GJB2
Chr 13ADARDigenic dominantgap junction protein beta 2
Also known as: BAPS, CX26, DFNA3, DFNA3A, DFNB1, DFNB1A, HID, KID
Connexin 26 forms gap junction channels that allow small molecules and ions to pass between adjacent cells. Mutations cause hearing loss ranging from isolated deafness (both autosomal recessive and dominant forms) to syndromic conditions involving skin abnormalities such as keratoderma and ichthyosis. This gene has very low constraint against loss-of-function variants and shows both autosomal recessive and dominant inheritance patterns depending on the specific variant.
Definitive — sufficient evidence for diagnostic panels
2 total gene-disease associations curated
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly tolerant — LoF variants common in population
Tolerant to missense variation
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.
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
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
200 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 17 | 5 | 6 | 0 | 28 |
Likely Pathogenic | 9 | 39 | 0 | 0 | 48 |
VUS | 2 | 62 | 11 | 1 | 76 |
Likely Benign | 0 | 0 | 3 | 41 | 44 |
Benign | 0 | 0 | 0 | 0 | 0 |
Conflicting | — | 2 | |||
| Total | 28 | 106 | 20 | 42 | 198 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
GJB2 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Natural History in Children up to 16 Years With Mild to Profound Hearing Loss Due to Mutations in GJB2 / OTOF Genes
RECRUITINGCross-sectional and Prospective Study to Characterize Early-onset Presbycusis
RECRUITINGCohort Of DEafness-gene Screening
ACTIVE NOT RECRUITINGExternal Resources
Links to major genomics databases and tools