GeneBe

GJB2

protein-coding

gap junction protein beta 2, the group of Gap junction proteins

Gene summary

This gene encodes a member of the gap junction protein family (gap junction beta 2) but is more commonly known as connexin 26. The gap junctions were first characterized by electron microscopy as regionally specialized structures on plasma membranes of contacting adherent cells. These structures were shown to consist of cell-to-cell channels that facilitate the transfer of ions and small molecules between cells. Connexins form hexameric channels in the plasma membrane which regulate passage of ions and small molecules between the cell and its environment or, when joined with another cell, form a dodecameric intercellular gap junction channel. The connexin proteins are grouped into alpha, beta, and gamma subfamilies. Mutations in this gene are responsible for as much as 50% of pre-lingual, recessive deafness. [provided by RefSeq, Mar 2026]

Previous symbols:
  • DFNB1
  • DFNA3

MANE transcript

NM_004004.6

Inheritance

AD, AR, Digenic

ClinVar variants

P:295U:146B:141

Top phenotype

Deafness, autosomal dominant 3A; Keratitis-icthyosis-deafness syndrome, autosomal dominant; Deafness, autosomal recessive 1A; Deafness, digenic; Hystrix-like ichthyosis with deafness; Bart-Pumphrey syndrome; Keratoderma, palmoplantar, with deafness; Vohwinkel syndrome

gnomAD constraint

pLI —, LoF o/e 2.62

Max pathogenic AF

—

Genomic locus

chr13:20,187,463-20,192,938

External References & Databases

Ensembl (ENSG00000165474)NCBI Gene (2706)OMIM (121011)HGNC:4284GenCCUniProt (P29033)AlphaFoldClinVar (GJB2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~5.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ichthyosis, hystrix-like, with hearing lossSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011245

Submitter: Genomics England PanelApp

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019497

Submitter: ClinGen

GJB2 was first reported in relation to autosomal recessive nonsyndromic hearing loss (DFNB1) in 1997 (Kelsell et al., PMID: 9139825). 8 variants (missense, nonsense, frameshift, and canonical splice site) that have been reported in 6 probands in 4 publications (PMIDs: 9139825, 9482292, 9529365, 16380907) are included in this curation. Variants in GJB2 are found in up to 50% of patients with autosomal recessive nonsyndromic hearing loss (PMID: 16380907). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be loss of function. This gene-disease relationship is also supported by experimental evidence. Expression studies in the human cochlea, mouse models with wildtype GJB2 rescuing hearing loss and abnormal inner ear morphology, and in vitro dye transfer and electrical coupling assays demonstrating significant differences between functionally impaired variants and wildtype GJB2 all support this gene-disease relationship (PMIDs: 9507396, 12176036, 15241677, 21876744, 25801282). In summary, there is definitive evidence supporting the relationship between GJB2 and autosomal recessive nonsyndromic hearing loss. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Gene Curation Expert Panel on March 2, 2017. As of September 24, 2024, this record underwent administrative updates to update the SOP version (SOP Version 10.1). No new evidence has been reviewed or added.

Bart-Pumphrey syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007866

Submitter: Genomics England PanelApp

hearing loss, autosomal recessiveSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019588

Submitter: Orphanet

palmoplantar keratoderma-deafness syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007852

Submitter: Genomics England PanelApp

keratoderma hereditarium mutilansSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007422

Submitter: Genomics England PanelApp

autosomal dominant keratitis-ichthyosis-hearing loss syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007850

Submitter: Genomics England PanelApp

autosomal recessive nonsyndromic hearing loss 1ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009076

Submitter: PanelApp Australia

Bart-Pumphrey syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007866

Submitter: G2P

autosomal recessive nonsyndromic hearing loss 1ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009076

Submitter: G2P

autosomal dominant nonsyndromic hearing loss 3ASTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011103

Submitter: Ambry Genetics

autosomal recessive nonsyndromic hearing loss 1ADEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009076

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

keratoderma hereditarium mutilansDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007422

Submitter: G2P

palmoplantar keratoderma-deafness syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007852

Submitter: G2P

hearing loss disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0005365

Submitter: ClinGen

GJB2 was first reported in relation to autosomal dominant hearing loss with or without skin findings in 1998 (Richard et al., 9856479). At least 30 missense variants have been reported in humans. Association is seen in at least 11 probands in 11 publications (PMIDs: 11354642, 11912510, 15337980, 20937258, 21868108, 9856479, 9620796, 10369869, 10807696, 16226720, 28102197). Variants in this gene segregated with disease in 49 additional family members. Much more evidence is available in the literature, but the maximum score for genetic evidence and/or experimental evidence (12 pts.) has been reached. This gene-disease relationship is supported by animal models, expression studies, in vitro functional assays, and biochemical functional studies, which support a dominant-negative mechanism of disease. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern for AD nonsyndromic hearing loss, AD keratitis ichthyosis deafness (KID) and AD palmoplantar keratoderma (PPK) with deafness. It is possible that these phenotypes exist on a spectrum of disease. In summary, GJB2 is definitively associated with autosomal dominant Hearing Loss with or without Skin Findings. This classification was approved by the ClinGen Hearing Loss Working Group on 6/26/2018.

autosomal dominant keratitis-ichthyosis-hearing loss syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0007850

Submitter: Ambry Genetics

autosomal dominant nonsyndromic hearing lossSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: Orphanet

autosomal dominant nonsyndromic hearing loss 3ASTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011103

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive nonsyndromic hearing loss 1ASTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009076

Submitter: Labcorp Genetics (formerly Invitae)

keratoderma hereditarium mutilansSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007422

Submitter: Orphanet

KID syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0018781

Submitter: Orphanet

ichthyosis, hystrix-like, with hearing lossDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0011245

Submitter: G2P

Bart-Pumphrey syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007866

Submitter: Labcorp Genetics (formerly Invitae)

palmoplantar keratoderma-deafness syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007852

Submitter: Orphanet

autosomal dominant keratitis-ichthyosis-hearing loss syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007850

Submitter: PanelApp Australia

autosomal dominant nonsyndromic hearing loss 3ASTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0011103

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Deafness, autosomal dominant 3A; Keratitis-icthyosis-deafness syndrome, autosomal dominant; Deafness, autosomal recessive 1A; Deafness, digenic; Hystrix-like ichthyosis with deafness; Bart-Pumphrey syndrome; Keratoderma, palmoplantar, with deafness; Vohwinkel syndromeAD/AR/Digenic

Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Dermatologic; Oncologic; Ophthalmologic

Intervention: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic; Oncologic

Rationale: Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development; In certain conditions (eg, KID syndrome), infectious and malignant complications may benefit from surveillance leading to microbial prophylaxis and early and aggressive treatment of infections and early detection and treatment of malignancy

Comments: In nonsyndromic deafness, onset of AD disease can be pre or postlingual; In syndromic disease, although skin and other findings may be obvious in some individuals, the syndromic combination of features may not be as readily appreciated as being related to hearing impairment; Digenic inheritance (with GJB3, GJB6) has been described

Refs: 6015974; 1532426; 8010352; 7748756; 9139825; 9529365; 9620796; 10218527; 10369869; 10633135; 10807696; 11298683; 11807148; 12047643; 11960582; 11912510; 11889383; 12372058; 12072059; 11918723; 12560944; 14694360; 15150777; 15482471; 14700667; 16222667; 16380907; 15994881; 15633193; 15691545; 15996214; 16840571; 17041943; 17330861; 993581; 17041943; 19050930; 18843290; 20815033; 20412116Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GJB2 variants in ClinVar

43 Conditions Cataloged
not providedTotal: 429
Autosomal recessive nonsyndromic hearing loss 1ATotal: 302
Autosomal dominant nonsyndromic hearing loss 3ATotal: 147
not specifiedTotal: 132
Ichthyosis, hystrix-like, with hearing lossTotal: 120
Autosomal dominant keratitis-ichthyosis-hearing loss syndromeTotal: 108
Palmoplantar keratoderma-deafness syndromeTotal: 108
Mutilating keratodermaTotal: 105

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004004.6. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
3
clinvar
122
clinvar
1
clinvar
 126
missense
46
clinvar
132
clinvar
140
clinvar
15
clinvar
3
clinvar
 336
nonsense
21
clinvar
13
clinvar
1
clinvar
 35
start loss
4
clinvar
1
clinvar
 5
frameshift
40
clinvar
33
clinvar
1
clinvar
 74
splice donor/acceptor (+/-2bp)
5
clinvar
1
clinvar
 6
Total1111841461374582

Highest pathogenic variant AF is 0.012041303

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 20 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_004004.6RefSeqNP_003995.21MANE Select
ENST00000382848.5EnsemblENSP00000372299.41MANE Select
ENST00000382844.2EnsemblENSP00000372295.11Standard
ENST00000906230.1EnsemblENSP00000576289.11Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
cx30.3Danio rerio

Structure: sagitta

Quality: decreased width

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Calcium Regulation in the Cardiac Cell
  • Vesicle-mediated transport
  • Membrane Trafficking
  • Transport of connexins along the secretory pathway
  • Oligomerization of connexins into connexons

Biological Process

  • response to ischemia
  • cell-cell signaling
  • aging
  • sensory perception of sound
  • gap junction assembly

Molecular Function

  • gap junction channel activity
  • identical protein binding

Cellular Component

  • endoplasmic reticulum-Golgi intermediate compartment
  • cytosol
  • plasma membrane
  • connexin complex
  • integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000382844
Coding exons
1
Length
5429
Individuals with no LoFs
0
Homozygous LoFs
0
Heterozygous LoFs
0
Defined
0
p
0.00
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.7201611371.170.000008461481
Missense (PolyPhen)7067.1241.0428721
Synonymous-0.2936461.11.050.00000437446
Loss of Function-3.82176.502.622.82e-769

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian00.0absent
Finnish00.0absent
European (Non-Finnish)00.0absent
South Asian00.0absent
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.;
Disease
DISEASE: Deafness, autosomal recessive, 1A (DFNB1A) [MIM:220290]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. {ECO:0000269|PubMed:10830906, ECO:0000269|PubMed:11313763, ECO:0000269|PubMed:11439000, ECO:0000269|PubMed:12121355, ECO:0000269|PubMed:12239718, ECO:0000269|PubMed:12786758, ECO:0000269|PubMed:14722929, ECO:0000269|PubMed:15592461, ECO:0000269|PubMed:15666300, ECO:0000269|PubMed:15994881, ECO:0000269|PubMed:17660464, ECO:0000269|PubMed:17666888, ECO:0000269|PubMed:19384972, ECO:0000269|PubMed:23680645, ECO:0000269|PubMed:28281779, ECO:0000269|PubMed:9328482, ECO:0000269|PubMed:9336442, ECO:0000269|PubMed:9471561, ECO:0000269|PubMed:9529365}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, autosomal dominant, 3A (DFNA3A) [MIM:601544]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. {ECO:0000269|PubMed:10807696, ECO:0000269|PubMed:11313763, ECO:0000269|PubMed:11439000, ECO:0000269|PubMed:12668604, ECO:0000269|PubMed:12786758, ECO:0000269|PubMed:19384972, ECO:0000269|PubMed:9620796}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Vohwinkel syndrome (VOWNKL) [MIM:124500]: An autosomal dominant disease characterized by hyperkeratosis, constriction on fingers and toes and congenital deafness. {ECO:0000269|PubMed:10369869, ECO:0000269|PubMed:12668604, ECO:0000269|PubMed:15954104, ECO:0000269|PubMed:18688874}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Keratoderma, palmoplantar, with deafness (PPKDFN) [MIM:148350]: An autosomal dominant disorder characterized by the association of palmoplantar hyperkeratosis with progressive, bilateral, high-frequency, sensorineural deafness. {ECO:0000269|PubMed:10633135, ECO:0000269|PubMed:10757647, ECO:0000269|PubMed:12372058, ECO:0000269|PubMed:12668604, ECO:0000269|PubMed:15996214, ECO:0000269|PubMed:17993581, ECO:0000269|PubMed:9856479}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Keratitis-ichthyosis-deafness syndrome (KID syndrome) [MIM:148210]: An autosomal dominant form of ectodermal dysplasia. Ectodermal dysplasia defines a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. Keratitis-ichthyosis-deafness syndrome is characterized by the association of hyperkeratotic skin lesions with vascularizing keratitis and profound sensorineural hearing loss. Clinical features include deafness, ichthyosis, photophobia, absent or decreased eyebrows, sparse or absent scalp hair, decreased sweating and dysplastic finger and toenails. {ECO:0000269|PubMed:11912510, ECO:0000269|PubMed:12548749, ECO:0000269|PubMed:12752120}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Bart-Pumphrey syndrome (BPS) [MIM:149200]: An autosomal dominant disorder characterized by sensorineural hearing loss, palmoplantar keratoderma, knuckle pads, and leukonychia, It shows considerable phenotypic variability. {ECO:0000269|PubMed:15482471, ECO:0000269|PubMed:15952212}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ichthyosis hystrix-like with deafness syndrome (HID syndrome) [MIM:602540]: An autosomal dominant keratinizing disorder characterized by sensorineural deafness and spiky hyperkeratosis affecting the entire skin. HID syndrome is considered to differ from the similar KID syndrome in the extent and time of occurrence of skin symptoms and the severity of the associated keratitis. {ECO:0000269|PubMed:12072059}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.506

Intolerance Scores

LoFtool
0.163
RVIS EVS
0.66
RVIS percentile EVS
84.55

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.801

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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