GJB2

Chr 13ADARDigenic dominant

gap junction protein beta 2

Also known as: BAPS, CX26, DFNA3, DFNA3A, DFNB1, DFNB1A, HID, KID

NCBI Gene: 2706 ENSG00000165474 UniProt: P29033 OMIM: 121011

Connexin 26 forms gap junction channels that allow small molecules and ions to pass between adjacent cells. Mutations cause hearing loss ranging from isolated deafness (both autosomal recessive and dominant forms) to syndromic conditions involving skin abnormalities such as keratoderma and ichthyosis. This gene has very low constraint against loss-of-function variants and shows both autosomal recessive and dominant inheritance patterns depending on the specific variant.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the gap junction protein family (gap junction beta 2) but is more commonly known as connexin 26. The gap junctions were first characterized by electron microscopy as regionally specialized structures on plasma membranes of contacting adherent cells. These structures were shown to consist of cell-to-cell channels that facilitate the transfer of ions and small molecules between cells. Connexins form hexameric channels in the plasma membrane which regulate passage of ions and small molecules between the cell and its environment or, when joined with another cell, form a dodecameric intercellular gap junction channel. The connexin proteins are grouped into alpha, beta, and gamma subfamilies. Mutations in this gene are responsible for as much as 50% of pre-lingual, recessive deafness. [provided by RefSeq, Mar 2026]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAD/AR/Digenic dominantLOEUF 1.987 OMIM phenotypes

Clinical Summary— GJB2

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Gene-Disease Validity (ClinGen)

nonsyndromic genetic hearing loss · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

262 unique Pathogenic / Likely Pathogenic· 188 VUS of 668 total submissions

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Clinical Trials

4 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GJB2

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?

1.98LOEUF

pLI 0.000

Z-score -3.82

OE 2.62 (1.39–1.98)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.72Z-score

OE missense 1.17 (1.03–1.34)

161 obs / 137.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?2.62 (1.39–1.98)

0≤0.351.4

Missense OE?1.17 (1.03–1.34)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 17 / 6.5Missense obs/exp: 161 / 137.2Syn Z: -0.29

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveGJB2-related ichthyosis hystrix-like with deafness syndromeOTHERAD

definitiveGJB2-related deafnessLOFAR

definitiveGJB2-related keratoderma, palmoplantar, with deafnessOTHERAD

moderateGJB2-related keratitis-ichthyosis-deafness syndromeOTHERAD

definitiveGJB2-related knuckle pads, leuconychia and sensorineural deafnessOTHERAD

definitiveGJB2-related Vohwinkel syndromeOTHERAD

This gene — mechanism propensity

0.7131th %ile

GOF

0.76top 25%

LOF

0.3261th %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

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

DNTransgenic expression of a dominant-negative connexin26 causes degeneration of the organ of Corti and non-syndromic deafness1

GOFNumerous autosomal dominant mutations in the Cx26-encoding GJB2 gene lead to many skin disorders and sensorineural hearing loss.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

ClinVar Variant Classifications

668 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic114

Likely Pathogenic148

VUS188

Likely Benign139

Benign16

Conflicting59

114

Pathogenic

148

Likely Pathogenic

188

VUS

139

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	56	49	9	0	114
Likely Pathogenic	41	103	4	0	148
VUS	3	138	44	3	188
Likely Benign	0	8	13	118	139
Benign	0	2	14	0	16
Conflicting	—				59
Total	100	300	84	121	664

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

View in ClinVar →

47 pathogenic / likely-pathogenic (of 65) ClinVar copy-number / structural variants overlap GJB2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →