CTNNA2

Chr 2AR

catenin alpha 2

Also known as: CAP-R, CAPR, CDCBM9, CT114, CTNR

NCBI Gene: 1496 ENSG00000066032 UniProt: P26232 OMIM: 114025

The protein functions as a linker between cadherin adhesion receptors and the cytoskeleton, regulating cortical neuronal migration and neurite growth by suppressing excessive actin branching. Mutations cause autosomal recessive cortical dysplasia with other brain malformations, affecting brain development during early life. The gene is highly constrained against loss-of-function variants, indicating its critical importance for normal neurological function.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Enables actin filament binding activity. Involved in negative regulation of Arp2/3 complex-mediated actin nucleation; regulation of neuron migration; and regulation of neuron projection development. Located in cytoplasm. Implicated in complex cortical dysplasia with other brain malformations. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.381 OMIM phenotype

Clinical Summary— CTNNA2

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.22) despite low pLI — interpret in context.

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ClinVar Variants

10 unique Pathogenic / Likely Pathogenic· 132 VUS of 229 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Missense constrained — critical functional residues

LoF Constraint?

0.38LOEUF

pLI 0.425

Z-score 4.82

OE 0.22 (0.14–0.38)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

3.63Z-score

OE missense 0.56 (0.51–0.62)

306 obs / 544.3 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.22 (0.14–0.38)

0≤0.351.4

Missense OE?0.56 (0.51–0.62)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 10 / 44.8Missense obs/exp: 306 / 544.3Syn Z: -0.22

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongCTNNA2-related disordered cortical neuronal migrationLOFAR

This gene — mechanism propensity

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

0.7132th %ile

GOF

0.6931th %ile

LOF

0.3842th %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

229 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6

Likely Pathogenic4

VUS132

Likely Benign31

Benign41

Pathogenic

Likely Pathogenic

132

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	5	0	1	0	6
Likely Pathogenic	4	0	0	0	4
VUS	3	127	1	1	132
Likely Benign	0	3	5	23	31
Benign	0	2	33	6	41
Total	12	132	40	30	214

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 38) ClinVar copy-number / structural variants overlap CTNNA2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →