the master ciliogenesis transcription factor FOXJ1 [PMID:32376681]. CFAP206 docks radial spoke and inner dynein arm components onto the axonemal microtubules; its loss eliminates the radial spoke proteins WDR66 and RSPH1, producing severe radial spoke and CASA (calmodulin/spoke-associated) complex defects [PMID:34255152]. Functionally, loss of CFAP206 disrupts ciliary beat coordination and mucociliary clearance and renders sperm flagella immotile with ultrastructural defects [PMID:32376681, PMID:34255152]. In humans, bi-allelic loss-of-function variants in CFAP206 cause male infertility with multiple morphological abnormalities of the flagella (MMAF), a connection recapitulated in knockout mice [PMID:34255152]. Stable axonemal docking of CFAP206 at the RS2 radial spoke is itself dependent on Cfap91, which acts upstream to position and stabilize the protein [PMID:36552811].","teleology":[{"year":2020,"claim":"Established that CFAP206 is a FOXJ1-regulated motile-cilia protein localizing to the basal body and axoneme, with a role in radial spoke formation, answering where the protein acts and which structure it builds.","evidence":"Immunofluorescence localization, Xenopus CRISPR crispants (ciliary beat frequency and bead transport assays), and electron tomography of Cfap206 knockout mouse sperm flagella","pmids":["32376681"],"confidence":"High","gaps":["Molecular interaction partners on the axoneme not identified","Mechanism by which loss enhances beat frequency yet impairs transport unresolved","Did not define which radial spoke components depend on CFAP206"]},{"year":2021,"claim":"Defined CFAP206 as a microtubule-docking adapter for radial spoke and inner dynein arm components and linked its loss to human MMAF male infertility, establishing both molecular role and disease relevance.","evidence":"Exome sequencing of an infertile patient with a homozygous frameshift variant, patient-sperm immunostaining for WDR66 and RSPH1, and a CRISPR-Cas9 Cfap206 knockout mouse with motility, ultrastructure, and ICSI readouts","pmids":["34255152"],"confidence":"High","gaps":["Direct physical interaction between CFAP206 and WDR66/RSPH1 not demonstrated biochemically","Structural basis of microtubule docking not resolved","Whether CFAP206 acts on dynein arms directly or indirectly via spoke integrity unclear"]},{"year":2022,"claim":"Placed CFAP206 within the radial spoke assembly hierarchy by showing its RS2 docking and stability depend on the upstream factor Cfap91.","evidence":"Proteomics and immunofluorescence quantification of Cfap206 levels in Tetrahymena CFAP91-knockout cells","pmids":["36552811"],"confidence":"Medium","gaps":["Single lab in Tetrahymena; mammalian dependence on CFAP91 not confirmed","Direct Cfap91-CFAP206 binding not shown","Order of recruitment relative to other RS2 subunits incomplete"]},{"year":null,"claim":"How CFAP206 physically engages microtubules and radial spoke/inner dynein arm subunits at atomic resolution, and the full recruitment hierarchy, remain undefined.","evidence":"","pmids":[],"confidence":"High","gaps":["No structural model of the CFAP206 docking interface","No reconstituted biochemistry of CFAP206 with radial spoke or dynein components","Mechanistic basis of altered beat frequency versus transport unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[1]}],"complexes":["radial spoke (RS2)"],"partners":["CFAP91"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IYR0","full_name":"Cilia- and flagella-associated protein 206","aliases":[],"length_aa":622,"mass_kda":71.2,"function":"Essential for sperm motility and is involved in the regulation of the beating frequency of motile cilia on the epithelial cells of the respiratory tract (By similarity). Required for the establishment of radial spokes in sperm flagella (By similarity)","subcellular_location":"Cytoplasm, cytoskeleton, cilium axoneme; Cytoplasm, cytoskeleton, cilium basal body","url":"https://www.uniprot.org/uniprotkb/Q8IYR0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CFAP206","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CFAP206","total_profiled":1310},"omim":[{"mim_id":"621387","title":"SPERMATOGENIC FAILURE 102; SPGF102","url":"https://www.omim.org/entry/621387"},{"mim_id":"621378","title":"CILIA- AND FLAGELLA-ASSOCIATED PROTEIN 161; CFAP161","url":"https://www.omim.org/entry/621378"},{"mim_id":"621376","title":"CILIA- AND FLAGELLA-ASSOCIATED PROTEIN 206; CFAP206","url":"https://www.omim.org/entry/621376"},{"mim_id":"258150","title":"SPERMATOGENIC FAILURE 1; SPGF1","url":"https://www.omim.org/entry/258150"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"fallopian tube","ntpm":21.0},{"tissue":"testis","ntpm":55.2}],"url":"https://www.proteinatlas.org/search/CFAP206"},"hgnc":{"alias_symbol":["FLJ25974","dJ382I10.1"],"prev_symbol":["C6orf165"]},"alphafold":{"accession":"Q8IYR0","domains":[{"cath_id":"-","chopping":"6-72","consensus_level":"high","plddt":85.75,"start":6,"end":72},{"cath_id":"-","chopping":"120-202","consensus_level":"high","plddt":93.9454,"start":120,"end":202},{"cath_id":"-","chopping":"385-490","consensus_level":"high","plddt":90.2089,"start":385,"end":490},{"cath_id":"1.20.140","chopping":"212-371","consensus_level":"high","plddt":92.5347,"start":212,"end":371}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IYR0","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IYR0-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IYR0-F1-predicted_aligned_error_v6.png","plddt_mean":85.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CFAP206","jax_strain_url":"https://www.jax.org/strain/search?query=CFAP206"},"sequence":{"accession":"Q8IYR0","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IYR0.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IYR0/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IYR0"}},"corpus_meta":[{"pmid":"35207567","id":"PMC_35207567","title":"Omics and Male Infertility: Highlighting the Application of Transcriptomic Data.","date":"2022","source":"Life (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/35207567","citation_count":30,"is_preprint":false},{"pmid":"34255152","id":"PMC_34255152","title":"Bi-allelic truncating variants in CFAP206 cause male infertility in human and mouse.","date":"2021","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/34255152","citation_count":27,"is_preprint":false},{"pmid":"32376681","id":"PMC_32376681","title":"The FOXJ1 target Cfap206 is required for sperm motility, mucociliary clearance of the airways and brain development.","date":"2020","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/32376681","citation_count":22,"is_preprint":false},{"pmid":"36552811","id":"PMC_36552811","title":"Cfap91-Dependent Stability of the RS2 and RS3 Base Proteins and Adjacent Inner Dynein Arms in Tetrahymena Cilia.","date":"2022","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/36552811","citation_count":13,"is_preprint":false},{"pmid":"39104315","id":"PMC_39104315","title":"Obesity impairs ciliary function and mucociliary clearance in the murine airway epithelium.","date":"2024","source":"American journal of physiology. Lung cellular and molecular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/39104315","citation_count":8,"is_preprint":false},{"pmid":"36714547","id":"PMC_36714547","title":"High-throughput proteomic characterization of seminal plasma from bulls with contrasting semen quality.","date":"2023","source":"3 Biotech","url":"https://pubmed.ncbi.nlm.nih.gov/36714547","citation_count":8,"is_preprint":false},{"pmid":"38033870","id":"PMC_38033870","title":"Cascading effects of hypobaric hypoxia on the testis: insights from a single-cell RNA sequencing analysis.","date":"2023","source":"Frontiers in cell and developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/38033870","citation_count":3,"is_preprint":false},{"pmid":"38051303","id":"PMC_38051303","title":"Genetic Factors and Long-term Treatment-Related Neurocognitive Deficits, Anxiety, and Depression in Childhood Leukemia Survivors: An Exome-Wide Association Study.","date":"2024","source":"Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/38051303","citation_count":2,"is_preprint":false},{"pmid":"38200094","id":"PMC_38200094","title":"Strong selection signatures for Aleutian disease tolerance acting on novel candidate genes linked to immune and cellular responses in American mink (Neogale vison).","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38200094","citation_count":1,"is_preprint":false},{"pmid":"41583004","id":"PMC_41583004","title":"Exploring rare coding variants in UK biobank: preliminary associations with motor neuron disease.","date":"2026","source":"Frontiers in aging neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/41583004","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":8197,"output_tokens":1057,"usd":0.020223,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":7563,"output_tokens":1817,"usd":0.04162,"stage2_stop_reason":"end_turn"},"total_usd":0.061843,"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\": \"CFAP206 protein localizes to the basal body and to the axoneme of motile cilia in mouse and Xenopus, and is transcriptionally regulated downstream of FOXJ1. Loss of Cfap206 in Xenopus crispants enhanced ciliary beat frequency of skin multiciliated cells while reducing bead transport across the epidermal mucociliary epithelium. Electron tomography of immotile Cfap206 knockout mouse sperm flagella indicated a role in radial spoke formation, consistent with FAP206 function in Tetrahymena.\",\n      \"method\": \"CRISPR crispant Xenopus larvae (ciliary beat frequency, bead transport assay), Cfap206 knockout mice (electron tomography of sperm flagella), immunofluorescence localization to basal body and axoneme\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (KO mouse ultrastructure, Xenopus crispant functional assay, direct protein localization) in a single rigorous study\",\n      \"pmids\": [\"32376681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Bi-allelic loss-of-function variants in CFAP206 cause male infertility with multiple morphological abnormalities of the flagella (MMAF) phenotype. CFAP206 functions as a microtubule-docking adapter for radial spoke and inner dynein arm components; its absence leads to loss of WDR66 and RSPH1 proteins, indicating severe radial spoke and calmodulin/spoke-associated complex (CASA complex) defects. Cfap206 knockout mice generated by CRISPR-Cas9 recapitulate male infertility with structural and ultrastructural sperm flagellum defects and very low ICSI embryo development rates.