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…

Primary Disease Associations & Inheritance

Charcot-Marie-Tooth neuropathy, X-linked dominant, 1MIM #302800

XLD

UniProtDejerine-Sottas syndrome

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Charcot-Marie-Tooth disease X-linked dominant 1 · XL · ClinGen 2020

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.49

LOEUF

GOF

Mechanism· predicted

📖

GeneReview available — GJB1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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

Background carrier burden — how many people carry a rare variant somewhere in GJB1?

gnomAD v4 · ~732k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 460

149 rare PASS variants

Rare truncating (LoF)

1 in 61,000

3 rare PASS variants

Rare synonymous (reference)

1 in 560

118 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for GJB1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~561k	1 in 590	1 in 33,000
South Asian	~36k	1 in 350	none seen
Remaining (unassigned)	~31k	1 in 430	none seen
European (Finnish)	~27k	1 in 1,400	none seen
Admixed American	~23k	1 in 440	≈ 1 in 22,000
African / African American	~20k	1 in 820	none seen
East Asian	~20k	1 in 770	none seen
Ashkenazi Jewish	~13k	≈ 1 in 3,200	none seen
Middle Eastern	~2,758	1 in 250	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 1 coding exons well covered in gnomAD exomes and genomes.? see exons ↓