GJB6

Chr 13ADARDigenic dominant

gap junction protein beta 6

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

NCBI Gene: 10804 ENSG00000121742 UniProt: O95452 OMIM: 604418

GJB6 encodes connexin-30, a gap junction protein that forms transmembrane channels allowing small molecules and ions to pass between adjacent cells. Mutations cause autosomal recessive or dominant nonsyndromic hearing loss and hidrotic ectodermal dysplasia, a condition affecting hair, nails, teeth, and sweat glands. This gene is not highly constrained against loss-of-function variants.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismAD/AR/Digenic dominantLOEUF 1.744 OMIM phenotypes

Clinical Summary— GJB6

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Gene-Disease Validity (ClinGen)

nonsyndromic genetic hearing loss · ARRefuted

Refuted — evidence has disproved this relationship

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

15 unique Pathogenic / Likely Pathogenic· 121 VUS of 238 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GJB6

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

0.45Z-score

OE missense 0.90 (0.78–1.03)

134 obs / 149.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.07 (0.66–1.74)

0≤0.351.4

Missense OE?0.90 (0.78–1.03)

0≤0.61.4

Synonymous OE?1.08

0≤1.21.6

LoF obs/exp: 10 / 9.3Missense obs/exp: 134 / 149.6Syn Z: -0.49

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

limitedGJB6-related deafnessLOFAR

definitiveGJB6-related ectodermal dysplasia, Clouston typeOTHERAD

This gene — mechanism propensity

0.80top 10%

GOF

0.86top 5%

LOF

0.2288th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median · 1 literature citation

DNprediction above median · 1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNT5MCX30 suppressed the wild-type transjunctional conductance in a dominant-negative manner (Fig. 2b,c), resulting in inhibition of intercellular coupling.1

GOFA gain of function was observed for G11R and A88V CX30, which formed functional hemichannels at the cell surface and, when expressed in HeLa cells, generated a leakage of ATP into the extracellular medium.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

ClinVar Variant Classifications

238 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11

Likely Pathogenic4

VUS121

Likely Benign56

Benign31

Conflicting15

Pathogenic

Likely Pathogenic

121

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	5	5	0	11
Likely Pathogenic	2	2	0	0	4
VUS	11	82	23	5	121
Likely Benign	0	6	25	25	56
Benign	0	0	31	0	31
Conflicting	—				15
Total	14	95	84	30	238

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

View in ClinVar →

55 pathogenic / likely-pathogenic (of 88) ClinVar copy-number / structural variants overlap GJB6 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →