GJB3

Chr 1ADARDigenic dominant

gap junction protein beta 3

Also known as: CX31, DFNA2, DFNA2B, EKV, EKVP1

NCBI Gene: 2707ENSG00000188910UniProt: O75712

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. Mutations in this gene can cause non-syndromic deafness or erythrokeratodermia variabilis, a skin disorder. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Deafness, autosomal dominant 2B, with or without peripheral neuropathyMIM #612644
AD
Deafness, digenic, GJB2/GJB3MIM #220290
ARDigenic dominant
Erythrokeratodermia variabilis et progressiva 1MIM #133200
ADAR
254
ClinVar variants
20
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— GJB3
🧬
Gene-Disease Validity (ClinGen)
nonsyndromic genetic hearing loss · ADDisputed

Disputed — evidence questions this relationship

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
20 Pathogenic / Likely Pathogenic· 153 VUS of 254 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

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.
1.32LOEUF
pLI 0.002
Z-score 0.96
OE 0.63 (0.33–1.32)
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.
-0.53Z-score
OE missense 1.11 (0.99–1.26)
187 obs / 167.8 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.0.63 (0.33–1.32)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.11 (0.99–1.26)
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.0.87
0≤1.21.6
LoF obs/exp: 5 / 7.9Missense obs/exp: 187 / 167.8Syn Z: 0.89

ClinVar Variant Classifications

254 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic13
Likely Pathogenic7
VUS153
Likely Benign38
Benign19
Conflicting24
13
Pathogenic
7
Likely Pathogenic
153
VUS
38
Likely Benign
19
Benign
24
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
5
8
0
13
Likely Pathogenic
0
5
2
0
7
VUS
7
106
38
2
153
Likely Benign
0
3
2
33
38
Benign
0
2
13
4
19
Conflicting
—24
Total71216339254

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

View in ClinVar →

Protein Context — Lollipop Plot

GJB3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

GJB3-related erythrokeratodermia variabilis et progressiva

strong
ADUndeterminedAltered Gene Product Structure
Dev. DisordersSkin
G2P ↗
missense variantinframe deletioninframe insertion

GJB3-related deafness (biallelic)

moderate
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersSkin
G2P ↗

GJB3-related deafness (monoallelic)

moderate
ADLoss Of FunctionAbsent Gene Product
Dev. DisordersSkin
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Deafness, autosomal dominant 2B, with or without peripheral neuropathy

MIM #612644

Molecular basis of disorder known

Autosomal dominant

Deafness, digenic, GJB2/GJB3

MIM #220290

Molecular basis of disorder known

Autosomal recessiveDigenic dominant

Erythrokeratodermia variabilis et progressiva 1

MIM #133200

Molecular basis of disorder known

Autosomal dominantAutosomal recessive
📖
GeneReview available — GJB3
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
The relationship between the GJB3 c.538C>T variant and hearing phenotype in the Chinese population.
Huang S et al.·Int J Pediatr Otorhinolaryngol
2017
Development of a reliable risk prognostic model for lung adenocarcinoma based on the genes related to endotheliocyte senescence.
Li H et al.·Sci Rep
2025Functional
Absence of GJB3 and GJB6 mutations in Moroccan familial and sporadic patients with autosomal recessive non-syndromic deafness.
Nahili H et al.·Int J Pediatr Otorhinolaryngol
2008Cohort
GJB3/GJB6 screening in GJB2 carriers with idiopathic hearing loss: Is it necessary?
Chen K et al.·J Clin Lab Anal
2018
A nicotinamide metabolism-related gene signature for predicting immunotherapy response and prognosis in lung adenocarcinoma patients.
Wang M et al.·PeerJ
2025Cohort
Further delineation of the hypotrichosis-deafness syndrome.
Van Steensel MA et al.·Eur J Dermatol
2005Case report
Genotypes and phenotypes of a family with a deaf child carrying combined heterozygous mutations in SLC26A4 and GJB3 genes.
Li Y et al.·Mol Med Rep
2016
Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis.
Richard G et al.·Nat Genet
1998
Deafness gene mutations in newborns in Beijing.
Han S et al.·Acta Otolaryngol
2016
Evaluation of the pathogenicity of GJB3 and GJB6 variants associated with nonsyndromic hearing loss.
Oh SK et al.·Biochim Biophys Acta
2013
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Cholesterol metabolism in LUAD progression: GJB3 as a key target for cell‑based therapeutic interventions.
Yan Q et al.·Mol Med Rep
2025🔓 Open Access
The GJB3 correlates with the prognosis, immune cell infiltration, and therapeutic responses in lung adenocarcinoma.
Dou R et al.·Open Med (Wars)
2024🔓 Open Access
Impairment of α-tubulin and F-actin interactions of GJB3 induces aneuploidy in urothelial cells and promotes bladder cancer cell invasion.
Liu J et al.·Cell Mol Biol Lett
2024🔓 Open Access
GJB3: a comprehensive biomarker in pan-cancer prognosis and immunotherapy prediction.
Zeng J et al.·Aging (Albany NY)
2024🔓 Open Access
An ion channel-based prognostic model identified TRPV2 and GJB3 as immunotherapy determinants in pancreatic cancer.
Mao J et al.·Heliyon
2024🔓 Open AccessFunctional
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)

External Resources

Links to major genomics databases and tools