C2CD3

Chr 11AR

C2 domain containing 3 centriole elongation regulator

Also known as: OFD14

NCBI Gene: 26005ENSG00000168014UniProt: Q4AC94

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]

Primary Disease Associations & Inheritance

Orofaciodigital syndrome XIVMIM #615948
AR
460
ClinVar variants
25
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— C2CD3
🧬
Gene-Disease Validity (ClinGen)
orofaciodigital syndrome type 14 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
25 Pathogenic / Likely Pathogenic· 271 VUS of 460 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.64LOEUF
pLI 0.000
Z-score 4.40
OE 0.50 (0.40–0.64)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.53Z-score
OE missense 0.95 (0.90–1.00)
980 obs / 1028.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.50 (0.40–0.64)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.95 (0.90–1.00)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.00
0≤1.21.6
LoF obs/exp: 46 / 91.4Missense obs/exp: 980 / 1028.3Syn Z: -0.05

ClinVar Variant Classifications

460 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic19
Likely Pathogenic6
VUS271
Likely Benign152
Benign2
Conflicting10
19
Pathogenic
6
Likely Pathogenic
271
VUS
152
Likely Benign
2
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
12
0
7
0
19
Likely Pathogenic
5
0
1
0
6
VUS
3
256
9
3
271
Likely Benign
0
9
59
84
152
Benign
0
1
1
0
2
Conflicting
—10
Total202667787460

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

View in ClinVar →

Protein Context — Lollipop Plot

C2CD3 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

C2CD3-related orofaciodigital syndrome

strong
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Orofaciodigital syndrome XIV

MIM #615948

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — C2CD3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Mutations in human C2CD3 cause skeletal dysplasia and provide new insights into phenotypic and cellular consequences of altered C2CD3 function.
Cortés CR et al.·Sci Rep
2016
Use of patient-derived cell models for characterization of compound heterozygous hypomorphic C2CD3 variants in a patient with isolated nephronophthisis.
Sentell ZT et al.·Hum Mol Genet
2025Case report
The oral-facial-digital syndrome gene C2CD3 encodes a positive regulator of centriole elongation.
Thauvin-Robinet C et al.·Nat Genet
2014
Characterization of three ciliopathy pedigrees expands the phenotype associated with biallelic C2CD3 variants.
Boczek NJ et al.·Eur J Hum Genet
2018Case report
Myelomeningocele genotype-phenotype correlation findings in cilia, HH, PCP, and WNT signaling pathways.
Ortiz-Cruz G et al.·Birth Defects Res
2021
Fifteen years of research on oral-facial-digital syndromes: from 1 to 16 causal genes.
Bruel AL et al.·J Med Genet
2017Review
High diagnostic yield in skeletal ciliopathies using massively parallel genome sequencing, structural variant screening and RNA analyses.
Hammarsjö A et al.·J Hum Genet
2021
Search for chromosome rearrangements: new approaches toward discovery of novel translocations in head and neck squamous cell carcinoma.
Wang VW et al.·Head Neck
2013
Whole-genome sequencing reveals new Alzheimer's disease-associated rare variants in loci related to synaptic function and neuronal development.
Prokopenko D et al.·Alzheimers Dement
2021
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools