CC2D2A

Chr 4AR

coiled-coil and C2 domain containing 2A

Also known as: COACH2, JBTS9, MKS6, RP93

NCBI Gene: 57545ENSG00000048342UniProt: Q9P2K1

This gene encodes a coiled-coil and calcium binding domain protein that appears to play a critical role in cilia formation. Mutations in this gene cause Meckel syndrome type 6, as well as Joubert syndrome type 9. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2009]

Primary Disease Associations & Inheritance

COACH syndrome 2MIM #619111
AR
Joubert syndrome 9MIM #612285
AR
Meckel syndrome 6MIM #612284
AR
Retinitis pigmentosa 93MIM #619845
AR
2450
ClinVar variants
71
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— CC2D2A
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
71 Pathogenic / Likely Pathogenic· 75 VUS of 2450 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.
0.78LOEUF
pLI 0.000
Z-score 3.32
OE 0.63 (0.51–0.78)
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.
0.65Z-score
OE missense 0.94 (0.88–0.99)
758 obs / 809.8 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.0.63 (0.51–0.78)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.94 (0.88–0.99)
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.0.96
0≤1.21.6
LoF obs/exp: 58 / 92.4Missense obs/exp: 758 / 809.8Syn Z: 0.55

ClinVar Variant Classifications

2450 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic51
Likely Pathogenic20
VUS75
Likely Benign334
Benign2
51
Pathogenic
20
Likely Pathogenic
75
VUS
334
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
22
1
28
0
51
Likely Pathogenic
17
2
1
0
20
VUS
1
70
4
0
75
Likely Benign
0
10
157
167
334
Benign
0
0
2
0
2
Total4083192167482

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

View in ClinVar →

Protein Context — Lollipop Plot

CC2D2A · protein map & ClinVar variants

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

Gene2Phenotype Curations

CC2D2A-related Joubert syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

COACH syndrome 2

MIM #619111

Molecular basis of disorder known

Autosomal recessive

Joubert syndrome 9

MIM #612285

Molecular basis of disorder known

Autosomal recessive

Meckel syndrome 6

MIM #612284

Molecular basis of disorder known

Autosomal recessive

Retinitis pigmentosa 93

MIM #619845

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Whole exome sequencing resolves complex phenotype and identifies CC2D2A mutations underlying non-syndromic rod-cone dystrophy.
Méjécase C et al.·Clin Genet
2019
New insights into CC2D2A-related Joubert syndrome.
Harion M et al.·J Med Genet
2023
CC2D2A mutations in Meckel and Joubert syndromes indicate a genotype-phenotype correlation.
Mougou-Zerelli S et al.·Hum Mutat
2009
Biallelic CC2D2A variants, SNV and LINE-1 insertion simultaneously identified in siblings using long-read whole-genome sequencing and haplotype phasing.
Yanagi K et al.·J Hum Genet
2023Case report
Primary cilia biogenesis and associated retinal ciliopathies.
Chen HY et al.·Semin Cell Dev Biol
2021Review
Exome Analysis Reveals Novel Missense and Deletion Variants in the CC2D2A Gene as Causative of Joubert Syndrome.
Cabrita Pinto RL et al.·Genes (Basel)
2023
Genotype-phenotype correlation in CC2D2A-related Joubert syndrome reveals an association with ventriculomegaly and seizures.
Bachmann-Gagescu R et al.·J Med Genet
2012
Update of genetic variants in CEP120 and CC2D2A-With an emphasis on genotype-phenotype correlations, tissue specific transcripts and exploring mutation specific exon skipping therapies.
Barroso-Gil M et al.·Mol Genet Genomic Med
2021
The Ciliopathy Protein CC2D2A Associates with NINL and Functions in RAB8-MICAL3-Regulated Vesicle Trafficking.
Bachmann-Gagescu R et al.·PLoS Genet
2015
Prenatal diagnosis and clinical significance of cephalocele-A single institution experience and literature review.
Dąbkowska S et al.·Prenat Diagn
2020Review
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