GJB2

Chr 13

gap junction protein beta 2

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

NCBI Gene: 2706 ENSG00000165474 UniProt: P29033

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 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 ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

UniProtDeafness, autosomal recessive, 1A

UniProtDeafness, autosomal dominant, 3A

UniProtVohwinkel syndrome

UniProtKeratoderma, palmoplantar, with deafness

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

213

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.98

LOEUF

LOF*

Mechanism· G2P

📖

GeneReview available — GJB2

Authoritative clinical overview · Recommended first read

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Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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

Background carrier burden — how many people carry a rare variant somewhere in GJB2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 86

303 rare PASS variants

Rare truncating (LoF)

1 in 190

90 rare PASS variants

Rare synonymous (reference)

1 in 440

131 rare PASS variants

Rare missense and truncating variants are carried at similar rates in GJB2; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 75	1 in 290
South Asian	~43k	1 in 81	1 in 260
Remaining (unassigned)	~30k	1 in 70	1 in 290
European (Finnish)	~27k	1 in 240	1 in 5,300
Admixed American	~22k	1 in 53	1 in 190
African / African American	~21k	1 in 58	1 in 430
East Asian	~20k	1 in 71	1 in 170
Ashkenazi Jewish	~13k	1 in 200	none seen
Middle Eastern	~2,884	1 in 83	1 in 400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.