autosomal dominant nonsyndromic hearing loss 3A

Summary

autosomal dominant nonsyndromic hearing loss 3A (MONDO:0011103) is a disease caused by GJB2 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: GJB2 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 183

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant nonsyndromic hearing loss 3A
Mondo ID	MONDO:0011103
MeSH	C567277
OMIM	601544
DOID	DOID:0110564
UMLS	C2675750
MedGen	436512
GARD	0009933
Is cancer (heuristic)	no

Also known as: autosomal dominant deafness 3A · autosomal dominant nonsyndromic deafness 3A · autosomal dominant nonsyndromic deafness caused by mutation in GJB2 · autosomal dominant nonsyndromic deafness type 3A · deafness, autosomal dominant 3A · deafness, autosomal dominant 3a · deafness, autosomal dominant nonsyndromic sensorineural 3 · deafness, autosomal dominant type 3A · DFNA3 · DFNA3A · GJB2 autosomal dominant nonsyndromic deafness · neurosensory nonsyndromic dominant deafness 1 · NSRD1

Data availability: 183 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant nonsyndromic hearing loss › autosomal dominant nonsyndromic hearing loss 3A

Related subtypes (75): autosomal dominant nonsyndromic hearing loss 1, autosomal dominant nonsyndromic hearing loss 2A, autosomal dominant nonsyndromic hearing loss 4A, autosomal dominant nonsyndromic hearing loss 6, autosomal dominant nonsyndromic hearing loss 5, autosomal dominant nonsyndromic hearing loss 10, autosomal dominant nonsyndromic hearing loss 11, autosomal dominant nonsyndromic hearing loss 9, autosomal dominant nonsyndromic hearing loss 7, autosomal dominant nonsyndromic hearing loss 12, autosomal dominant nonsyndromic hearing loss 13, autosomal dominant nonsyndromic hearing loss 15, autosomal dominant nonsyndromic hearing loss 17, autosomal dominant nonsyndromic hearing loss 16, autosomal dominant nonsyndromic hearing loss 20, autosomal dominant nonsyndromic hearing loss 23, autosomal dominant nonsyndromic hearing loss 25, autosomal dominant nonsyndromic hearing loss 18, autosomal dominant nonsyndromic hearing loss 24, autosomal dominant nonsyndromic hearing loss 22, autosomal dominant nonsyndromic hearing loss 30, autosomal dominant nonsyndromic hearing loss 36, autosomal dominant nonsyndromic hearing loss 21, autosomal dominant nonsyndromic hearing loss 44, autosomal dominant nonsyndromic hearing loss 48, autosomal dominant nonsyndromic hearing loss 41, autosomal dominant nonsyndromic hearing loss 49, autosomal dominant nonsyndromic hearing loss 43, autosomal dominant nonsyndromic hearing loss 28, autosomal dominant nonsyndromic hearing loss 31, autosomal dominant nonsyndromic hearing loss 47, autosomal dominant auditory neuropathy 1, autosomal dominant nonsyndromic hearing loss 53, autosomal dominant nonsyndromic hearing loss 27, autosomal dominant nonsyndromic hearing loss 59, autosomal dominant nonsyndromic hearing loss 3B, autosomal dominant nonsyndromic hearing loss 2B, autosomal dominant nonsyndromic hearing loss 50, autosomal dominant nonsyndromic hearing loss 51, autosomal dominant nonsyndromic hearing loss 64, autosomal dominant nonsyndromic hearing loss 33, autosomal dominant nonsyndromic hearing loss 4B, autosomal dominant nonsyndromic hearing loss 56, autosomal dominant nonsyndromic hearing loss 54, autosomal dominant nonsyndromic hearing loss 58, autosomal dominant nonsyndromic hearing loss 65, autosomal dominant nonsyndromic hearing loss 67, autosomal dominant nonsyndromic hearing loss 40, autosomal dominant nonsyndromic hearing loss 69, autosomal dominant nonsyndromic hearing loss 68, autosomal dominant nonsyndromic hearing loss 70, autosomal dominant nonsyndromic hearing loss 66, hearing loss, autosomal dominant 74, hearing loss, autosomal dominant 77, hearing loss, autosomal dominant 81, hearing loss, autosomal dominant 82, hearing loss, autosomal dominant 83, hearing loss, autosomal dominant 84, hearing loss, autosomal dominant 80, hearing loss, autosomal dominant 37, hearing loss, autosomal dominant 75, hearing loss, autosomal dominant 76, hearing loss, autosomal dominant 71, hearing loss, autosomal dominant 72, hearing loss, autosomal dominant 73, hearing loss, autosomal dominant 34, with or without inflammation, hearing loss, autosomal dominant 78, hearing loss, autosomal dominant 79, hearing loss, autosomal dominant 85, hearing loss, autosomal dominant 86, hearing loss, autosomal dominant 87, hearing loss, autosomal dominant 88, hearing loss, autosomal dominant 89, hearing loss, autosomal dominant 90, autosomal dominant nonsyndromic hearing loss 91

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

183 retrieved; paginated sample, class counts are floors:

44 pathogenic, 35 uncertain significance, 31 pathogenic/likely pathogenic, 28 conflicting classifications of pathogenicity, 19 likely pathogenic, 11 benign, 9 benign/likely benign, 3 likely benign, 3 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
158607	NM_004004.6(GJB2):c.298C>T (p.His100Tyr)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
158609	NM_004004.6(GJB2):c.647_650del (p.Arg216fs)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
163514	NM_004004.6(GJB2):c.379C>T (p.Arg127Cys)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17000	NM_004004.6(GJB2):c.101T>C (p.Met34Thr)	GJB2	Pathogenic	reviewed by expert panel
17001	NM_004004.6(GJB2):c.231G>A (p.Trp77Ter)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17002	NM_004004.6(GJB2):c.71G>A (p.Trp24Ter)	GJB2	Pathogenic	reviewed by expert panel
17003	NM_004004.6(GJB2):c.229T>C (p.Trp77Arg)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17004	NM_004004.6(GJB2):c.35del (p.Gly12fs)	GJB2	Pathogenic	reviewed by expert panel
17005	NM_004004.6(GJB2):c.139G>T (p.Glu47Ter)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17006	NM_004004.6(GJB2):c.355GAG[1] (p.Glu120del)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17007	NM_004004.6(GJB2):c.551G>C (p.Arg184Pro)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17009	NM_004004.6(GJB2):c.427C>T (p.Arg143Trp)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17010	NM_004004.6(GJB2):c.167del (p.Leu56fs)	GJB2	Pathogenic	reviewed by expert panel
17011	NM_004004.6(GJB2):c.223C>T (p.Arg75Trp)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17013	NM_004004.6(GJB2):c.51_62delinsA (p.Thr18fs)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17014	NM_004004.6(GJB2):c.235del (p.Leu79fs)	GJB2	Pathogenic	reviewed by expert panel
17016	NM_004004.6(GJB2):c.269T>C (p.Leu90Pro)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17017	NM_004004.6(GJB2):c.428G>A (p.Arg143Gln)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17023	NM_004004.6(GJB2):c.109G>A (p.Val37Ile)	GJB2	Pathogenic	reviewed by expert panel
17026	NM_004004.6(GJB2):c.535G>A (p.Asp179Asn)	GJB2	Pathogenic	criteria provided, single submitter
17027	NM_004004.6(GJB2):c.224G>A (p.Arg75Gln)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17029	NM_004004.6(GJB2):c.-23+1G>A	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17032	NM_004004.6(GJB2):c.250G>C (p.Val84Leu)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17033	NM_004004.6(GJB2):c.134G>A (p.Gly45Glu)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
17036	NM_004004.6(GJB2):c.250G>A (p.Val84Met)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
177737	NM_004004.6(GJB2):c.269dup (p.Val91fs)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
188756	NM_004004.6(GJB2):c.246C>G (p.Ile82Met)	GJB2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188758	NM_004004.6(GJB2):c.94C>T (p.Arg32Cys)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
188821	NM_004004.6(GJB2):c.290dup (p.Tyr97Ter)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts
188830	NM_004004.6(GJB2):c.131G>A (p.Trp44Ter)	GJB2	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 26 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
GJB2	Definitive	Autosomal dominant	hearing loss disorder	26

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GJB2	Orphanet:166286	Porokeratotic eccrine ostial and dermal duct nevus
GJB2	Orphanet:2202	Palmoplantar keratoderma-deafness syndrome
GJB2	Orphanet:2698	Knuckle pads-leukonychia-sensorineural deafness-palmoplantar hyperkeratosis syndrome
GJB2	Orphanet:477	KID syndrome
GJB2	Orphanet:494	Keratoderma hereditarium mutilans
GJB2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
GJB2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
GJB4	Orphanet:317	Erythrokeratodermia variabilis

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GJB2	HGNC:4284	ENSG00000165474	P29033	Gap junction beta-2 protein	gencc,clinvar
GJB4	HGNC:4286	ENSG00000189433	Q9NTQ9	Gap junction beta-4 protein	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GJB2	Gap junction beta-2 protein	Structural component of gap junctions.
GJB4	Gap junction beta-4 protein	Structural component of gap junctions.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GJB2	Other/Unknown	no		Connexin, Connexin26, Connexin_N
GJB4	Other/Unknown	no		Connexin, Connexin-30.3, Connexin_N

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gingiva	1
gingival epithelium	1
penis	1
skin of abdomen	1
skin of leg	1
zone of skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GJB2	196	broad	marker	gingival epithelium, gingiva, penis
GJB4	70	tissue_specific	yes	skin of abdomen, zone of skin, skin of leg

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GJB2	1,391
GJB4	469

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GJB2	P29033	24

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GJB4	Q9NTQ9	78.75

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 2 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Gap junction assembly	2	292.8×	5e-05	GJB2, GJB4
Oligomerization of connexins into connexons	1	1903.3×	7e-04	GJB2
Transport of connexins along the secretory pathway	1	1903.3×	7e-04	GJB2
Transport of connexons to the plasma membrane	1	271.9×	0.004	GJB2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
gap junction-mediated intercellular transport	2	2808.7×	7e-07	GJB2, GJB4
cell-cell signaling	2	69.6×	7e-04	GJB2, GJB4
gap junction assembly	1	1053.2×	0.002	GJB2
olfactory behavior	1	936.2×	0.002	GJB4
transmembrane transport	1	84.3×	0.015	GJB2
sensory perception of smell	1	78.0×	0.015	GJB4
sensory perception of sound	1	50.5×	0.020	GJB2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
GJB2	KANAMYCIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GJB2	1	4
GJB4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
KANAMYCIN	4	GJB2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
GJB2	5	Binding:5

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
KANAMYCIN	4	GJB2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	GJB2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	GJB4

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
GJB4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.