CC2D1A

Chr 19AR

coiled-coil and C2 domain containing 1A

Also known as: Aki-1, FREUD-1, Freud-1/Aki1, Lgd2, MRT3, TAPE

NCBI Gene: 54862ENSG00000132024UniProt: Q6P1N0

This gene encodes a transcriptional repressor that binds to a conserved 14-bp 5'-repressor element and regulates expression of the 5-hydroxytryptamine (serotonin) receptor 1A gene in neuronal cells. The DNA binding and transcriptional repressor activities of the protein are inhibited by calcium. A mutation in this gene results in a nonsyndromic form of cognitive disability (MRT3). [provided by RefSeq, Jul 2017]

Primary Disease Associations & Inheritance

Intellectual developmental disorder, autosomal recessive 3MIM #608443
AR
637
ClinVar variants
72
Pathogenic / LP
0.01
pLI score
0
Active trials
Clinical Summary— CC2D1A
🧬
Gene-Disease Validity (ClinGen)
complex neurodevelopmental disorder · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.27) despite low pLI — interpret in context.
📋
ClinVar Variants
72 Pathogenic / Likely Pathogenic· 187 VUS of 637 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
0.42LOEUF
pLI 0.008
Z-score 4.99
OE 0.27 (0.18–0.42)
Moderately constrained

More LoF-intolerant than ~75% of genes

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.
0.94Z-score
OE missense 0.89 (0.83–0.96)
541 obs / 606.2 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.0.27 (0.18–0.42)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.89 (0.83–0.96)
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.0.98
0≤1.21.6
LoF obs/exp: 15 / 55.0Missense obs/exp: 541 / 606.2Syn Z: 0.21

ClinVar Variant Classifications

637 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic39
Likely Pathogenic33
VUS187
Likely Benign333
Benign20
Conflicting25
39
Pathogenic
33
Likely Pathogenic
187
VUS
333
Likely Benign
20
Benign
25
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
19
0
20
0
39
Likely Pathogenic
28
1
4
0
33
VUS
0
175
10
2
187
Likely Benign
1
29
158
145
333
Benign
0
4
12
4
20
Conflicting
—25
Total48209204151637

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

View in ClinVar →

Protein Context — Lollipop Plot

CC2D1A · protein map & ClinVar variants

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

Gene2Phenotype Curations

CC2D1A-related intellectual developmental disorder

definitive
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

Intellectual developmental disorder, autosomal recessive 3

MIM #608443

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — CC2D1A
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Developmental and sex-specific expression of alpha-synuclein in blood and hippocampus of Cc2d1a mice: Implications for autism spectrum disorders.
Dana H et al.·J Psychiatr Res
2026
Interactome Analysis of the CC2D1A Scaffold Reveals Novel Neuronal Interactions and a Postsynaptic Role.
Heller AT et al.·Mol Cell Proteomics
2026
Characterization, expression, and mutational analysis of endosomal protein lethal giant disc (Lgd/CC2D1A) as a biomarker in patients with T-cell acute lymphoblastic leukemia.
Pandey S et al.·Discov Oncol
2025🔓 Open AccessCohort
Computational Analysis of CC2D1A Missense Mutations: Insight into Protein Structure and Interaction Dynamics.
Abuelrub A et al.·ACS Chem Neurosci
2025🔓 Open Access
Autism-Related Cc2d1a Heterozygous Mice: Increased Levels of miRNAs Retained in DNA/RNA Hybrid Profiles (R-Loop).
Sener EF et al.·Biomolecules
2024🔓 Open Access
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