GJA1

Chr 6ARAD

gap junction protein alpha 1

Also known as: AVSD3, CMDR, CX43, EKVP, EKVP3, GJAL, HLHS1, HSS

NCBI Gene: 2697 ENSG00000152661 UniProt: P17302 OMIM: 121014

The encoded protein forms connexin 43, the major gap junction protein that creates intercellular channels allowing diffusion of small molecules between cells, particularly important for synchronized cardiac contraction and embryonic development. Mutations cause oculodentodigital dysplasia, craniometaphyseal dysplasia, erythrokeratodermia variabilis et progressiva, and syndactyly through both autosomal dominant and autosomal recessive inheritance patterns. Disease can result from multiple mechanisms including gain-of-function effects from specific mutations that disrupt normal gap junction function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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. The encoded protein is the major protein of gap junctions in the heart that are thought to have a crucial role in the synchronized contraction of the heart and in embryonic development. A related intronless pseudogene has been mapped to chromosome 5. Mutations in this gene have been associated with oculodentodigital dysplasia, autosomal recessive craniometaphyseal dysplasia and heart malformations. [provided by RefSeq, May 2014]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAR/ADLOEUF 0.626 OMIM phenotypes

Clinical Summary— GJA1

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Gene-Disease Validity (ClinGen)

congenital heart disease · UDLimited

Limited evidence — not for standalone diagnostic reporting

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.27) despite low pLI — interpret in context.

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ClinVar Variants

60 unique Pathogenic / Likely Pathogenic· 207 VUS of 370 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GJA1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.62LOEUF

pLI 0.155

Z-score 2.58

OE 0.27 (0.13–0.62)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.28Z-score

OE missense 0.75 (0.65–0.85)

150 obs / 201.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.27 (0.13–0.62)

0≤0.351.4

Missense OE?0.75 (0.65–0.85)

0≤0.61.4

Synonymous OE?1.38

0≤1.21.6

LoF obs/exp: 4 / 14.7Missense obs/exp: 150 / 201.0Syn Z: -2.65

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveGJA1-related oculodentodigital dysplasia (biallelic)LOFAR

moderateGJA1-related erythrokeratodermia variabilis et progressivaOTHERAD

limitedGJA1-related palmoplantar keratoderma with congenital alopeciaOTHERAD

definitiveGJA1-related oculodentodigital dysplasia (monoallelic)DNAD

This gene — mechanism propensity

0.77top 25%

GOF

0.82top 10%

LOF

0.3259th %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 · 1 literature citation · 90% of P/LP are missense

DNprediction above median · 1 literature citation

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

DNThe substitution of histidine with proline is predicted to dramatically alter the correct folding of the protein, preventing the formation of the entire connexon in a dominant negative manner.1

GOFPatch-clamp studies in transfected HEK293 cells demonstrated a gain-of-function effect with G8V hemichannels.2

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

References

ClinVar Variant Classifications

370 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic31

Likely Pathogenic29

VUS207

Likely Benign76

Benign7

Conflicting20

Pathogenic

Likely Pathogenic

207

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	4	27	0	0	31
Likely Pathogenic	2	27	0	0	29
VUS	10	161	32	4	207
Likely Benign	0	1	1	74	76
Benign	0	0	6	1	7
Conflicting	—				20
Total	16	216	39	79	370

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

View in ClinVar →

20 pathogenic / likely-pathogenic (of 26) ClinVar copy-number / structural variants overlap GJA1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →