GJB4

Chr 1AD

gap junction protein beta 4

Also known as: CX30.3, EKV, EKVP2

NCBI Gene: 127534 ENSG00000189433 UniProt: Q9NTQ9 OMIM: 605425

This gene encodes a connexin protein that forms gap junction channels allowing small molecules and ions to pass between adjacent cells. Mutations cause erythrokeratodermia variabilis et progressiva 2, a skin disorder characterized by variable and progressive red, thickened patches of skin. The condition follows autosomal dominant inheritance.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 1.741 OMIM phenotype

Clinical Summary— GJB4

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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

6 unique Pathogenic / Likely Pathogenic· 78 VUS of 134 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

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?

-0.64Z-score

OE missense 1.14 (1.01–1.28)

193 obs / 169.7 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.91 (0.47–1.74)

0≤0.351.4

Missense OE?1.14 (1.01–1.28)

0≤0.61.4

Synonymous OE?1.23

0≤1.21.6

LoF obs/exp: 5 / 5.5Missense obs/exp: 193 / 169.7Syn Z: -1.57

This gene — mechanism propensity

0.81top 10%

GOF

0.85top 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

DNprediction above median

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.

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

ClinVar Variant Classifications

134 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic2

VUS78

Likely Benign19

Benign22

Conflicting7

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	4	0	0	4
Likely Pathogenic	0	2	0	0	2
VUS	3	75	0	0	78
Likely Benign	2	5	0	12	19
Benign	1	8	3	10	22
Conflicting	—				7
Total	6	94	3	22	132

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

View in ClinVar →

9 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap GJB4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →