GJA5

Chr 1AD

gap junction protein alpha 5

ENSG00000265107 UniProt: P36382 OMIM: 121013

The protein forms connexons that create gap junction channels allowing diffusion of small molecules between adjacent cells. Mutations cause familial atrial fibrillation and atrial standstill (when combined with SCN5A mutations), representing cardiac arrhythmia disorders that primarily affect heart rhythm regulation. The gene follows autosomal dominant inheritance.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.812 OMIM phenotypes

Clinical Summary— GJA5

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Gene-Disease Validity (ClinGen)

congenital heart disease · ADDisputed

Disputed — evidence questions this relationship

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Population Constraint (gnomAD)

Low constraint (pLI 0.02) — loss-of-function variants are relatively tolerated in the population.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.81LOEUF

pLI 0.018

Z-score 2.04

OE 0.39 (0.20–0.81)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.11Z-score

OE missense 0.79 (0.69–0.89)

169 obs / 214.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.39 (0.20–0.81)

0≤0.351.4

Missense OE?0.79 (0.69–0.89)

0≤0.61.4

Synonymous OE?0.95

0≤1.21.6

LoF obs/exp: 5 / 12.9Missense obs/exp: 169 / 214.8Syn Z: 0.33

This gene — mechanism propensity

0.84top 10%

GOF

0.85top 5%

LOF

0.2287th %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.