\",\n      \"method\": \"Exome sequencing identifying homozygous frameshift variant in patient; immunostaining of patient sperm for WDR66 and RSPH1; CRISPR-Cas9 Cfap206 KO mouse with sperm motility/morphology/ultrastructure analysis and ICSI embryo development assay\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — human genetic evidence corroborated by KO mouse model with multiple orthogonal readouts (immunostaining, ultrastructure, functional ICSI assay)\",\n      \"pmids\": [\"34255152\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In Tetrahymena, CFAP206 (FAP206) is an RS2-associated protein whose stable docking at the axoneme depends on Cfap91. Loss of Cfap91 significantly reduces the level of RS2-associated Cfap206, indicating that Cfap91 is required upstream of CFAP206 for radial spoke RS2 positioning and stability.\",\n      \"method\": \"Proteomic and localization studies in Tetrahymena CFAP91-KO cells; immunofluorescence quantification of Cfap206 levels; genetic and microscopic approaches\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — proteomic and localization data in Tetrahymena KO, single lab, two orthogonal methods\",\n      \"pmids\": [\"36552811\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CFAP206 is a conserved axonemal protein that localizes to the basal body and axoneme of motile cilia and flagella, where it functions as a microtubule-docking adapter required for radial spoke (particularly RS2) and inner dynein arm assembly; its loss disrupts radial spoke integrity (including WDR66 and RSPH1 localization), impairs ciliary/flagellar beat, and causes male infertility and mucociliary clearance defects in mammals, while its axonemal stability is itself dependent on Cfap91.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CFAP206 is a conserved axonemal protein of motile cilia and flagella that functions as a microtubule-docking adapter required for radial spoke and inner dynein arm assembly [#0, #1]. It localizes to the basal body and the ciliary axoneme, and its expression is controlled downstream of the master ciliogenesis transcription factor FOXJ1 [#0]. CFAP206 docks radial spoke and inner dynein arm components onto the axonemal microtubules; its loss eliminates the radial spoke proteins WDR66 and RSPH1, producing severe radial spoke and CASA (calmodulin/spoke-associated) complex defects [#1]. Functionally, loss of CFAP206 disrupts ciliary beat coordination and mucociliary clearance and renders sperm flagella immotile with ultrastructural defects [#0, #1]. In humans, bi-allelic loss-of-function variants in CFAP206 cause male infertility with multiple morphological abnormalities of the flagella (MMAF), a connection recapitulated in knockout mice [#1]. Stable axonemal docking of CFAP206 at the RS2 radial spoke is itself dependent on Cfap91, which acts upstream to position and stabilize the protein [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2020,\n      \"claim\": \"Established that CFAP206 is a FOXJ1-regulated motile-cilia protein localizing to the basal body and axoneme, with a role in radial spoke formation, answering where the protein acts and which structure it builds.\",\n      \"evidence\": \"Immunofluorescence localization, Xenopus CRISPR crispants (ciliary beat frequency and bead transport assays), and electron tomography of Cfap206 knockout mouse sperm flagella\",\n      \"pmids\": [\"32376681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular interaction partners on the axoneme not identified\",\n        \"Mechanism by which loss enhances beat frequency yet impairs transport unresolved\",\n        \"Did not define which radial spoke components depend on CFAP206\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined CFAP206 as a microtubule-docking adapter for radial spoke and inner dynein arm components and linked its loss to human MMAF male infertility, establishing both molecular role and disease relevance.\",\n      \"evidence\": \"Exome sequencing of an infertile patient with a homozygous frameshift variant, patient-sperm immunostaining for WDR66 and RSPH1, and a CRISPR-Cas9 Cfap206 knockout mouse with motility, ultrastructure, and ICSI readouts\",\n      \"pmids\": [\"34255152\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Direct physical interaction between CFAP206 and WDR66/RSPH1 not demonstrated biochemically\",\n        \"Structural basis of microtubule docking not resolved\",\n        \"Whether CFAP206 acts on dynein arms directly or indirectly via spoke integrity unclear\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Placed CFAP206 within the radial spoke assembly hierarchy by showing its RS2 docking and stability depend on the upstream factor Cfap91.\",\n      \"evidence\": \"Proteomics and immunofluorescence quantification of Cfap206 levels in Tetrahymena CFAP91-knockout cells\",\n      \"pmids\": [\"36552811\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single lab in Tetrahymena; mammalian dependence on CFAP91 not confirmed\",\n        \"Direct Cfap91-CFAP206 binding not shown\",\n        \"Order of recruitment relative to other RS2 subunits incomplete\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CFAP206 physically engages microtubules and radial spoke/inner dynein arm subunits at atomic resolution, and the full recruitment hierarchy, remain undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structural model of the CFAP206 docking interface\",\n        \"No reconstituted biochemistry of CFAP206 with radial spoke or dynein components\",\n        \"Mechanistic basis of altered beat frequency versus transport unresolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"complexes\": [\"radial spoke (RS2)\"],\n    \"partners\": [\"CFAP91\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}