13-20189488-G-A

Variant names:

• chr13-20189488-G-A
• rs371024165
• NM_004004.6:c.94C>T
• GJB2 p.Arg32Cys

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+7 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 7 classification points (ACGS-UK Somatic Oncogenicity v2025). O1_ModerateO4_SupportingO5_SupportingO6_SupportingO7_SupportingO8_Supporting

The NM_004004.6(GJB2):c.94C>T (p.Arg32Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The gene GJB2 is a tumor suppressor gene (CancerMine: 5 TSG, 1 oncogene citations). The gene GJB2 is a known oncogene (CancerMine: 5 TSG, 1 oncogene citations). The variant allele was found at a cumulative frequency of 0.0000353 (AC=57) in the gnomAD database across 1,613,850 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000359. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.94). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.R32H: Pathogenic (ClinVar VariationId 44766, 2 stars) The variant has been observed in cBioPortal in 12 samples across 10 studies and 6 cancer types; somatic enrichment level: SUPPORTING (Observed repeatedly in cBioPortal somatic datasets.). This exact variant is curated in the UniProt human variants database as Pathogenic, associated with Adenomas and Adenocarcinomas; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: GJB2 NM_004004.6 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 9.94
• Publications: 36 publications found

Genes affected

GJB2 (HGNC:4284): (gap junction protein beta 2) 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]

GJB2 Gene-Disease associations (from GenCC):

• Bart-Pumphrey syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
• hearing loss disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• ichthyosis, hystrix-like, with hearing loss

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P
• keratoderma hereditarium mutilans

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
• palmoplantar keratoderma-deafness syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet
• autosomal recessive nonsyndromic hearing loss 1A

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant keratitis-ichthyosis-hearing loss syndrome

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Ambry Genetics, PanelApp Australia
• autosomal dominant nonsyndromic hearing loss 3A

  Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• KID syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000296095 (HGNC:):

Classification according to ACGS-UK Somatic Oncogenicity v2025

Specifications for GJB2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Likely_pathogenic. The variant received 7 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O1Established oncogenic variant		TSG gene: ClinVar germline P/LP ★★+ — Moderate (O1); O1 contributing sources (2.0 pts): ClinVar germline P/LP in TSG (★★)
	O4Enriched in somatic variant database		Enriched in cBioPortal (pre-computed score ≥ 1.0) — Supporting (O4); cBioPortal: samples=12 | studies=10 | cancer types=6 | level=SUPPORTING | points=1.0 | reason: Observed repeatedly in cBioPortal somatic datasets.
	O5Same location/impact as known oncogenic		Different AA at same residue with oncogenic evidence (or germline P/LP in TSG), or same AA change SCI Tier II Potential — Supporting (O5); ClinVar same-AA oncogenic/T1: false | ClinVar same-AA SCI tier: — | CGI same-AA oncogenic: false | TSG: true | ClinVar same-AA germline P/LP: false | CIViC LOF: false | ClinVar diff-AA oncogenic: false | ClinVar diff-AA germline P/LP: true
	O6Computational evidence supports deleterious effect		Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect
	O7Mutational hotspot or critical domain		Supporting: cancerhotspots.org hit, critical domain, or missense neighbourhood hotspot; No cancerhotspots.org hit at this position; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 17 pathogenic, 1 benign (OR vs. background: 58.3); Variant does not impact splicing — splice-hotspot path not applicable
	O8Missense constraint in gene or region		Missense in gene/domain constrained for missense variation where missense is common disease mechanism (O8 supporting); Gene/disease mechanism: missense is a common mechanism of oncogenesis; gnomAD missense Z-score: 0.44 (threshold ≥3.09 for constraint); Domain-level constraint: variant is in a critically constrained functional domain (IS_AT_CRITICAL_DOMAIN)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_004004.6. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	GJB2 NM_004004.6	MANE Select	c.94C>T p.Arg32Cys	missense	Exon 2 of 2	Prot: NP_003995.2

