CFAP410

Inheritance Pattern: AD

Disease ID:MONDO:0015993

Submitter: Orphanet

Inheritance Pattern: SD

Disease ID:MONDO:0004976

Submitter: ClinGen

*CFAP410*, previously *C21orf2*, was first reported in relation to amyotrophic lateral sclerosis (ALS) in 2016 (van Rheenen et al., PMID: 27455348). *CFAP410* encodes cilia-and flagella-associated protein 410 and has a role in ciliogenesis and DNA damage repair. *CFAP410* has also been associated with autosomal recessive retinal dystrophy with macular staphyloma and autosomal recessive axial spondylometaphyseal dysplasia. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in inheritance pattern and phenotypic variability among these diseases. Therefore, the following disease entities have been split into separate disease entities: semi-dominant ALS (OMIM: 105400), autosomal recessive retinal dystrophy with macular staphyloma (OMIM: 617547) and autosomal recessive axial spondylometaphyseal dysplasia (OMIM: 602271). The association between *CFAP410* and ALS was first established in a genome-wide variant case-control analysis that identified an association between a risk variant in the gene, described as rs75087725 (Val58Leu), and the phenotype based on the genome sequencing of 12,577 ALS cases and 23,475 controls (van Rheenen et al., PMID:27455348). Per criteria set by the ALS GCEP, the missense variant found in this study is outside the established gnomAD minor allele frequency cutoffs (<0.00005) and, while is unlikely to be a main cause of disease, reached a level of significance. To date, no causal variants in *CFAP410* have been documented in ALS patients in the literature. The mechanism of pathogenicity is currently unclear. This gene-disease association is supported by experimental evidence describing expression of* CFAP410* in neuronal tissues, physical interaction with known ALS associated gene *NEK1* and functional alterations in non-patient cells (PMIDs: 36131690, 26290490, and 32891887). In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. It is important to understand that in the clinical diagnostic setting the identification of variants of uncertain significance may be common and variant interpretation must be completed with caution. This classification was approved by the ClinGen ALS GCEP on December 12, 2023.

Inheritance Pattern: AD

Disease ID:MONDO:0004976

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: ClinGen

*CFAP410* (a.k.a. C21orf2) was first reported in relation to CFAP410-related ciliopathy, an autosomal recessive condition, in 2013 (Abu-Safieh et al, PMID: 23105016). In OMIM, *CFAP410 *is associated with two conditions, retinal dystrophy with macular staphyloma (MIM# 617547) and spondylometaphyseal dysplasia, axial (MIM# 602271). The gene has also been associated with Jeune Asphyxiating Thoracic Dystrophy (McInerney-Leo et al, 2017, PMID: 28422394). These three conditions are characterized by variable retinal findings and skeletal features, and autosomal recessive inheritance. Per criteria outlined by the ClinGen Lumping & Splitting guidelines, we found no difference in the molecular mechanisms or inheritance pattern or phenotypic variability between these conditions. Therefore, these disease entities have been lumped together as *CFAP410*-related ciliopathy. *CFAP410 *has also been reported as a risk factor for amyotrophic lateral sclerosis (ALS) in case-control studies (van Rheenen et al, 2016, PMID: 27455348; Scaber et al, 2022, PMID: 37159497) and further studies have indicated that ciliary defects may be involved in the pathogenesis of ALS. Two adult siblings have been reported to have ALS and retinopathy (Kurashige et al, 2020, PMID: 31431468). However, given that this is the only case of phenotypic overlap, ALS has been split from *CFAP410*-related ciliopathy at the current time. The split curation for ALS has been performed by the ClinGen ALS GCEP. Over 50 probands with *CFAP410*-related ciliopathy have been reported in the literature (Shinbashi et al, 2023, PMID: 36950666; Schmidt et al, 2025, PMID: 40246852). Twelve variants (five missense, three splice site/intronic, three frameshift, and one deletion resulting in loss of the start codon) that have been reported in nine probands in three publications (Abu-Safieh et al, PMID: 23105016; Wang et al, 2016; Schmidt et al, 2025, PMID: 40246852) are included in this curation. Variants reported in more than one proband include c.218G>C (p.Arg73Pro) and c.319T>C (p.Tyr107His). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity appears to be loss of function. This gene-disease relationship is also supported by experimental evidence. *CFAP410* encodes Cilia- and Flagella-Associated Protein 410. Results of multiple experimental types indicate that this gene is important in ciliogenesis. siRNA knockdown of the gene in various cell types, including mIMCD3), hTERT-RPE1, and SH-SY5Y, results in fewer and shorter cilia ((Wheway et al, 2015, PMID: 26167768). CFAP410 localizes to cilia, mainly the basal body, and the photoreceptor connecting cilium, where it has been shown to physically interact with NEK1 and SPATA7 (Wheway et al, 2015, PMID: 26167768). Variants in these genes cause retinopathy and "short-rib thoracic dysplasia with or without polydactyly" respectively. The functional interaction between CFAP410 and NEK1 was shown by the partial rescue of phenotype in zebrafish in which Nek1 had been knocked down (De Decker et al, 2025, PMID: 39703094). The ClinGen Retina GCEP classified the relationship between SPATA7 and retinopathy as definitive. The relationship between NEK1 and retinopathy has not yet been assessed by any ClinGen GCEP; but in OMIM this gene is associated with "short-rib thoracic dysplasia 6 with or without polydactyly" which includes skeletal features and retinopathy in rare cases. Drosophila with knockdown of the CFAP410 orthologue have symptoms consistent with ciliary dysfunction (De Decker et al, 2025, PMID: 39703094) Multiple genes that localize to and function in cilia have been found to have a definitive gene-disease clinical validity by the ClinGen Retina GCEP (experimental evidence 2.5 points). In summary, there is Definitive evidence supporting the relationship between *CFAP410* and autosomal recessive *CFAP410*-related cliliopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time without the emergence of conflicting evidence. This classification was approved by the ClinGen Retina gene Curation Expert Panel on January 15, 2026 (SOP Version 11).

Inheritance Pattern: AR

Disease ID:MONDO:0011211

Submitter: G2P