GJB1

Chr XXLD

gap junction protein beta 1

Also known as: CMTX, CMTX1, CX32

NCBI Gene: 2705 ENSG00000169562 UniProt: P08034 OMIM: 304040

The protein forms gap junction channels that facilitate transfer of ions and small molecules between cells. Mutations cause X-linked dominant Charcot-Marie-Tooth neuropathy type 1, an inherited peripheral neuropathy. The predicted mechanism of pathogenicity is gain-of-function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a member of the gap junction protein family. The gap junction proteins are membrane-spanning proteins that assemble to form gap junction channels that facilitate the transfer of ions and small molecules between cells. According to sequence similarities at the nucleotide and amino acid levels, the gap junction proteins are divided into two categories, alpha and beta. Mutations in this gene cause X-linked Charcot-Marie-Tooth disease, an inherited peripheral neuropathy. Alternatively spliced transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Oct 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismXLDLOEUF 0.491 OMIM phenotype

Clinical Summary— GJB1

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Gene-Disease Validity (ClinGen)

Charcot-Marie-Tooth disease X-linked dominant 1 · XLDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.85) — some intolerance to loss-of-function variants.

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ClinVar Variants

231 unique Pathogenic / Likely Pathogenic· 407 VUS of 826 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — GJB1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.49LOEUF

pLI 0.846

Z-score 2.30

OE 0.00 (0.00–0.49)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.03Z-score

OE missense 0.50 (0.41–0.62)

66 obs / 131.4 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.49)

0≤0.351.4

Missense OE?0.50 (0.41–0.62)

0≤0.61.4

Synonymous OE?0.93

0≤1.21.6

LoF obs/exp: 0 / 6.2Missense obs/exp: 66 / 131.4Syn Z: 0.41

This gene — mechanism propensity

0.5868th %ile

GOF

0.76top 25%

LOF

0.51top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF35% of P/LP variants are LoF · LOEUF 0.49

GOFprediction 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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

826 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic123

Likely Pathogenic108

VUS407

Likely Benign107

Benign12

Conflicting63

123

Pathogenic

108

Likely Pathogenic

407

VUS

107

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	63	54	4	2	123
Likely Pathogenic	19	85	4	0	108
VUS	48	337	19	3	407
Likely Benign	0	3	6	98	107
Benign	0	0	7	5	12
Conflicting	—				63
Total	130	479	40	108	820

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

View in ClinVar →

63 pathogenic / likely-pathogenic (of 75) ClinVar copy-number / structural variants overlap GJB1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →