GJB4

Chr 1AD

gap junction protein beta 4

Also known as: CX30.3, EKV, EKVP2

NCBI Gene: 127534ENSG00000189433UniProt: Q9NTQ9

This gene encodes a transmembrane connexin protein that is a component of gap junctions. Mutations in this gene have been associated with erythrokeratodermia variabilis, progressive symmetric erythrokeratoderma and hearing impairment. [provided by RefSeq, Dec 2009]

Primary Disease Associations & Inheritance

Erythrokeratodermia variabilis et progressiva 2MIM #617524
AD
143
ClinVar variants
14
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— GJB4
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
14 Pathogenic / Likely Pathogenic· 82 VUS of 143 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.
1.74LOEUF
pLI 0.001
Z-score 0.20
OE 0.91 (0.47–1.74)
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.
-0.64Z-score
OE missense 1.14 (1.01–1.28)
193 obs / 169.7 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.0.91 (0.47–1.74)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.14 (1.01–1.28)
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.1.23
0≤1.21.6
LoF obs/exp: 5 / 5.5Missense obs/exp: 193 / 169.7Syn Z: -1.57

ClinVar Variant Classifications

143 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11
Likely Pathogenic3
VUS82
Likely Benign18
Benign22
Conflicting7
11
Pathogenic
3
Likely Pathogenic
82
VUS
18
Likely Benign
22
Benign
7
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
4
7
0
11
Likely Pathogenic
0
1
2
0
3
VUS
1
74
7
0
82
Likely Benign
1
4
1
12
18
Benign
1
8
3
10
22
Conflicting
—7
Total3912022143

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

View in ClinVar →

Protein Context — Lollipop Plot

GJB4 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Erythrokeratodermia variabilis et progressiva 2

MIM #617524

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
GJB4 and GJC3 variants in non-syndromic hearing impairment in Ghana.
Adadey SM et al.·Exp Biol Med (Maywood)
2020
Clinical variability of the GJB4:c.35G > A gene variant: a study of a large Brazilian erythrokeratodermia pedigree.
de Oliveira RTG et al.·Int J Dermatol
2020Case report
Erythrokeratodermia variabilis: report of two cases and a novel missense variant in GJB4 encoding connexin 30.3.
Kokotas H et al.·Eur J Dermatol
2012Case report
Genetic heterogeneity in erythrokeratodermia variabilis: novel mutations in the connexin gene GJB4 (Cx30.3) and genotype-phenotype correlations.
Richard G et al.·J Invest Dermatol
2003
Erythrokeratodermia variabilis et progressiva due to a novel mutation in GJB4.
Zhang X et al.·Exp Dermatol
2022Case report
Evidence for the absence of mutations at GJB3, GJB4 and LOR in progressive symmetrical erythrokeratodermia.
Wei S et al.·Clin Exp Dermatol
2011Case report
Further delineation of the hypotrichosis-deafness syndrome.
Van Steensel MA et al.·Eur J Dermatol
2005Case report
Skin disease-associated GJB4 variants differentially influence connexin stability, cell viability and channel function.
Lucaciu SA et al.·J Physiol
2025
Clinical and genetic heterogeneity of erythrokeratoderma variabilis.
Common JE et al.·J Invest Dermatol
2005
Digenic inheritance in autosomal recessive non-syndromic hearing loss cases carrying GJB2 heterozygote mutations: assessment of GJB4, GJA1, and GJC3.
Kooshavar D et al.·Int J Pediatr Otorhinolaryngol
2013Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools