{"gene":"CFAP46","run_date":"2026-06-09T22:57:18","timeline":{"discoveries":[{"year":2024,"finding":"Pathogenic variants in CFAP46 cause primary ciliary dyskinesia (PCD) characterized by a defective C1d projection of the ciliary central apparatus, leading to insufficient ciliary clearance as demonstrated by in vitro ciliary transport assays, despite normal nasal nitric oxide levels, normal ciliary ultrastructure by TEM, and normal ciliary beating by high-speed videomicroscopy.","method":"High-throughput sequencing of C1d component genes, in vitro ciliary transport assays, transmission electron microscopy, high-speed videomicroscopy analysis","journal":"The European respiratory journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic identification combined with functional in vitro ciliary transport assay in affected individuals, single study but multiple orthogonal methods","pmids":["39362668"],"is_preprint":false},{"year":2023,"finding":"CFAP46 encodes a component of the ciliary central apparatus C1d projection, as evidenced by its concurrent loss alongside WDR93 (another C1d component) in phylogenetically independent bird lineages through large segmental deletions, and confirmed by absence of transcripts in species with gene-disrupting changes.","method":"Comparative genomic analysis of ~500 vertebrate genomes, transcript expression analysis in species with and without intact CFAP46 gene","journal":"Royal Society open science","confidence":"Low","confidence_rationale":"Tier 4 / Moderate — comparative genomics and expression analysis; no direct biochemical or cell biological experiment on CFAP46 protein function","pmids":["37621660"],"is_preprint":false}],"current_model":"CFAP46 is a component of the C1d projection of the ciliary central apparatus whose loss-of-function causes primary ciliary dyskinesia with defective mucociliary clearance, while maintaining normal ciliary ultrastructure and beating pattern by standard diagnostic measures."},"narrative":{"mechanistic_narrative":"CFAP46 encodes a component of the C1d projection of the ciliary central apparatus, and its loss disrupts effective ciliary clearance [PMID:39362668]. In affected individuals, pathogenic CFAP46 variants cause primary ciliary dyskinesia in which mucociliary transport is defective in vitro despite normal nasal nitric oxide, normal ciliary ultrastructure by TEM, and a normal ciliary beating pattern by high-speed videomicroscopy, indicating a functional defect in central-apparatus output rather than a gross structural or motility lesion [PMID:39362668]. Beyond its assignment to the C1d projection and its co-evolutionary linkage with the other C1d component WDR93 [PMID:39362668, PMID:37621660], no further molecular or biochemical detail of CFAP46 has been characterized in the available corpus.","teleology":[{"year":2023,"claim":"Whether CFAP46 belongs to a specific central-apparatus substructure was unknown; coordinate evolutionary loss with a known C1d component placed it within the C1d projection.","evidence":"comparative genomics across ~500 vertebrate genomes plus transcript analysis showing concurrent loss of CFAP46 and WDR93 in independent bird lineages","pmids":["37621660"],"confidence":"Low","gaps":["Inference is evolutionary/correlative with no direct biochemical or cell-biological assay of CFAP46 protein","Physical interaction between CFAP46 and WDR93 not demonstrated","Subcellular localization of the CFAP46 protein not shown directly"]},{"year":2024,"claim":"Whether CFAP46 loss causes human ciliary disease was unknown; identifying pathogenic variants in PCD patients tied CFAP46 to a defective C1d projection and impaired ciliary clearance.","evidence":"high-throughput sequencing of C1d genes plus in vitro ciliary transport assays, TEM, and high-speed videomicroscopy in affected individuals","pmids":["39362668"],"confidence":"Medium","gaps":["Mechanism by which CFAP46 supports the C1d projection at the protein level is undefined","Normal beating and ultrastructure leave the link between C1d defect and impaired transport mechanistically unexplained","No reconstitution or structural characterization of CFAP46 within the central apparatus"]},{"year":null,"claim":"How CFAP46 assembles into the C1d projection, what proteins it directly binds, and how its loss translates into defective ciliary transport remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No direct interaction partners biochemically defined","No structural model of CFAP46 in the central apparatus","Mechanistic coupling between C1d integrity and mucociliary clearance unestablished"]}],"mechanism_profile":{"molecular_activity":[],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,1]}],"pathway":[],"complexes":["ciliary central apparatus C1d projection"],"partners":["WDR93"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IYW2","full_name":"Cilia- and flagella-associated protein 46","aliases":["Tetratricopeptide repeat protein 40"],"length_aa":2715,"mass_kda":303.5,"function":"As part of the central apparatus of the cilium axoneme plays a role in cilium movement","subcellular_location":"Cytoplasm, cytoskeleton, cilium axoneme","url":"https://www.uniprot.org/uniprotkb/Q8IYW2/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/CFAP46","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/CFAP46","total_profiled":1310},"omim":[{"mim_id":"618704","title":"CILIA- AND FLAGELLA-ASSOCIATED PROTEIN 221; CFAP221","url":"https://www.omim.org/entry/618704"},{"mim_id":"618543","title":"CILIA- AND FLAGELLA-ASSOCIATED PROTEIN 46; CFAP46","url":"https://www.omim.org/entry/618543"},{"mim_id":"279000","title":"CILIARY DYSKINESIA, PRIMARY, 55; CILD55","url":"https://www.omim.org/entry/279000"},{"mim_id":"244400","title":"CILIARY DYSKINESIA, PRIMARY, 1; CILD1","url":"https://www.omim.org/entry/244400"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mid piece","reliability":"Approved"},{"location":"Principal piece","reliability":"Approved"},{"location":"Annulus","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"skeletal muscle","ntpm":29.3},{"tissue":"testis","ntpm":39.9}],"url":"https://www.proteinatlas.org/search/CFAP46"},"hgnc":{"alias_symbol":["DKFZp434A1721","bA288G11.4","bA288G11.5","bB137A17.2","FLJ25954","bB137A17.3"],"prev_symbol":["C10orf123","C10orf124","C10orf93","C10orf92","TTC40"]},"alphafold":{"accession":"Q8IYW2","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IYW2","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IYW2-3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8IYW2-3-F1-predicted_aligned_error_v6.png","plddt_mean":88.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CFAP46","jax_strain_url":"https://www.jax.org/strain/search?query=CFAP46"},"sequence":{"accession":"Q8IYW2","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8IYW2.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8IYW2/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8IYW2"}},"corpus_meta":[{"pmid":"31754096","id":"PMC_31754096","title":"The 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CFAP221 cause primary ciliary dyskinesia with a defective C1d projection of the central apparatus.","date":"2024","source":"The European respiratory journal","url":"https://pubmed.ncbi.nlm.nih.gov/39362668","citation_count":15,"is_preprint":false},{"pmid":"37621660","id":"PMC_37621660","title":"Concurrent loss of ciliary genes WDR93 and CFAP46 in phylogenetically distant birds.","date":"2023","source":"Royal Society open science","url":"https://pubmed.ncbi.nlm.nih.gov/37621660","citation_count":7,"is_preprint":false},{"pmid":"34995380","id":"PMC_34995380","title":"Newborn DNA methylation and asthma acquisition across adolescence and early adulthood.","date":"2022","source":"Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology","url":"https://pubmed.ncbi.nlm.nih.gov/34995380","citation_count":6,"is_preprint":false},{"pmid":"31602373","id":"PMC_31602373","title":"Detection of Novel Fusion Transcript VTI1A-CFAP46 in Hepatocellular 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sciences","url":"https://pubmed.ncbi.nlm.nih.gov/42074143","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":7756,"output_tokens":533,"usd":0.015631,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":6896,"output_tokens":1199,"usd":0.032227,"stage2_stop_reason":"end_turn"},"total_usd":0.047858,"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\": 2024,\n      \"finding\": \"Pathogenic variants in CFAP46 cause primary ciliary dyskinesia (PCD) characterized by a defective C1d projection of the ciliary central apparatus, leading to insufficient ciliary clearance as demonstrated by in vitro ciliary transport assays, despite normal nasal nitric oxide levels, normal ciliary ultrastructure by TEM, and normal ciliary beating by high-speed videomicroscopy.\",\n      \"method\": \"High-throughput sequencing of C1d component genes, in vitro ciliary transport assays, transmission electron microscopy, high-speed videomicroscopy analysis\",\n      \"journal\": \"The European respiratory journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic identification combined with functional in vitro ciliary transport assay in affected individuals, single study but multiple orthogonal methods\",\n      \"pmids\": [\"39362668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"CFAP46 encodes a component of the ciliary central apparatus C1d projection, as evidenced by its concurrent loss alongside WDR93 (another C1d component) in phylogenetically independent bird lineages through large segmental deletions, and confirmed by absence of transcripts in species with gene-disrupting changes.\",\n      \"method\": \"Comparative genomic analysis of ~500 vertebrate genomes, transcript expression analysis in species with and without intact CFAP46 gene\",\n      \"journal\": \"Royal Society open science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Moderate — comparative genomics and expression analysis; no direct biochemical or cell biological experiment on CFAP46 protein function\",\n      \"pmids\": [\"37621660\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"CFAP46 is a component of the C1d projection of the ciliary central apparatus whose loss-of-function causes primary ciliary dyskinesia with defective mucociliary clearance, while maintaining normal ciliary ultrastructure and beating pattern by standard diagnostic measures.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CFAP46 encodes a component of the C1d projection of the ciliary central apparatus, and its loss disrupts effective ciliary clearance [#0]. In affected individuals, pathogenic CFAP46 variants cause primary ciliary dyskinesia in which mucociliary transport is defective in vitro despite normal nasal nitric oxide, normal ciliary ultrastructure by TEM, and a normal ciliary beating pattern by high-speed videomicroscopy, indicating a functional defect in central-apparatus output rather than a gross structural or motility lesion [#0]. Beyond its assignment to the C1d projection and its co-evolutionary linkage with the other C1d component WDR93 [#0, #1], no further molecular or biochemical detail of CFAP46 has been characterized in the available corpus.\",\n  \"teleology\": [\n    {\n      \"year\": 2023,\n      \"claim\": \"Whether CFAP46 belongs to a specific central-apparatus substructure was unknown; coordinate evolutionary loss with a known C1d component placed it within the C1d projection.\",\n      \"evidence\": \"comparative genomics across ~500 vertebrate genomes plus transcript analysis showing concurrent loss of CFAP46 and WDR93 in independent bird lineages\",\n      \"pmids\": [\"37621660\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Inference is evolutionary/correlative with no direct biochemical or cell-biological assay of CFAP46 protein\",\n        \"Physical interaction between CFAP46 and WDR93 not demonstrated\",\n        \"Subcellular localization of the CFAP46 protein not shown directly\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Whether CFAP46 loss causes human ciliary disease was unknown; identifying pathogenic variants in PCD patients tied CFAP46 to a defective C1d projection and impaired ciliary clearance.\",\n      \"evidence\": \"high-throughput sequencing of C1d genes plus in vitro ciliary transport assays, TEM, and high-speed videomicroscopy in affected individuals\",\n      \"pmids\": [\"39362668\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which CFAP46 supports the C1d projection at the protein level is undefined\",\n        \"Normal beating and ultrastructure leave the link between C1d defect and impaired transport mechanistically unexplained\",\n        \"No reconstitution or structural characterization of CFAP46 within the central apparatus\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How CFAP46 assembles into the C1d projection, what proteins it directly binds, and how its loss translates into defective ciliary transport remain unresolved.\",\n      \"evidence\": null,\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct interaction partners biochemically defined\",\n        \"No structural model of CFAP46 in the central apparatus\",\n        \"Mechanistic coupling between C1d integrity and mucociliary clearance unestablished\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [],\n    \"complexes\": [\"ciliary central apparatus C1d projection\"],\n    \"partners\": [\"WDR93\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":2,"faith_total":2,"faith_pct":100.0}}