GJB3

Summary

GJB3 (gap junction protein beta 3, HGNC:4285) is a protein-coding gene on chromosome 1p34.3, encoding Gap junction beta-3 protein (O75712). 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.

This gene is a member of the connexin gene family. The encoded protein is a component of gap junctions, which are composed of arrays of intercellular channels that provide a route for the diffusion of low molecular weight materials from cell to cell. Mutations in this gene can cause non-syndromic deafness or erythrokeratodermia variabilis, a skin disorder. Alternative splicing results in multiple transcript variants encoding the same protein.

Source: NCBI Gene 2707 — RefSeq curated summary.

At a glance

• Gene–disease (curated): erythrokeratodermia variabilis (Definitive, ClinGen) — +7 more curated relationships
• GWAS associations: 2
• Clinical variants (ClinVar): 243 total — 6 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 40
• MANE Select transcript: NM_024009

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4285
Approved symbol	GJB3
Name	gap junction protein beta 3
Location	1p34.3
Locus type	gene with protein product
Status	Approved
Aliases	CX31
Ensembl gene	ENSG00000188910
Ensembl biotype	protein_coding
OMIM	603324
Entrez	2707

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000373362, ENST00000373366, ENST00000902771

RefSeq mRNA: 2 — MANE Select: NM_024009 NM_001005752, NM_024009

CCDS: CCDS384

Canonical transcript exons

ENST00000373366 — 2 exons

Exon	Start	End
ENSE00001377704	34781214	34781778
ENSE00001957248	34784738	34786364

Expression profiles

Bgee: expression breadth ubiquitous, 183 present calls, max score 96.74.

FANTOM5 (CAGE): breadth broad, TPM avg 5.5790 / max 382.9817, expressed in 337 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
2074	2.9404	269
2073	1.1562	256
2080	0.4261	151
2077	0.3851	171
2079	0.2833	137
2081	0.2015	85
2078	0.1863	119

Top tissues by expression

285 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
skin of abdomen	UBERON:0001416	96.74	gold quality
skin of leg	UBERON:0001511	96.40	gold quality
upper arm skin	UBERON:0004263	96.00	gold quality
zone of skin	UBERON:0000014	95.81	gold quality
upper leg skin	UBERON:0004262	95.61	gold quality
lower esophagus mucosa	UBERON:0035834	95.54	gold quality
esophagus mucosa	UBERON:0002469	93.89	gold quality
gingival epithelium	UBERON:0001949	93.73	gold quality
tongue squamous epithelium	UBERON:0006919	93.50	gold quality
gingiva	UBERON:0001828	93.34	gold quality
mammalian vulva	UBERON:0000997	91.67	gold quality
squamous epithelium	UBERON:0006914	88.34	gold quality
cervix epithelium	UBERON:0004801	88.17	gold quality
nipple	UBERON:0002030	88.09	gold quality
oral cavity	UBERON:0000167	87.83	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	87.69	gold quality
epithelium of esophagus	UBERON:0001976	87.30	gold quality
skin of hip	UBERON:0001554	86.78	gold quality
pancreatic ductal cell	CL:0002079	86.73	silver quality
esophagus squamous epithelium	UBERON:0006920	86.41	gold quality
amniotic fluid	UBERON:0000173	86.28	gold quality
hair follicle	UBERON:0002073	85.19	silver quality
pharyngeal mucosa	UBERON:0000355	85.12	gold quality
nasal cavity epithelium	UBERON:0005384	84.91	gold quality
palpebral conjunctiva	UBERON:0001812	84.08	gold quality
cervix squamous epithelium	UBERON:0006922	83.98	silver quality
penis	UBERON:0000989	82.67	gold quality
mucosa of sigmoid colon	UBERON:0004993	81.58	gold quality
endometrium epithelium	UBERON:0004811	80.65	gold quality
nasal cavity mucosa	UBERON:0001826	80.44	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	114.34
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EGR2

miRNA regulators (miRDB)

32 targeting GJB3, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-3606-5P	99.31	69.67	1168
HSA-MIR-324-3P	99.26	66.31	1034
HSA-MIR-4721	99.26	66.05	818
HSA-MIR-4727-5P	99.23	67.55	1154
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-7160-5P	99.11	67.17	2207
HSA-MIR-485-5P	99.10	64.78	1889
HSA-MIR-6884-5P	99.10	64.50	1987
HSA-MIR-6830-5P	99.01	68.73	1884
HSA-MIR-1199-5P	98.44	66.51	829
HSA-MIR-6751-3P	98.44	66.35	835
HSA-MIR-6509-3P	98.32	67.33	1343
HSA-MIR-561-5P	98.25	68.13	1365
HSA-MIR-6834-3P	98.16	65.77	551
HSA-MIR-6511B-5P	97.98	65.64	823
HSA-MIR-6811-5P	97.98	64.96	848
HSA-MIR-450A-2-3P	97.91	67.56	1459
HSA-MIR-6799-3P	97.35	65.60	1302
HSA-MIR-3173-5P	97.35	65.82	1282

Literature-anchored findings (GeneRIF, showing 40)

• a homozygote mutation in the connexin 31 gene, found in a family that shows recessive inheritance of the disorder, thus providing the first molecular support for a recessive variant of erythrokeratodermia variabilis (PMID:12019212)
• Connexin 31 mutation is associated with defective trafficking and cell death in skin disease (PMID:12165562)
• Expression of a connexin31 mutation causing erythrokeratodermia variabilis is lethal for HeLa cells (PMID:12176042)
• pathogenic mutations of CX31 are infrequent in sporadic non-syndromic hearing impairment (PMID:12630965)
• effects of sequence variants G12D and R32W on Cx31 biogenesis and gap junction activity (PMID:12702148)
• These results not only provide new insights into epidermal connexin synthesis and polymerization, but also allow a novel molecular explanation for the similarity of EKV phenotypes. (PMID:14583444)
• In summary, disease-associated Cx31 mutants impair the formation of normal gap junctions at different levels. (PMID:16077902)
• Not all clincally diagnosed inviduals with erythrokeratoderma variabilis harbor Cx31 disease-associated mutations. (PMID:16297190)
• provide an important first step in evaluating the pathogenesis of inherited human diseases associated with mutations in the gene for Cx31 (PMID:16549784)
• Some GJB2, GJB3, and GJB6 mutations occurred in deaf students. (PMID:18338563)
• The intent of this study was to investigate the prevalence of the point and digenic mutations including large deletions and duplications in the Cx26, 30, and 31 genes in a Swiss patient cohort with autosomal recessive nonsyndromic hearing impairment. (PMID:18607988)
• Two different GJB3 mutations (N166S and A194T) occurring in compound heterozygosity with the 235delC and 299delAT of GJB2 were identified in three unrelated families (235delC/N166S, 235delC/A194T and 299delAT/A194T). (PMID:19050930)
• endoplasmic reticulum stress leading to the unfolded protein response is the main mechanism of mutant Cx31-associated cell death. (PMID:19755382)
• Mutations in GJB3 and GJB2 might interact to produce deafness in a digenic mode of inheritance. (PMID:20627047)
• GJB3 gene mutations were not the main cause of hereditary nonsyndromic hearing loss in Uighur and Han people. (PMID:21055240)
• There were no mutations found in the GJB3 gene and the true pathogenesis of progressive symmetrical erythrokeratodermia remains unknown. (PMID:21198793)
• A neonatal hearing screening program in Campania, Italy did not find any incidence of GJB6 or GJB3 mutations. (PMID:21916817)
• Mutation analysis of GJB3 and GJB4 in Chinese patients with erythrokeratodermia variabilis. (PMID:21950330)
• Pathogenic connexin-31 forms constitutively active hemichannels to promote necrotic cell death (PMID:22393412)
• GJB3 and GJB6 genetic variants are associated with the pathogenicity of nonsyndromic sensorineural hearing loss. (PMID:22617145)
• We report a missense mutation p.G45E in the GJB3 gene, which was responsible for Erythrokeratodermia variabilis in a Chinese family. (PMID:22681493)
• mutations prevalent in hearing loss patients (PMID:23638949)
• In this study, we found no mutations of GJB3 in two Progressive symmetrical erythrokeratoderma families. (PMID:23678955)
• The CX31 V174M mutant may have an effect on the formation and function of the gap junction, in nonsyndromic hearing loss. (PMID:24913888)
• identified dominant pathogenic missense mutation in the M4 transmembrane domain of GJB3; mutation led to the erythrokeratodermia variabilis (EKV) phenotype in the patient’s family; results, combined with literature review, suggest dominant missense mutations outside the E2 domain in GJB3 are associated with EKV, and those within the E2 domain cause ADNSHL (PMID:25556823)
• Mutations in 12S rRNA, SLC26A4, GJB2 and GJB3 are highly associated with deafness. (PMID:26037344)
• study suggests that Connexin-31 mutant proteins are un/misfolded to cause erythrokeratodermia variabilis likely via an AP-1-mediated mechanism and identifies a small molecule with therapeutic potential of the disease (PMID:26251042)
• The results of the present study indicated that combined heterozygous mutations of the SLC264 and GJB3 genes may result in severe hearing loss. These results contribute to the understanding of clinical phenotype of deaf patients carrying combined mutations in the SLC26A4 and GJB3 genes. (PMID:27176802)
• GJB3 c.538C>T does not contribute to hearing loss, and this conclusion will assist with genetic counseling and risk prediction for deafness related to the GJB3 c.538C>T variant (PMID:29106878)
• A rare missense mutation in GJB3 (Cx31G45E) is associated with a unique cellular phenotype resulting in necrotic cell death. (PMID:29570224)
• The results of this study showed that GJB3 mutants appear to account for a small proportion in double heterozygous state with autosomal recessive GJB2 mutation . (PMID:29926981)
• Here, we reported a novel compound heterozygous mutations of GJB3 gene in a Chinese EKPV family with autosomal recessive inheritance pattern. (PMID:29992552)
• Almost half of the children with sensorineural hearing loss carried a common deafness-related mutation, and nearly one-third carried a pathogenic mutation. At least one mutated allele was detected in 48 patients and 30 patients carried pathogenic mutations. Among all the detected mutations, the most common were GJB2 c.235delC and SLC26A4 c.919-2A>G. (PMID:30036422)
• The mutation frequencies of GJB2, SLC26A4, GJB3, and mitochondrial genes were 3.04%, 3.51%, 0.16%, and 0.88%, respectively among the Hakka population of Southern China (PMID:30235673)
• GJB3 gene mutation was not involved with hearing loss in Shanghai area. (PMID:30298483)
• Four patients were identified to carry the GJB3 mutation in a heterozygous state, including three with c.538C > T and one with c.547G > A (PMID:31035178)
• Case of erythrokeratodermia variabilis successfully treated with narrowband ultraviolet B. (PMID:31599015)
• The mutation frequencies of GJB2, GJB3, SLC26A4 and MT-RNR1 of patients with severe to profound sensorineural hearing loss in northwest China. (PMID:32645618)
• Mutation analysis of GJB2, SLC26A4, GJB3 and mtDNA12SrRNA genes in 251 non-syndromic hearing loss patients in Fujian, China. (PMID:38029595)
• Impairment of alpha-tubulin and F-actin interactions of GJB3 induces aneuploidy in urothelial cells and promotes bladder cancer cell invasion. (PMID:38956497)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	gjb3	ENSDARG00000042866
mus_musculus	Gjb3	ENSMUSG00000042367
rattus_norvegicus	Gjb3	ENSRNOG00000014372