GJB2 NM_004004.6

MANE Select

HGVSc / HGVSpc.94C>Tp.Arg32Cys

Exon rankExon 2 of 2

missense

Prot: NP_003995.2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	GJB2 ENST00000382848.5	TSL:1MANE Select	c.94C>T p.Arg32Cys	missense	Exon 2 of 2	Prot: ENSP00000372299.4 UniProt:
	GJB2 ENST00000382844.2	TSL:6	c.94C>T p.Arg32Cys	missense	Exon 1 of 1	Prot: ENSP00000372295.1 UniProt:
	GJB2 ENST00000906230.1		c.94C>T p.Arg32Cys	missense	Exon 2 of 2	Prot: ENSP00000576289.1 UniProt:

GJB2 ENST00000382848.5

TSL:1MANE Select

HGVSc / HGVSpc.94C>Tp.Arg32Cys

Exon rankExon 2 of 2

missense

Prot: ENSP00000372299.4UniProt: P29033

GJB2 ENST00000382844.2

TSL:6

HGVSc / HGVSpc.94C>Tp.Arg32Cys

Exon rankExon 1 of 1

missense

Prot: ENSP00000372295.1UniProt: P29033

GJB2 ENST00000906230.1

HGVSc / HGVSpc.94C>Tp.Arg32Cys

Exon rankExon 2 of 2

missense

Prot: ENSP00000576289.1UniProt: P29033

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.000145	AC:22	Hom:0	AN:152184	Cov:33
GnomAD2 exomes	AF: 0.0000319	AC:8	Hom:	AN:250496	Cov:
GnomAD4 exome	AF: 0.0000239	AC:35	Hom:0	AN:1461666	Cov:33
GnomAD4 genome	AF: 0.000145	AC:22	Hom:0	AN:152184	Cov:33
TOPMed (Bravo)	AF: 0.000132	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.000138	AC:28	Hom:0	AN:203270	Cov:
Local & regional cohorts 2 sources Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.0000769	AC:1	Hom:	AN:13006	Cov:
Turkish Variome	AF: 0.000177	AC:1	Hom:0	AN:5170	Cov:

Showing 8 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.00	0	28418	0.0000347	1	28844
Epi25(Epilepsy)	0.0000477	2	41958	0.0000449	3	66886
SCHEMA(Schizophrenia)	0.0000678	7	103224	0.0000109	2	184320

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Autosomal recessive nonsyndromic hearing loss 1A (6)
5	-	-	not provided (5)
1	-	-	Autosomal dominant keratitis-ichthyosis-hearing loss syndrome;C0265964:Mutilating keratoderma;C0266004:Knuckle pads, deafness AND leukonychia syndrome;C1835672:Palmoplantar keratoderma-deafness syndrome;C1865234:Ichthyosis, hystrix-like, with hearing loss;C2673759:Autosomal recessive nonsyndromic hearing loss 1A;C2675750:Autosomal dominant nonsyndromic hearing loss 3A (1)
1	-	-	Monogenic hearing loss (1)
1	-	-	not specified (1)
1	-	-	Rare genetic deafness (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	27
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
FuncVEP CTI	Pathogenic	0.99
GPN-Star LLR	N/A	-8.5
GPN-Star score	N/A	8.5
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.63	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	0.96	D
Mutation Taster	N/A	0/100	disease causing (ClinVar)
MutationAssessor	Pathogenic	3.7	H
PhyloP100	Pathogenic	9.9
popEVE	Benign	-3.8
PrimateAI	Uncertain	0.68	T
PromoterAI	N/A	-0.025	Neutral
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.015	D
Varity_R	N/A	0.79
VESM-3B	Benign	-12

Showing 29 of 29 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs371024165;

hg19: chr13-20763627;

COSMIC: COSV67010543;

COSMIC: COSV67010543;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar