GJA5

Chr 1AD

gap junction protein alpha 5

Also known as: ATFB11, CX40

NCBI Gene: 2702ENSG00000265107UniProt: P36382

This gene is 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 may be associated with atrial fibrillation. Alternatively spliced transcript variants encoding the same isoform have been described. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Atrial fibrillation, familial, 11MIM #614049
AD
Atrial standstill, digenic (GJA5/SCN5A)MIM #108770
AD
UniProtAtrial standstill 1
656
ClinVar variants
293
Pathogenic / LP
0.02
pLI score
0
Active trials
Clinical Summary— GJA5
🧬
Gene-Disease Validity (ClinGen)
congenital heart disease · ADDisputed

Disputed — evidence questions this relationship

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.02) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
293 Pathogenic / Likely Pathogenic· 251 VUS of 656 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.81LOEUF
pLI 0.018
Z-score 2.04
OE 0.39 (0.20–0.81)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
1.11Z-score
OE missense 0.79 (0.69–0.89)
169 obs / 214.8 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.39 (0.20–0.81)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.79 (0.69–0.89)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.95
0≤1.21.6
LoF obs/exp: 5 / 12.9Missense obs/exp: 169 / 214.8Syn Z: 0.33

ClinVar Variant Classifications

656 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic255
Likely Pathogenic38
VUS251
Likely Benign96
Benign6
Conflicting10
255
Pathogenic
38
Likely Pathogenic
251
VUS
96
Likely Benign
6
Benign
10
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
5
249
0
255
Likely Pathogenic
0
0
38
0
38
VUS
15
184
51
1
251
Likely Benign
0
0
4
92
96
Benign
0
0
5
1
6
Conflicting
—10
Total1618934794656

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

View in ClinVar →

Protein Context — Lollipop Plot

GJA5 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Atrial fibrillation, familial, 11

MIM #614049

Molecular basis of disorder known

Autosomal dominant

Atrial standstill, digenic (GJA5/SCN5A)

MIM #108770

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — GJA5
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Cardiac Pressure Overload Decreases ETV1 Expression in the Left Atrium, Contributing to Atrial Electrical and Structural Remodeling.
Yamaguchi N et al.·Circulation
2021Functional
Phenotype-specific effect of chromosome 1q21.1 rearrangements and GJA5 duplications in 2436 congenital heart disease patients and 6760 controls.
Soemedi R et al.·Hum Mol Genet
2012Cohort
Prevalence and spectrum of GJA5 mutations associated with lone atrial fibrillation.
Shi HF et al.·Mol Med Rep
2013
Single-Cell RNA Sequencing Reveals the Association Between a Novel GJA5 Variant and Trifascicular Block.
Tang J et al.·JACC Clin Electrophysiol
2022
Rare variants in GJA5 are associated with early-onset lone atrial fibrillation.
Christophersen IE et al.·Can J Cardiol
2013
Somatic mutations in the connexin 40 gene (GJA5) in atrial fibrillation.
Gollob MH et al.·N Engl J Med
2006
A variant in the carboxyl-terminus of connexin 40 alters GAP junctions and increases risk for tetralogy of Fallot.
Guida V et al.·Eur J Hum Genet
2013
Proteomic analysis of human fetal atria and ventricle.
Lu ZQ et al.·J Proteome Res
2014
Transcription factor ETV1 is essential for rapid conduction in the heart.
Shekhar A et al.·J Clin Invest
2016
[Analysis of clinical characteristics and molecular genetics in eighteen patients with 1q21.1 microdeletion syndrome].
Luo X et al.·Zhonghua Yi Xue Yi Chuan Xue Za Zhi
2024Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools