CEP41

protein-coding

centrosomal protein 41

Gene summary

This gene encodes a centrosomal and microtubule-binding protein which is predicted to have two coiled-coil domains and a rhodanese domain. In human retinal pigment epithelial cells the protein localized to centrioles and cilia. Mutations in this gene have been associated with Joubert Syndrome 15; an autosomal recessive ciliopathy and neurological disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2012]

Previous symbols:

TSGA14

MANE transcript

NM_018718.3

Inheritance

AR, Digenic

ClinVar variants

P:24U:164B:72

Top phenotype

Joubert syndrome 15

gnomAD constraint

pLI —, LoF o/e 0.57

Max pathogenic AF

—

Genomic locus

chr7:130,393,771-130,442,433

External References & Databases

Ensembl (ENSG00000106477)

Transcript & Mutation Effects

hg38 • Region Span ~48.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ciliopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: ClinGen

*CEP41* is located on chromosome 7 (7q32.2) at chr7: 130,393,771-130,442,433 and comprises 11 exons that make up a 373 amino acid protein (PMID: 22246503). The gene product is *CEP41*, a centrosomal protein that facilitates axonemal glutamylation. This protein is predicted to contain two coiled-coils and a rhodanese-like domain which is structurally related to the catalytic subunit of Cdc25 class of phosphatases (but lacks activity). The cellular role of *CEP41* is an area of active investigation currently and has been shown to aid microtubule assembly and cell proliferation (PMID: 38841887). Bi-allelic alterations in *CEP41* have only been reported to cause autosomal recessive Joubert Syndrome and related disorders. Therefore, per criteria outlined by the Clingen Lumping and Splitting Workgroup, this disease entity has been lumped into one group with an autosomal recessive mode of inheritance. The preferred disease name suggested for this disorder is ciliopathy-*CEP41*. *CEP41* was first reported in relation to autosomal recessive Joubert Syndrome in 2012 by Lee JE et al., (PMID: 22246503). In this study, the authors utilized an initial linkage analysis mapping and direct *CEP41* sequencing to identify bi-allelic loss of function mutations in *CEP41* in three individuals from unrelated families with reported consanguinity. These probands demonstrated phenotypes including polydactyly, nephronophthisis, hypotonia, developmental delay, liver abnormalities and the characteristic molar tooth sign (MTS), culminating in a clinical diagnosis of Joubert Syndrome for all of the affected individuals. Since the first report of *CEP41*’s in relation to Joubert Syndrome, other studies have reported other bi-allelic variants in this gene (identified via trio exome sequencing) to cause similar phenotypes in other affected individuals who share features of Joubert Syndrome (PMIDs: 22246503). So far, all reported *CEP41* variants are loss of function. The majority of the variants were found in the compound heterozygous state, while one study reported disease-causing homozygous variants (PMID: 22246503). A total of 8 points for genetic evidence has been reached. This gene disease relationship is also supported by experimental evidence that demonstrates a functional alteration upon the loss of *CEP41* in patient cells. Patient fibroblasts lacking *CEP41* demonstrate ciliogenesis defects as well as reduced glutamylation of the ciliary axoneme, which is rescued by the introduction of human *CEP41*(PMID: 22246503). Additionally, knockdown of cep41 in zebrafish results in similar ciliary phenotypes and heart asymmetry, some of which are partly rescued by reintroducing human *CEP41*. A total of 4 points for experimental evidence was curated. In summary, there is definitive evidence supporting the relationship between *CEP41* and ciliopathy. This classification was approved by the ClinGen Cystic and Ciliopathy Expert Panel on the meeting date 12/03/2025 (SOP Version 11).

Joubert syndrome 15DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013763

Submitter: G2P

Joubert syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018772

Submitter: Orphanet

Joubert syndrome with ocular defectSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016364

Submitter: Orphanet

Joubert syndrome 15STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013763

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Joubert syndrome 15AR/Digenic

Manifestation: Gastrointestinal; Neurologic; Ophthalmologic; Pulmonary; Renal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: The condition may involve multi-systemic manifestations, including sequelae affecting the renal and hepatic systems, and surveillance and avoidance of certain medications (eg, nephrotoxic agents) may be beneficial; Digenic inheritance has been reported

Refs: 20301500; 22246503

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CEP41 variants in ClinVar

11 Conditions Cataloged

Joubert syndrome 15Total: 283

not providedTotal: 57

Inborn genetic diseasesTotal: 51

not specifiedTotal: 50

CEP41-related disorderTotal: 17

Familial Autism Spectrum DisorderTotal: 8

Congenital stationary night blindness 2ATotal: 2

Intellectual disabilityTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018718.3. 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			3 clinvar	57 clinvar		60
missense		1 clinvar	149 clinvar	15 clinvar		165
nonsense	3 clinvar	2 clinvar	3 clinvar			8
start loss						0
frameshift	7 clinvar	1 clinvar	3 clinvar			11
splice donor/acceptor (+/-2bp)	4 clinvar	6 clinvar	6 clinvar			16
Total	14	10	164	72	0	260

Highest pathogenic variant AF is 0.000022305108

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 53 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018718.3	RefSeq	NP_061188.1	11	MANE Select
ENST00000223208.10	Ensembl	ENSP00000223208.4	11	MANE Select
NM_001257158.2	RefSeq	NP_001244087.1	10	Standard
NM_001257159.2	RefSeq	NP_001244088.1	9	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
cep41	Danio rerio	Structure: otolith Quality: position abnormal

Gene / Model

Organism

Observed Phenotype

cep41

Danio rerio

Structure: otolith

Quality: position

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Regulation of PLK1 Activity at G2/M Transition
Recruitment of mitotic centrosome proteins and complexes
Loss of Nlp from mitotic centrosomes
Loss of proteins required for interphase microtubule organization from the centrosome
Centrosome maturation

Biological Process

G2/M transition of mitotic cell cycle
regulation of G2/M transition of mitotic cell cycle
protein transport
protein polyglutamylation
cilium assembly

Molecular Function

protein binding

Cellular Component

centrosome
centriole
cytosol
cilium
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000223208
Coding exons: 11
Length: 48663
Individuals with no LoFs: 125704
Homozygous LoFs: 0
Heterozygous LoFs: 44
Defined: 125748
p: 0.000175

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.347	188	202	0.931	0.0000109	2423
Missense (PolyPhen)		36	48.299	0.74536		558
Synonymous	0.329	75	78.7	0.953	0.00000461	731
Loss of Function	1.83	12	21.1	0.569	0.00000109	252

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00044	0.00043	rare
Latino/Admixed American	0.00038	0.00038	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.00013	0.00013	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required during ciliogenesis for tubulin glutamylation in cilium. Probably acts by participating in the transport of TTLL6, a tubulin polyglutamylase, between the basal body and the cilium. {ECO:0000269|PubMed:22246503}.;
Disease: DISEASE: Joubert syndrome 15 (JBTS15) [MIM:614464]: An autosomal recessive disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy, renal disease, liver fibrosis and polydactyly. {ECO:0000269|PubMed:22246503}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Note=Genetic variations in CEP41 may be associated with susceptibility to autism (PubMed:21438139). {ECO:0000269|PubMed:21438139}.;

Recessive Scores

pRec: 0.123

Intolerance Scores

RVIS EVS: 0.55
RVIS percentile EVS: 81.48

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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