GJA4

Chr 1

gap junction protein alpha 4

Also known as: CX37

NCBI Gene: 2701ENSG00000187513UniProt: P35212

This gene encodes a member of the connexin gene family. The encoded protein is a component of gap junctions, which are composed of arrays of intercellular channels that provide a route for the diffusion of low molecular weight materials from cell to cell. Mutations in this gene have been associated with atherosclerosis and a higher risk of myocardial infarction. [provided by RefSeq, Jul 2008]

0
Active trials
10
Pathogenic / LP
71
ClinVar variants
12
Pubs (1 yr)
1.2
Missense Z
0.78
LOEUF
Clinical Summary— GJA4
⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.
📋
ClinVar Variants
10 Pathogenic / Likely Pathogenic· 57 VUS of 71 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
0.78LOEUF
pLI 0.056
Z-score 2.08
OE 0.34 (0.17–0.78)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
1.21Z-score
OE missense 0.77 (0.68–0.87)
166 obs / 216.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.34 (0.17–0.78)
0≤0.351.4
Missense OE0.77 (0.68–0.87)
0≤0.61.4
Synonymous OE0.89
0≤1.21.6
LoF obs/exp: 4 / 11.7Missense obs/exp: 166 / 216.3Syn Z: 0.83
GOFDN
DN
0.82top 10%
GOF
0.87top 5%
LOF
0.1993th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median
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.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

71 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8
Likely Pathogenic2
VUS57
Likely Benign2
Benign2
8
Pathogenic
2
Likely Pathogenic
57
VUS
2
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
1
7
0
8
Likely Pathogenic
0
0
2
0
2
VUS
0
52
5
0
57
Likely Benign
0
1
0
1
2
Benign
0
2
0
0
2
Total05614171

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

View in ClinVar →

GJA4 · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients