GJA1

Chr 6ARAD

gap junction protein alpha 1

NCBI Gene: 2697 ENSG00000152661 UniProt: P17302

Structural component of the gap junction, a specialized intercellular structure consisting of a cluster of closely packed pairs of transmembrane channels, the connexons, that allow passage of small molecules and electrical signals between neighboring cells (By similarity). Forms homotypic and heterotypic channels gated by transjunctional voltage (By similarity). May play a critical role in the physiology of hearing by participating in the recycling of potassium to the cochlear endolymph (Probable). Negative regulator of bladder functional capacity: acts by enhancing intercellular electrical and chemical transmission, thus sensitizing bladder muscles to cholinergic neural stimuli and causing them to contract (By similarity). May play a role in the conductive system of ventricular myocardium and heart morphogenesis (By similarity). May play a role in cell growth inhibition through the regulation of NOV expression and localization (By similarity). Involved in intercellular innate immune signaling (PubMed:24077100, PubMed:31992625, PubMed:40010341). Mediates translocation of 2',3'-cGAMP and 2',5'-oligoadenylates (2-5A) second messengers from virus-infected cells to macrophages and uninfected neighboring cells to propagate and amplify the antiviral immune response (PubMed:24077100, PubMed:31992625, PubMed:40010341)

Primary Disease Associations & Inheritance

Craniometaphyseal dysplasia, autosomal recessiveMIM #218400

Erythrokeratodermia variabilis et progressiva 3MIM #617525

Oculodentodigital dysplasiaMIM #164200

Oculodentodigital dysplasia, autosomal recessiveMIM #257850

Palmoplantar keratoderma with congenital alopeciaMIM #104100

Syndactyly, type IIIMIM #186100

UniProtSyndactyly 3

UniProtHypoplastic left heart syndrome 1

UniProtHallermann-Streiff syndrome

393

ClinVar variants

Pathogenic / LP

0.16

pLI score

Active trials

Clinical Summary— GJA1

⚡

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

393 total variants — no pathogenic classifications of 393 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.

0.62LOEUF

pLI 0.155

Z-score 2.58

OE 0.27 (0.13–0.62)

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.

1.28Z-score

OE missense 0.75 (0.65–0.85)

150 obs / 201.0 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.0.27 (0.13–0.62)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.75 (0.65–0.85)

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.1.38

0≤1.21.6

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

ClinVar Variant Classifications

393 submitted variants in ClinVar

ClinVar

Classification Summary

Protein Context — Lollipop Plot

GJA1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

GJA1-related oculodentodigital dysplasia (biallelic)

definitive

ARLoss Of FunctionAbsent Gene Product, Altered Gene Product Structure

Dev. DisordersEyeSkinSkeletal

G2P ↗

stop gainedmissense variant

GJA1-related erythrokeratodermia variabilis et progressiva

moderate

ADUndeterminedAltered Gene Product Structure

Skin

G2P ↗

GJA1-related palmoplantar keratoderma with congenital alopecia

limited

ADUndeterminedAltered Gene Product Structure

Skin

G2P ↗

GJA1-related oculodentodigital dysplasia (monoallelic)

definitive

ADDominant NegativeAltered Gene Product Structure

Dev. DisordersEyeSkinSkeletal

G2P ↗

frameshift variantmissense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

GAP JUNCTION PROTEIN, ALPHA-1; GJA1

MIM #121014 · *

Craniometaphyseal dysplasia, autosomal recessive

MIM #218400