GJB6

Chr 13ADARDigenic dominant

gap junction protein beta 6

Also known as: CX30, DFNA3, DFNA3B, DFNB1B, ECTD2, ED2, EDH, HED

NCBI Gene: 10804ENSG00000121742UniProt: O95452

Gap junctions allow the transport of ions and metabolites between the cytoplasm of adjacent cells. They are formed by two hemichannels, made up of six connexin proteins assembled in groups. Each connexin protein has four transmembrane segments, two extracellular loops, a cytoplasmic loop formed between the two inner transmembrane segments, and the N- and C-terminus both being in the cytoplasm. The specificity of the gap junction is determined by which connexin proteins comprise the hemichannel. In the past, connexin protein names were based on their molecular weight, however the new nomenclature uses sequential numbers based on which form (alpha or beta) of the gap junction is present. This gene encodes one of the connexin proteins. Mutations in this gene have been found in some forms of deafness and in some families with hidrotic ectodermal dysplasia. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Deafness, autosomal dominant 3BMIM #612643
AD
Deafness, autosomal recessive 1BMIM #612645
AR
Deafness, digenic GJB2/GJB6MIM #220290
ARDigenic dominant
Ectodermal dysplasia 2, Clouston typeMIM #129500
AD
322
ClinVar variants
67
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— GJB6
🧬
Gene-Disease Validity (ClinGen)
nonsyndromic genetic hearing loss · ARRefuted

Refuted — evidence has disproved 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
67 Pathogenic / Likely Pathogenic· 152 VUS of 322 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 0.000
Z-score -0.21
OE 1.07 (0.66–1.74)
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.
0.45Z-score
OE missense 0.90 (0.78–1.03)
134 obs / 149.6 exp
Tolerant

Mild missense constraint

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.1.07 (0.66–1.74)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.90 (0.78–1.03)
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.1.08
0≤1.21.6
LoF obs/exp: 10 / 9.3Missense obs/exp: 134 / 149.6Syn Z: -0.49

ClinVar Variant Classifications

322 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic61
Likely Pathogenic6
VUS152
Likely Benign56
Benign32
Conflicting15
61
Pathogenic
6
Likely Pathogenic
152
VUS
56
Likely Benign
32
Benign
15
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
5
55
0
61
Likely Pathogenic
2
2
2
0
6
VUS
9
81
57
5
152
Likely Benign
0
6
25
25
56
Benign
0
0
32
0
32
Conflicting
—15
Total129417130322

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

View in ClinVar →

Protein Context — Lollipop Plot

GJB6 · protein map & ClinVar variants

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

Gene2Phenotype Curations

GJB6-related deafness

limited
ARLoss Of FunctionAbsent Gene Product
Skin
G2P ↗

GJB6-related ectodermal dysplasia, Clouston type

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

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Deafness, autosomal dominant 3B

MIM #612643

Molecular basis of disorder known

Autosomal dominant

Deafness, autosomal recessive 1B

MIM #612645

Molecular basis of disorder known

Autosomal recessive

Deafness, digenic GJB2/GJB6

MIM #220290

Molecular basis of disorder known

Autosomal recessiveDigenic dominant

Ectodermal dysplasia 2, Clouston type

MIM #129500

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — GJB6
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Global Distribution of Founder Variants Associated with Non-Syndromic Hearing Impairment.
Aboagye ET et al.·Genes (Basel)
2023Review
GJB2 and GJB6 Genetic Variant Curation in an Argentinean Non-Syndromic Hearing-Impaired Cohort.
Buonfiglio P et al.·Genes (Basel)
2020Cohort
A novel variant in the GJB6 gene in a large Chinese family with a unique phenotype of Clouston syndrome.
Huang H et al.·Front Med
2023Case report
Hearing Impairment Overview in Africa: the Case of Cameroon.
Wonkam Tingang E et al.·Genes (Basel)
2020Review
Recent insights into gap junction biogenesis in the cochlea.
Defourny J et al.·Dev Dyn
2023Review
Frequency of GJB2 mutations, GJB6-D13S1830 and GJB6-D13S1854 deletions among patients with non-syndromic hearing loss from the central region of Iran.
Naddafnia H et al.·Mol Genet Genomic Med
2019Cohort
GJB2 and GJB6 mutations: genotypic and phenotypic correlations in a large cohort of hearing-impaired patients.
Marlin S et al.·Arch Otolaryngol Head Neck Surg
2005Cohort
Analyses of del(GJB6-D13S1830) and del(GJB6-D13S1834) deletions in a large cohort with hearing loss: Caveats to interpretation of molecular test results in multiplex families.
Pandya A et al.·Mol Genet Genomic Med
2020Cohort
Connexins and gap junctions in the inner ear--it's not just about K⁺ recycling.
Jagger DJ et al.·Cell Tissue Res
2015Review
Two molecular assays for the rapid and inexpensive detection of GJB2 and GJB6 mutations.
Cascella R et al.·Electrophoresis
2016
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
GJB6 missense variant in a Labrador Retriever with paw pad hyperkeratosis.
Rietmann SJ et al.·Anim Genet
2026🔓 Open Access
Connexin 30 (GJB6) deletion as a cause of a false positive sweat test result.
Rossell A et al.·Eur J Pediatr
2025🔓 Open Access
A new syndromic case of hearing loss and ectodermal anomalies associated with a recurrent missense variation in GJB6 gene.
Elmakhzen B et al.·Mol Genet Genomic Med
2025🔓 Open Access
A murine model for the del(GJB6-D13S1830) deletion recapitulating the phenotype of human DFNB1 hearing impairment: generation and functional and histopathological study.
Domínguez-Ruiz M et al.·BMC Genomics
2024🔓 Open AccessFunctional
Audiological Phenotypes of Connexin Gene Mutation Patterns: A Glance at Different GJB2/GJB6 Gene Mutation Profiles.
Franz L et al.·Children (Basel)
2024🔓 Open Access
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