CTNNA1

Chr 5AD

catenin alpha 1

Also known as: CAP102, MDBS2, MDPT2

NCBI Gene: 1495 ENSG00000044115 UniProt: P35221

This gene encodes a member of the catenin family of proteins that play an important role in cell adhesion process by connecting cadherins located on the plasma membrane to the actin filaments inside the cell. The encoded mechanosensing protein contains three vinculin homology domains and undergoes conformational changes in response to cytoskeletal tension, resulting in the reconfiguration of cadherin-actin filament connections. Certain mutations in this gene cause butterfly-shaped pigment dystrophy. [provided by RefSeq, May 2016]

Primary Disease Associations & Inheritance

Macular dystrophy, patterned, 2MIM #608970

Active trials

Pathogenic / LP

ClinVar variants

Pubs (1 yr)

3.7

Missense Z· constrained

0.31

LOEUF· LoF intolerant

Clinical Summary— CTNNA1

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Gene-Disease Validity (ClinGen)

CTNNA1-related diffuse gastric and lobular breast cancer syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.97). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.31LOEUF

pLI 0.970

Z-score 5.20

OE 0.17 (0.10–0.31)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint

3.66Z-score

OE missense 0.55 (0.50–0.61)

294 obs / 531.6 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.17 (0.10–0.31)

0≤0.351.4

Missense OE0.55 (0.50–0.61)

0≤0.61.4

Synonymous OE0.99

0≤1.21.6

LoF obs/exp: 8 / 46.1Missense obs/exp: 294 / 531.6Syn Z: 0.11

LOFDN

Badonyi & Marsh 2024 ↗

0.6161th %ile

GOF

0.6151th %ile

LOF

0.53top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF1 literature citation · LOEUF 0.31

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

LOFClark et al. (2020) De-identified data from 151,425 individuals who underwent CTNNA1 testing at a commercial laboratory between October 2015 and July 2019 were reviewed. Fifty-two individuals (0.03% tested) had CTNNA1 loss-of-function (LOF) variants and 1057 individuals (0.7% tested) had a total of PMID:32051609

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.