GJA4

Chr 1

gap junction protein alpha 4

Also known as: CX37

NCBI Gene: 2701 ENSG00000187513 OMIM: 121012

The encoded protein is a connexin that forms gap junction channels, allowing diffusion of small molecules between neighboring cells. Mutations in this gene have been associated with atherosclerosis and increased risk of myocardial infarction. The gene shows tolerance to loss-of-function variants, suggesting haploinsufficiency may not be the primary disease mechanism.

OMIM ResearchSummary from RefSeq, UniProt

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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.78

Clinical Summary— GJA4

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.34) despite low pLI — interpret in context.

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ClinVar Variants

1 unique Pathogenic / Likely Pathogenic· 52 VUS of 58 total submissions

Explore recent and relevant literature in Research Assistant →

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 OE?0.34 (0.17–0.78)

0≤0.351.4

Missense OE?0.77 (0.68–0.87)

0≤0.61.4

Synonymous OE?0.89

0≤1.21.6

LoF obs/exp: 4 / 11.7Missense obs/exp: 166 / 216.3Syn Z: 0.83

This gene — mechanism propensity

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

58 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1

VUS52

Likely Benign2

Benign2

Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	1	0	1
Likely Pathogenic	0	0	0
VUS	52	0	52
Likely Benign	1	1	2
Benign	2	0	2
Total	56	1	57

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 15) ClinVar copy-number / structural variants overlap GJA4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →