GJB2

Chr 13

gap junction protein beta 2

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

NCBI Gene: 2706ENSG00000165474UniProt: P29033

This gene encodes a member of the gap junction protein family. 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. The gap junction proteins, also known as connexins, purified from fractions of enriched gap junctions from different tissues differ. According to sequence similarities at the nucleotide and amino acid levels, the gap junction proteins are divided into two categories, alpha and beta. Mutations in this gene are responsible for as much as 50% of pre-lingual, recessive deafness. [provided by RefSeq, Oct 2008]

Primary Disease Associations & Inheritance

UniProtDeafness, autosomal recessive, 1A
UniProtDeafness, autosomal dominant, 3A
UniProtVohwinkel syndrome
UniProtKeratoderma, palmoplantar, with deafness
718
ClinVar variants
131
Pathogenic / LP
0.00
pLI score
3
Active trials
Clinical Summary— GJB2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
131 Pathogenic / Likely Pathogenic· 131 VUS of 718 total submissions
💊
Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (2)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

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?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.
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?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.
-0.72Z-score
OE missense 1.17 (1.03–1.34)
161 obs / 137.2 exp
Tolerant

Tolerant to missense variation

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.2.62 (1.39–1.98)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.17 (1.03–1.34)
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.1.05
0≤1.21.6
LoF obs/exp: 17 / 6.5Missense obs/exp: 161 / 137.2Syn Z: -0.29

ClinVar Variant Classifications

718 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic64
Likely Pathogenic67
VUS131
Likely Benign113
Benign5
Conflicting18
64
Pathogenic
67
Likely Pathogenic
131
VUS
113
Likely Benign
5
Benign
18
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
22
13
29
0
64
Likely Pathogenic
7
52
8
0
67
VUS
2
86
42
1
131
Likely Benign
0
0
5
108
113
Benign
0
0
5
0
5
Conflicting
—18
Total3115189109398

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

View in ClinVar →

Protein Context — Lollipop Plot

GJB2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

GJB2-related ichthyosis hystrix-like with deafness syndrome

definitive
ADUndeterminedAltered Gene Product Structure
SkinEar
G2P ↗
missense variantinframe deletioninframe insertion

GJB2-related deafness

definitive
ARLoss Of FunctionAbsent Gene Product
SkinEar
G2P ↗

GJB2-related keratoderma, palmoplantar, with deafness

definitive
ADUndeterminedAltered Gene Product Structure
Skin
G2P ↗
missense variantinframe deletioninframe insertion

GJB2-related keratitis-ichthyosis-deafness syndrome

moderate
ADUndeterminedAltered Gene Product Structure
Skin
G2P ↗

GJB2-related knuckle pads, leuconychia and sensorineural deafness

definitive
ADUndeterminedAltered Gene Product Structure
Skin
G2P ↗
missense variantinframe deletioninframe insertion

GJB2-related Vohwinkel syndrome

definitive
ADUndeterminedAltered Gene Product Structure
Skin
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The germline mutational landscape of genitourinary cancers and its indication for prognosis and risk.
Yang Y et al.·BMC Urol
2022
Consensus interpretation of the p.Met34Thr and p.Val37Ile variants in GJB2 by the ClinGen Hearing Loss Expert Panel.
Shen J et al.·Genet Med
2019
Combined AAV-mediated specific Gjb2 expression restores hearing in DFNB1 mouse models.
Sun Q et al.·Mol Ther
2025Functional
Molecular diagnose of a large hearing loss population from China by targeted genome sequencing.
Wu J et al.·J Hum Genet
2022
Comprehensive interpretation of single-nucleotide substitutions in GJB2 reveals the genetic and phenotypic landscape of GJB2-related hearing loss.
Xiang J et al.·Hum Genet
2023
GJB2 as a novel prognostic biomarker associated with immune infiltration and cuproptosis in ovarian cancer.
Lei H et al.·Apoptosis
2025
AAV-mediated base editing restores cochlear gap junction in GJB2 dominant-negative mutation-associated syndromic hearing loss model.
Ukaji T et al.·JCI Insight
2025Functional
The pathogenesis of common Gjb2 mutations associated with human hereditary deafness in mice.
Li Q et al.·Cell Mol Life Sci
2023
Genomics and hearing impairment.
Keats BJ et al.·Genome Res
1999Review
Systematic review and meta-analysis of pathogenic GJB2 variants in the Asian population.
Ozgur Z et al.·Int J Pediatr Otorhinolaryngol
2025Meta-analysis
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Natural history and phenotype-genotype correlations in GJB2-related hearing loss: a systematic and comprehensive review.
Chen L et al.·J Genet Genomics
2026Review
A porcine congenital deafness model with unconditional knockout of GJB2 generated by CRISPR/Cas9 genomic editing.
Xie 谢飞 F et al.·Hear Res
2026Functional
Genetic screening for hearing impairment and the genotype-phenotype correlation of GJB2 c.109G>A variants in 47,729 neonates: a population-based study in southern China.
Li J et al.·Int J Pediatr Otorhinolaryngol
2026
Integrative analysis of EMT-driving genes identifies a prognostic signature and GJB2 as a potential biomarker in glioblastoma.
Liu XF et al.·Front Cell Dev Biol
2025🔓 Open Access
GJB2-Related Hearing Loss: Genotype-Phenotype Correlations, Natural History, and Emerging Therapeutic Strategies.
Morris JA et al.·Int J Mol Sci
2026🔓 Open AccessNatural history
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Hearing Loss

Cohort Of DEafness-gene Screening

ACTIVE NOT RECRUITING
NCT06133946Affiliated Hospital of Nantong UniversityStarted 2016-01-01
Genetic screening test (Deafness gene variant detection array kit)
Sensorineural Hearing Loss, Bilateral

Cross-sectional and Prospective Study to Characterize Early-onset Presbycusis

RECRUITING
NCT06354010SensorionStarted 2024-06-14
GenotypingAudiological assessments
Sensorineural Hearing Loss, BilateralAUNB1DFNB1A

Natural History in Children Up to 16 Years with Mild to Profound Hearing Loss Due to Mutations in GJB2 / OTOF Genes

RECRUITING
NCT05402813SensorionStarted 2022-11-18
Pure Tone Audiometry AssessmentQuality of Life Questionnaires

External Resources

Links to major genomics databases and tools