CFAP418

protein-coding

cilia and flagella associated protein 418

Gene summary

This gene encodes a ubiquitously expressed protein of unknown function. It has high levels of mRNA expression in the brain, heart, and retina and the protein co-localizes with polyglutamylated tubulin at the base of the primary cilium in human retinal pigment epithelial cells. Mutations in this gene have been associated with autosomal recessive cone-rod dystrophy (arCRD) and retinitis pigmentosa (arRP). [provided by RefSeq, Mar 2012]

Previous symbols:

C8orf37

MANE transcript

NM_177965.4

Inheritance

ClinVar variants

P:35U:125B:44

Top phenotype

Bardet-Biedl syndrome 21

gnomAD constraint

pLI —, LoF o/e 0.79

Max pathogenic AF

—

Genomic locus

chr8:95,244,913-95,269,201

External References & Databases

Ensembl (ENSG00000156172)

Transcript & Mutation Effects

hg38 • Region Span ~24.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cone-rod dystrophy 16MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013786

Submitter: Ambry Genetics

ciliopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: ClinGen

*CFAP418* (previously known as *C8orf37*) was first reported in relation to autosomal recessive Bardet Biedl syndrome in 2012 (Estrada-Cuzcano et al., PMID: 22177090). BBS is a rare genetically heterogeneous ciliopathy, characterized by rod-cone dystrophy, polydactyly, obesity, genital anomalies, renal anomalies, and intellectual disabilities. Additional families have affected members diagnosed with conditions such as retinitis pigmentosa or cone-rod dystrophy (PMID: 22177090, PMID: 25802487). Per criteria outlined by the ClinGen Lumping & Splitting Working Group, the mode of inheritance (autosomal recessive) and molecular mechanism (biallelic *CFAP418* disruption) were found to be consistent among patients diagnosed with Bardet-Biedl syndrome 21 (MIM# 617406), cone-rod dystrophy 16 (MIM# 614500), or retinitis pigmentosa 64 (MIM# 614500). The phenotypic variability between cases appears to represent a spectrum of disease rather than separate disease entities. Therefore, cases caused by inherited biallelic *CFAP418* variants have been lumped into a single disease entity, referred to as CFAP418-related ciliopathy. This curation includes eight variants (three canonical splicing, two missense, and three nonsense) that have been reported in nine probands in five publications (PMIDs: 22177090, 25802487, 27008867, 26854863, 26865426). The mechanism of pathogenicity is likely to be biallelic loss-of-function. This gene-disease association is also supported by an expression study showing that *CFAP418* is highly expressed in the retina, as well as localized at base of the photoreceptor connecting cilia and photoreceptor inner segments (PMID: 22177090). Using a zebrafish model with knockdown of the *CFAP418* ortholog, Heon et. al. show that the Kuppfer’s vesicle (a ciliated organ) of mutant zebrafish is smaller and has reduced cilia content compared to wild-type fish. Overexpressing the p.Arg177Trp or p.Gln182Arg variants in *CFAP418* results in Kuppfer’s vesicle defects and visual impairment (PMID: 27008867). Finally, a *CFAP418* knockout mouse model shows reduced scotopic and photopic ERG responses, progressive retinal degeneration, and a reduction in outer segment protein expression in the retina (PMID: 29440555). In summary, *CFAP418* is definitively associated with autosomal recessive CFAP418-related ciliopathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time without the emergence of contradictory evidence. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on July 11, 2024 (SOP Version 10).

bardet-biedl syndrome 21DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044308

Submitter: Natera

cone-rod dystrophy 16DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013786

Submitter: G2P

cone-rod dystrophy 16STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013786

Submitter: Labcorp Genetics (formerly Invitae)

bardet-biedl syndrome 21LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0044308

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Bardet-Biedl syndrome 21AR

Manifestation: Dental; Endocrine; Musculoskeletal; Neurologic; Ophthalmologic; Renal

Intervention: Endocrine

Rationale: Medical management of obesity with melanocortin-4 receptor (MC4R) agonist (setmelanotide) may be beneficial

Refs: 22177090; 26854863; 27008867; 36356613

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CFAP418 variants in ClinVar

13 Conditions Cataloged

not providedTotal: 180

CFAP418-related disorderTotal: 92

Cone-rod dystrophy 16Total: 43

Retinitis pigmentosaTotal: 35

Bardet-biedl syndrome 21Total: 27

not specifiedTotal: 19

Retinal dystrophyTotal: 17

C8orf37-related disorderTotal: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_177965.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			7 clinvar	38 clinvar		45
missense	1 clinvar	2 clinvar	114 clinvar	6 clinvar		123
nonsense	3 clinvar	5 clinvar	2 clinvar			10
start loss			2 clinvar			2
frameshift	7 clinvar	9 clinvar				16
splice donor/acceptor (+/-2bp)	3 clinvar	5 clinvar				8
Total	14	21	125	44	0	204

Highest pathogenic variant AF is 0.000023551958

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 7 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_177965.4	RefSeq	NP_808880.1	6	MANE Select
ENST00000286688.6	Ensembl	ENSP00000286688.5	6	MANE Select
NM_001363260.1	RefSeq	NP_001350189.1	5	Standard
ENST00000945329.1	Ensembl	ENSP00000615388.1	5	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
si:dkey-242e21.4	Danio rerio	Structure: Kupffer's vesicle Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

si:dkey-242e21.4

Danio rerio

Structure: Kupffer's vesicle

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

photoreceptor cell morphogenesis

Molecular Function

protein binding

Cellular Component

photoreceptor inner segment
cytoplasm
cytosol
plasma membrane
cell junction

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000286688
Coding exons: 6
Length: 24283
Individuals with no LoFs: 125731
Homozygous LoFs: 0
Heterozygous LoFs: 11
Defined: 125742
p: 0.0000437

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0721	117	115	1.02	0.00000562	1371
Missense (PolyPhen)		41	41.266	0.99355		486
Synonymous	1.49	27	38.8	0.695	0.00000179	361
Loss of Function	0.611	8	10.1	0.793	4.22e-7	140

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000060	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000055	0.000053	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May be involved in photoreceptor outer segment disk morphogenesis (By similarity). {ECO:0000250|UniProtKB:Q3UJP5}.;
Disease: DISEASE: Retinitis pigmentosa 64 (RP64) [MIM:614500]: A retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. {ECO:0000269|PubMed:22177090}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Bardet-Biedl syndrome 21 (BBS21) [MIM:617406]: A form of Bardet-Biedl syndrome, a syndrome characterized by usually severe pigmentary retinopathy, early-onset obesity, polydactyly, hypogenitalism, renal malformation and mental retardation. Secondary features include diabetes mellitus, hypertension and congenital heart disease. Bardet-Biedl syndrome inheritance is autosomal recessive, but three mutated alleles (two at one locus, and a third at a second locus) may be required for clinical manifestation of some forms of the disease. {ECO:0000269|PubMed:26854863, ECO:0000269|PubMed:27008867}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.448
RVIS EVS: 0.19
RVIS percentile EVS: 66.82

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium