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: 54862 ENSG00000132024 UniProt: Q6P1N0 OMIM: 610055

The protein functions as a calcium-inhibited transcriptional repressor that binds to regulatory sequences and controls expression of the serotonin receptor 1A gene in neurons. Mutations cause autosomal recessive intellectual developmental disorder (MRT3), a nonsyndromic form of cognitive disability. The pathogenic mechanism involves loss of normal transcriptional regulation of serotonergic signaling pathways.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Intellectual developmental disorder, autosomal recessive 3MIM #608443

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · complex neurodevelopmental disorder · AR · ClinGen 2020

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.42

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — CC2D1A

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

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?

0.94Z-score

OE missense 0.89 (0.83–0.96)

541 obs / 606.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.27 (0.18–0.42)

0≤0.351.4

Missense OE?0.89 (0.83–0.96)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 15 / 55.0Missense obs/exp: 541 / 606.2Syn Z: 0.21

Background carrier burden — how many people carry a rare variant somewhere in CC2D1A?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 32

1,281 rare PASS variants

Rare truncating (LoF)

1 in 360

166 rare PASS variants

Rare synonymous (reference)

1 in 76

525 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for CC2D1A. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 43	1 in 500
South Asian	~43k	1 in 28	1 in 490
Remaining (unassigned)	~30k	1 in 23	1 in 260
European (Finnish)	~27k	1 in 120	1 in 2,800
Admixed American	~22k	1 in 30	1 in 660
African / African American	~21k	1 in 30	1 in 930
East Asian	~20k	1 in 35	1 in 650
Ashkenazi Jewish	~13k	1 in 160	≈ 1 in 5,600
Middle Eastern	~2,884	1 in 25	1 in 410

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 28 of 29 coding exons well covered in gnomAD exomes; exon 1 marginal. Genomes: 27 of 29 (exons 25, 26 below).? see exons ↓