Paralogs (20): GJA8 (ENSG00000121634), GJB6 (ENSG00000121742), GJA3 (ENSG00000121743), GJA9 (ENSG00000131233), GJA10 (ENSG00000135355), GJA1 (ENSG00000152661), GJD2 (ENSG00000159248), GJB7 (ENSG00000164411), GJB2 (ENSG00000165474), GJB1 (ENSG00000169562), GJC3 (ENSG00000176402), GJD4 (ENSG00000177291), GJC1 (ENSG00000182963), GJD3 (ENSG00000183153), GJA4 (ENSG00000187513), GJB5 (ENSG00000189280), GJB4 (ENSG00000189433), GJC2 (ENSG00000198835), GJE1 (ENSG00000203733), GJA5 (ENSG00000265107)

Protein

Protein identifiers

Gap junction beta-3 protein — O75712 (reviewed: O75712)

Alternative names: Connexin-31

All UniProt accessions (2): A0A654ICK0, O75712

UniProt curated annotations — full annotation on UniProt →

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.

Subunit / interactions. A connexon is composed of a hexamer of connexins. Interacts with CNST.

Subcellular location. Cell membrane. Cell junction. Gap junction.

Disease relevance. Erythrokeratodermia variabilis et progressiva 1 (EKVP1) [MIM:133200] A form of erythrokeratodermia variabilis et progressiva, a genodermatosis characterized by the coexistence of two independent skin lesions: transient erythema and hyperkeratosis that is usually localized but occasionally occurs in its generalized form. Clinical presentation varies significantly within a family and from one family to another. Palmoplantar keratoderma is present in around 50% of cases. The disease is caused by variants affecting the gene represented in this entry. Deafness, autosomal dominant, 2B (DFNA2B) [MIM:612644] A form of non-syndromic sensorineural deafness characterized by progressive high frequency hearing loss in adulthood, with milder expression in females. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the connexin family. Beta-type (group I) subfamily.

RefSeq proteins (2): NP_001005752, NP_076872* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000500	Connexin	Family
IPR002269	Connexin31	Family
IPR013092	Connexin_N	Domain
IPR017990	Connexin_CS	Conserved_site
IPR019570	Connexin_CCC	Domain
IPR038359	Connexin_N_sf	Homologous_superfamily

Pfam: PF00029

UniProt features (21 total): sequence variant 9, topological domain 5, transmembrane region 4, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75712-F1	79.29	0.35

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-190861	Gap junction assembly
R-HSA-9725554	Differentiation of Keratinocytes in Interfollicular Epidermis in Mammalian Skin

MSigDB gene sets: 203 (showing top): TSENG_IRS1_TARGETS_UP, JAEGER_METASTASIS_DN, ENK_UV_RESPONSE_KERATINOCYTE_UP, REACTOME_MEMBRANE_TRAFFICKING, GOBP_CELL_CELL_SIGNALING, BILD_HRAS_ONCOGENIC_SIGNATURE, RICKMAN_METASTASIS_DN, SASAI_RESISTANCE_TO_NEOPLASTIC_TRANSFROMATION, CHARAFE_BREAST_CANCER_BASAL_VS_MESENCHYMAL_UP, chr1p34, TGANTCA_AP1_C, CHARAFE_BREAST_CANCER_LUMINAL_VS_BASAL_DN, AIGNER_ZEB1_TARGETS, AFFAR_YY1_TARGETS_DN, REACTOME_GAP_JUNCTION_ASSEMBLY

GO Biological Process (4): placenta development (GO:0001890), cell-cell signaling (GO:0007267), cell communication (GO:0007154), transmembrane transport (GO:0055085)

GO Molecular Function (2): gap junction channel activity (GO:0005243), protein binding (GO:0005515)

GO Cellular Component (8): cytoplasm (GO:0005737), gap junction (GO:0005921), connexin complex (GO:0005922), cell junction (GO:0030054), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), membrane (GO:0016020), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Gap junction trafficking	1
Developmental Cell Lineages of the Integumentary System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cellular process	2
animal organ development	1
cell communication	1
signaling	1
transport	1
wide pore channel activity	1
binding	1
intracellular anatomical structure	1
cell-cell junction	1
gap junction	1
plasma membrane protein complex	1
membrane	1
cell periphery	1
anchoring junction	1
cell junction	1

Protein interactions and networks

STRING

722 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GJB3	KCNQ4	P56696	931
GJB3	SLC26A4	O43511	810
GJB3	GJB2	P29033	741
GJB3	AP1S1	P61966	646
GJB3	GJB6	O95452	636
GJB3	MYO15A	Q9UKN7	593
GJB3	PKP1	Q13835	590
GJB3	OTOF	Q9HC10	583
GJB3	KCNQ3	O43525	576
GJB3	TMC1	Q8TDI8	573
GJB3	LORICRIN	P23490	551
GJB3	WFS1	O76024	547
GJB3	TMIE	Q8NEW7	541
GJB3	CDH23	Q9H251	517
GJB3	DSP	P15924	509

IntAct

41 interactions, top by confidence:

A	B	Type	Score
BTN2A2	GJB3	psi-mi:“MI:0915”(physical association)	0.560
TUSC5	GJB3	psi-mi:“MI:0915”(physical association)	0.560
COMT	GJB3	psi-mi:“MI:0915”(physical association)	0.560
MFSD11	GJB3	psi-mi:“MI:0915”(physical association)	0.560
IGFBP5	GJB3	psi-mi:“MI:0915”(physical association)	0.560
RPRM	GJB3	psi-mi:“MI:0915”(physical association)	0.560
GIMAP5	GJB3	psi-mi:“MI:0915”(physical association)	0.560
LHFPL5	GJB3	psi-mi:“MI:0915”(physical association)	0.560
LAT	GJB3	psi-mi:“MI:0915”(physical association)	0.560
GJB3	TMUB2	psi-mi:“MI:0915”(physical association)	0.560
GJB3	BTN2A2	psi-mi:“MI:0915”(physical association)	0.560
GJB3	COMT	psi-mi:“MI:0915”(physical association)	0.560
GJB3	LHFPL5	psi-mi:“MI:0915”(physical association)	0.560
GJB3	SERP1	psi-mi:“MI:0915”(physical association)	0.560
GJB3	IGFBP5	psi-mi:“MI:0915”(physical association)	0.560
GJB3	TMEM97	psi-mi:“MI:0915”(physical association)	0.560
GJB3	RPRM	psi-mi:“MI:0915”(physical association)	0.560
GJB3	GIMAP5	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (19): GJB2 (Phenotypic Enhancement), GJB3 (Two-hybrid), GJB3 (Two-hybrid), GJB3 (Two-hybrid), GJB3 (Two-hybrid), GJB3 (Two-hybrid), GJB3 (Two-hybrid), GJB3 (Two-hybrid), GJB3 (Two-hybrid), GJB3 (Two-hybrid), GIMAP5 (Two-hybrid), LHFPL5 (Two-hybrid), LAT (Two-hybrid), PCYOX1 (Affinity Capture-MS), ATP6V0A2 (Affinity Capture-MS)

ESM2 similar proteins: A0A1B0GTI8, A6NN92, E9Q9H8, F6RWY9, O18968, O64761, O70610, O75712, O93533, O95377, O95452, P08033, P08034, P08983, P25305, P28230, P28231, P28232, P28233, P36380, P49111, P51916, P70689, P79826, Q02738, Q02739, Q0IIL2, Q13571, Q2KJA5, Q3SZ36, Q3T110, Q3TUD9, Q49LS6, Q4VV71, Q58D78, Q5E9Z5, Q5F410, Q5JW98, Q5REZ0, Q60HF7

Diamond homologs: A2VE67, A4GG66, A4GVD1, A4IFL1, A6XKM2, O18968, O54851, O57474, O70610, O75712, O93533, O95377, O95452, P08033, P08034, P08050, P08983, P14154, P16863, P16864, P17302, P18246, P18860, P18861, P21994, P23242, P25305, P28228, P28229, P28230, P28231, P28232, P28233, P28234, P28235, P28236, P29033, P29414, P29415, P33725

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

243 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	5
Uncertain significance	149
Likely benign	31
Benign	19

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
627448	NM_024009.3(GJB3):c.8G>A (p.Trp3Ter)	Pathogenic
6482	NM_024009.3(GJB3):c.34G>C (p.Gly12Arg)	Pathogenic
6483	NM_024009.3(GJB3):c.35G>A (p.Gly12Asp)	Pathogenic
6484	NM_024009.3(GJB3):c.256T>A (p.Cys86Ser)	Pathogenic
6489	NM_024009.3(GJB3):c.125G>C (p.Arg42Pro)	Pathogenic
6491	NM_024009.3(GJB3):c.101T>C (p.Leu34Pro)	Pathogenic
1201181	NM_024009.3(GJB3):c.134G>C (p.Gly45Ala)	Likely pathogenic
2733870	NM_024009.3(GJB3):c.34G>A (p.Gly12Ser)	Likely pathogenic
421156	NM_024009.3(GJB3):c.110T>A (p.Val37Glu)	Likely pathogenic
426999	NM_024009.3(GJB3):c.298G>A (p.Glu100Lys)	Likely pathogenic
4782314	NM_024009.3(GJB3):c.134G>A (p.Gly45Glu)	Likely pathogenic

SpliceAI

153 predictions. Top by Δscore:

Variant	Effect	Δscore
1:34784727:A:AG	acceptor_gain	1.0000
1:34784728:A:G	acceptor_gain	1.0000
1:34784737:GGTA:G	acceptor_gain	1.0000
1:34781777:AGGT:A	donor_loss	0.9900
1:34781779:G:C	donor_loss	0.9900
1:34781779:G:GG	donor_gain	0.9900
1:34784737:GGT:G	acceptor_gain	0.9900
1:34781775:GCAG:G	donor_gain	0.9800
1:34781780:T:A	donor_loss	0.9800
1:34784736:AG:A	acceptor_gain	0.9800
1:34784737:GG:G	acceptor_gain	0.9800
1:34784736:A:AG	acceptor_gain	0.9700
1:34784737:G:GA	acceptor_gain	0.9700
1:34781776:CAG:C	donor_gain	0.9600
1:34781777:AG:A	donor_gain	0.9500
1:34781778:GG:G	donor_gain	0.9500
1:34781774:TGCAG:T	donor_gain	0.9400
1:34781775:GCAGG:G	donor_gain	0.9400
1:34784729:T:G	acceptor_gain	0.9300
1:34782062:A:T	donor_gain	0.8600
1:34782057:G:T	donor_gain	0.7700
1:34784741:GGC:G	acceptor_gain	0.7600
1:34781779:G:T	donor_gain	0.7400
1:34782057:G:GT	donor_gain	0.7400
1:34782066:G:GT	donor_gain	0.7400
1:34781554:G:GT	donor_gain	0.7100
1:34782801:G:T	donor_gain	0.6500
1:34782061:G:GT	donor_gain	0.6200
1:34782041:G:GT	donor_gain	0.5900
1:34782801:G:GT	donor_gain	0.5600

AlphaMissense

1756 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:34784919:T:A	C53S	0.999
1:34784920:G:C	C53S	0.999
1:34784921:C:G	C53W	0.999
1:34784940:T:A	C60S	0.999
1:34784941:G:C	C60S	0.999
1:34785290:C:G	C176W	0.999
1:34784892:T:A	W44R	0.998
1:34784892:T:C	W44R	0.998
1:34784894:G:C	W44C	0.998
1:34784894:G:T	W44C	0.998
1:34784914:T:G	F51C	0.998
1:34784920:G:A	C53Y	0.998
1:34784952:T:A	C64S	0.998
1:34784952:T:C	C64R	0.998
1:34784953:G:A	C64Y	0.998
1:34784953:G:C	C64S	0.998
1:34784954:C:G	C64W	0.998
1:34784991:T:A	W77R	0.998
1:34784991:T:C	W77R	0.998
1:34785055:G:C	R98P	0.998
1:34785162:A:C	S134R	0.998
1:34785164:C:A	S134R	0.998
1:34785164:C:G	S134R	0.998
1:34785288:T:A	C176S	0.998
1:34785289:G:A	C176Y	0.998
1:34785289:G:C	C176S	0.998
1:34785314:G:C	K184N	0.998
1:34785314:G:T	K184N	0.998
1:34784771:G:C	W3C	0.997
1:34784771:G:T	W3C	0.997

dbSNP variants (sampled 300 via entrez): RS1000947778 (1:34783276 A>C), RS1001537543 (1:34779882 A>C), RS1001652639 (1:34785901 A>G), RS1002411368 (1:34784840 C>T), RS1002758749 (1:34784545 C>T), RS1003320590 (1:34781158 C>A,G,T), RS1003430730 (1:34781330 CA>C), RS1003976199 (1:34784297 T>A,C), RS1004646950 (1:34786245 C>A), RS1005617356 (1:34785146 G>A), RS1006731339 (1:34785156 C>A,T), RS1007322488 (1:34786718 T>G), RS1007650620 (1:34780385 G>A), RS1007826830 (1:34782308 C>T), RS1008109628 (1:34782012 C>A,T)

Disease associations

OMIM: gene MIM:603324 | disease phenotypes: MIM:220290, MIM:612644, MIM:133200, MIM:601072, MIM:607197

GenCC curated gene-disease

Disease	Classification	Inheritance
erythrokeratodermia variabilis et progressiva 1	Strong	Autosomal dominant
autosomal recessive nonsyndromic hearing loss 1A	Moderate	Autosomal dominant
neuropathy with hearing impairment	Supportive	Autosomal dominant
erythrokeratodermia variabilis	Supportive	Autosomal dominant
autosomal dominant nonsyndromic hearing loss	Supportive	Autosomal dominant
hearing loss, autosomal recessive	Supportive	Autosomal recessive
autosomal dominant nonsyndromic hearing loss 2B	Limited	Unknown
nonsyndromic genetic hearing loss	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (2)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
erythrokeratodermia variabilis	Definitive	AD
nonsyndromic genetic hearing loss	Disputed	AD

Mondo (10): autosomal recessive nonsyndromic hearing loss 1A (MONDO:0009076), autosomal dominant nonsyndromic hearing loss 2B (MONDO:0012976), erythrokeratodermia variabilis et progressiva 1 (MONDO:0033010), autosomal recessive nonsyndromic hearing loss 8 (MONDO:0010987), hearing loss, autosomal recessive (MONDO:0019588), hearing loss disorder (MONDO:0005365), erythrokeratodermia variabilis (MONDO:0017851), nonsyndromic genetic hearing loss (MONDO:0019497), neuropathy with hearing impairment (MONDO:0015351), autosomal dominant nonsyndromic hearing loss (MONDO:0019587)

Orphanet (5): Erythrokeratodermia variabilis (Orphanet:317), Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635), Rare autosomal recessive non-syndromic sensorineural deafness type DFNB (Orphanet:90636), Progressive symmetric erythrokeratodermia (Orphanet:316), Erythrokeratoderma variabilis progressiva (Orphanet:308166)

HPO phenotypes

40 total (30 of 40 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000035	Abnormal testis morphology
HP:0000252	Microcephaly
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000411	Protruding ear
HP:0000501	Glaucoma
HP:0000518	Cataract
HP:0000819	Diabetes mellitus
HP:0000958	Dry skin
HP:0000962	Hyperkeratosis
HP:0000988	Skin rash
HP:0000992	Cutaneous photosensitivity
HP:0001019	Erythroderma
HP:0001034	Hypermelanotic macule
HP:0001156	Brachydactyly
HP:0001182	Tapered finger
HP:0001249	Intellectual disability
HP:0001595	Abnormal hair morphology
HP:0001596	Alopecia
HP:0001597	Abnormal nail morphology
HP:0001751	Abnormal vestibular function
HP:0001824	Weight loss
HP:0002230	Generalized hirsutism
HP:0003593	Infantile onset
HP:0004322	Short stature
HP:0005101	High-frequency hearing impairment
HP:0005588	Patchy palmoplantar hyperkeratosis
HP:0005595	Generalized hyperkeratosis

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST007998_5	Intraocular pressure	7.000000e-10
GCST009612_3	Triglyceride levels x thiazide or thiazide-like diuretics use interaction	6.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004695	intraocular pressure measurement
EFO:0004530	triglyceride measurement

MeSH disease descriptors (7)

Descriptor	Name	Tree numbers
D056266	Erythrokeratodermia Variabilis	C16.320.850.337; C17.800.229.606; C17.800.428.304; C17.800.827.337
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
C567214	Deafness, Autosomal Dominant 2B (supp.)
C564609	Deafness, Autosomal Recessive (supp.)
C567134	Deafness, Autosomal Recessive 1A (supp.)
C536154	Keratoderma palmoplantaris transgrediens (supp.)
C580334	Nonsyndromic Deafness (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other ic — Connexins and Pannexins

CTD chemical–gene interactions

31 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, decreases methylation, increases expression	3
Smoke	decreases expression, decreases reaction	2
sotorasib	affects cotreatment, decreases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
ethyl-p-hydroxybenzoate	increases expression	1
beta-lapachone	increases expression	1
sodium arsenite	decreases expression	1
dibenzo(a,l)pyrene	decreases expression	1
CGP 52608	affects binding, increases reaction	1
erucylphospho-N,N,N-trimethylpropylammonium	increases expression	1
nutlin 3	affects cotreatment, increases expression	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Decitabine	decreases expression, decreases reaction	1
Arsenic Trioxide	decreases response to substance	1
Arsenic	affects methylation	1
Camptothecin	increases expression	1
Dactinomycin	increases expression, affects cotreatment	1
Dichlorodiphenyl Dichloroethylene	decreases expression	1
Estradiol	affects binding, increases expression	1
Gasoline	affects cotreatment, increases abundance, increases expression	1
Lead	affects methylation	1
N-Nitrosopyrrolidine	increases expression	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, increases abundance, increases expression	1
Silicon Dioxide	increases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Cyclosporine	decreases expression	1
Okadaic Acid	increases expression	1
Permethrin	increases expression	1

Clinical trials (associated diseases)

301 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00205881	PHASE4	COMPLETED	Bilateral Benefit in Adult Users of the HiRes 90K Bionic Ear System
NCT00331539	PHASE4	UNKNOWN	Relationship Between Auto NRT and Behavioural T & C Levels With the Nucleus Freedom Cochlear Implant
NCT00424307	PHASE4	UNKNOWN	Bilateral Cochlear Implant Benefit in Young Children
NCT00765635	PHASE4	COMPLETED	Chlorobutanol, Potassium Carbonate, and Irrigation in Cerumen Removal
NCT03321006	PHASE4	COMPLETED	Treating Hearing Loss to Improve Mood and Cognition in Older Adults
NCT01499901	PHASE3	WITHDRAWN	Comparison of the Bilateral Sequential and Simultaneous Cochlear Implantation in the Deaf Children
NCT02561091	PHASE3	COMPLETED	AM-111 in the Treatment of Acute Inner Ear Hearing Loss
NCT03331627	PHASE3	COMPLETED	Safety and Efficacy of STR001-IT and STR001-ER in Patients With SSHL
NCT05532657	PHASE3	ACTIVE_NOT_RECRUITING	ACHIEVE Brain Health Follow-Up Study
NCT00013455	PHASE2	COMPLETED	Quantifying Auditory Perceptual Learning Following Hearing Aid Fitting
NCT00323427	PHASE2	COMPLETED	Clinical Trial of the Living Well With Hearing Loss Workshop
NCT00552786	PHASE2	COMPLETED	Antioxidation Medication for Noise-induced Hearing Loss
NCT00802425	PHASE2	COMPLETED	Efficacy of AM-111 in Patients With Acute Sensorineural Hearing Loss
NCT01139281	PHASE2	COMPLETED	The Protective Effect of Ginkgo Biloba Extract on Cisplatin-induced Ototoxicity in Humans
NCT01451853	PHASE2	UNKNOWN	SPI-1005 for Prevention and Treatment of Chemotherapy Induced Hearing Loss
NCT01588925	PHASE2	COMPLETED	Hearing Preservation Using Dexamethasone and Hyaluronic Acid for Cochlear Implantation
NCT01773278	PHASE2	RECRUITING	Cholesterol and Antioxidant Treatment in Patients With Smith-Lemli-Opitz Syndrome (SLOS)
NCT02832128	PHASE2	COMPLETED	Evaluating Possible Improvement in Speech and Hearing Tests After 28 Days of Dosing of the Study Drug AUT00063 Compared to Placebo (QuicKfire)
NCT04915183	PHASE2	RECRUITING	Atorvastatin to Reduce Cisplatin-Induced Hearing Loss Among Individuals With Head and Neck Cancer
NCT05258773	PHASE2	COMPLETED	Evaluation of the Presence of SENS-401 in the Perilymph
NCT06340633	PHASE2	RECRUITING	SPI-1005 in Adults Receiving Cochlear Implant
NCT00582946	PHASE1	COMPLETED	Wide-Bandwidth Open Canal Hearing Aid For Better Multitalker Speech Understanding
NCT00584155	PHASE1	WITHDRAWN	Protection From Cisplatin Ototoxicity by Lactated Ringers
NCT01206829	PHASE1	UNKNOWN	Hearing Impairment, Cognitive Therapy and Coping
NCT01256229	PHASE1	COMPLETED	Outcomes In Children With Developmental Delay And Deafness
NCT01343394	PHASE1	WITHDRAWN	Safety of Autologous Human Umbilical Cord Blood Mononuclear Fraction to Treat Acquired Hearing Loss in Children
NCT01452607	PHASE1	COMPLETED	Study to Evaluate the Safety and Pharmacokinetics of SPI-1005
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT04041440	PHASE1	COMPLETED	Speech Recognition Training in Children With Hearing Loss
NCT07218913	PHASE1	RECRUITING	Testing the Addition of Pedmark to Cisplatin Chemotherapy for Reducing Drug-Induced Ear Damage in Men With Stage II-III Metastatic Testicular Germ Cell Tumors
NCT05402813	Not specified	RECRUITING	Natural History in Children up to 16 Years With Mild to Profound Hearing Loss Due to Mutations in GJB2 / OTOF Genes
NCT01802190	Not specified	TERMINATED	Prevalence of POU4F3 and SLC17A8 Mutations
NCT00486577	PHASE2/PHASE3	COMPLETED	Chronic Electrical Stimulation of the Auditory Cortex for Intractable Tinnitus
NCT00789061	PHASE2/PHASE3	UNKNOWN	Applying Proton Pump Inhibitor to Prevent and Treat Acute Fluctuating Hearing Loss in Patients With SLC26A4 Mutation
NCT01423409	PHASE2/PHASE3	COMPLETED	Multicenter Trial Assessing an Innovative VAS of Pain Among Deaf People
NCT05786378	PHASE2/PHASE3	UNKNOWN	Assessment of The Efficacy of Intratympanic Platelet Rich Plasma for Treatment of Sensorineural Hearing Loss.
NCT01108601	PHASE1/PHASE2	UNKNOWN	Transtympanic Ringer’s Lactate for the Prevention of Cisplatin Ototoxicity
NCT01621256	PHASE1/PHASE2	COMPLETED	Efficacy, Safety, and Tolerability of Ancrod in Patients With Sudden Hearing Loss
NCT06370351	PHASE1/PHASE2	RECRUITING	A Phase I/II Clinical Trial with SENS-501 in Children Suffering from Severe to Profound Hearing Loss Due to Otoferlin (OTOF) Mutations
NCT06545175	PHASE1/PHASE2	RECRUITING	Intracochlear Application of VSF1.01 for the Reduction of Cochlear Implant Surgery Related Trauma