C2CD3

Chr 11AR

C2 domain containing 3 centriole elongation regulator

Also known as: OFD14

NCBI Gene: 26005 ENSG00000168014 UniProt: Q4AC94 OMIM: 615944

The C2CD3 protein regulates centriole elongation and promotes assembly of centriolar distal appendages, which are required for primary cilium formation and sonic hedgehog signaling. Mutations cause orofaciodigital syndrome XIV, an autosomal recessive ciliopathy characterized by malformations of the oral cavity, face, and digits. The gene shows minimal constraint against loss-of-function variants (very low pLI score), consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein that functions as a regulator of centriole elongation. Studies of the orthologous mouse protein show that it promotes centriolar distal appendage assembly and is also required for the recruitment of other ciliogenic proteins, including intraflagellar transport proteins. Mutations in this gene cause orofaciodigital syndrome XIV (OFD14), a ciliopathy resulting in malformations of the oral cavity, face and digits. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Nov 2014]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.641 OMIM phenotype

Clinical Summary— C2CD3

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Gene-Disease Validity (ClinGen)

orofaciodigital syndrome type 14 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

22 unique Pathogenic / Likely Pathogenic· 140 VUS of 299 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.64LOEUF

pLI 0.000

Z-score 4.40

OE 0.50 (0.40–0.64)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.53Z-score

OE missense 0.95 (0.90–1.00)

980 obs / 1028.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.50 (0.40–0.64)

0≤0.351.4

Missense OE?0.95 (0.90–1.00)

0≤0.61.4

Synonymous OE?1.00

0≤1.21.6

LoF obs/exp: 46 / 91.4Missense obs/exp: 980 / 1028.3Syn Z: -0.05

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongC2CD3-related orofaciodigital syndromeLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6454th %ile

GOF

0.5366th %ile

LOF

0.4430th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

299 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic16

Likely Pathogenic6

VUS140

Likely Benign95

Benign1

Conflicting1

Pathogenic

Likely Pathogenic

140

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	15	1	0	0	16
Likely Pathogenic	5	1	0	0	6
VUS	2	133	5	0	140
Likely Benign	0	6	42	47	95
Benign	0	0	0	1	1
Conflicting	—				1
Total	22	141	47	48	259

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

1 pathogenic / likely-pathogenic (of 1) ClinVar copy-number / structural variants overlap C2CD3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →