GJB1

Summary

GJB1 (gap junction protein beta 1, HGNC:4283) is a protein-coding gene on chromosome Xq13.1, encoding Gap junction beta-1 protein (P08034). 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 encodes a member of the gap junction protein family. The gap junction proteins are membrane-spanning proteins that assemble to form gap junction channels that facilitate the transfer of ions and small molecules between cells. According to sequence similarities at the nucleotide and amino acid levels, the gap junction proteins are divided into two categories, alpha and beta. Mutations in this gene cause X-linked Charcot-Marie-Tooth disease, an inherited peripheral neuropathy. Alternatively spliced transcript variants encoding the same protein have been found for this gene.

Source: NCBI Gene 2705 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Charcot-Marie-Tooth disease X-linked dominant 1 (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 870 total — 141 pathogenic, 80 likely-pathogenic
• Phenotypes (HPO): 64
• Druggable target: yes
• MANE Select transcript: NM_000166

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4283
Approved symbol	GJB1
Name	gap junction protein beta 1
Location	Xq13.1
Locus type	gene with protein product
Status	Approved
Aliases	CX32
Ensembl gene	ENSG00000169562
Ensembl biotype	protein_coding
OMIM	304040
Entrez	2705

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 24 protein_coding

ENST00000361726, ENST00000374029, ENST00000447581, ENST00000645009, ENST00000646835, ENST00000647424, ENST00000674549, ENST00000674844, ENST00000675209, ENST00000675368, ENST00000675609, ENST00000870748, ENST00000870749, ENST00000870750, ENST00000870751, ENST00000870752, ENST00000870753, ENST00000870754, ENST00000870755, ENST00000870756, ENST00000870757, ENST00000870758, ENST00000870759, ENST00000870760

RefSeq mRNA: 2 — MANE Select: NM_000166 NM_000166, NM_001097642

CCDS: CCDS14408

Canonical transcript exons

ENST00000361726 — 2 exons

Exon	Start	End
ENSE00001436286	71223224	71223335
ENSE00001462188	71223692	71225516

Expression profiles

Bgee: expression breadth ubiquitous, 207 present calls, max score 98.43.

FANTOM5 (CAGE): breadth broad, TPM avg 6.4472 / max 603.1336, expressed in 271 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
196661	2.9301	149
196665	1.9555	132
196664	1.1186	88
196666	0.1480	61
196669	0.0896	30
196663	0.0776	48
196667	0.0718	28
196662	0.0420	26
196668	0.0141	7

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	98.43	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.95	gold quality
liver	UBERON:0002107	97.12	gold quality
body of pancreas	UBERON:0001150	97.09	gold quality
spinal cord	UBERON:0002240	97.01	gold quality
mucosa of transverse colon	UBERON:0004991	95.71	gold quality
inferior vagus X ganglion	UBERON:0005363	93.68	gold quality
gall bladder	UBERON:0002110	93.55	gold quality
olfactory bulb	UBERON:0002264	93.17	silver quality
pancreas	UBERON:0001264	92.53	gold quality
subthalamic nucleus	UBERON:0001906	91.60	gold quality
substantia nigra	UBERON:0002038	91.07	gold quality
midbrain	UBERON:0001891	90.90	gold quality
inferior olivary complex	UBERON:0002127	90.41	gold quality
pons	UBERON:0000988	90.19	gold quality
dorsal plus ventral thalamus	UBERON:0001897	89.71	gold quality
parotid gland	UBERON:0001831	89.34	gold quality
medulla oblongata	UBERON:0001896	89.19	gold quality
middle frontal gyrus	UBERON:0002702	88.86	gold quality
ventral tegmental area	UBERON:0002691	88.81	gold quality
right uterine tube	UBERON:0001302	88.56	gold quality
type B pancreatic cell	CL:0000169	88.52	gold quality
adult mammalian kidney	UBERON:0000082	88.40	gold quality
lateral nuclear group of thalamus	UBERON:0002736	88.38	gold quality
rectum	UBERON:0001052	87.71	gold quality
substantia nigra pars reticulata	UBERON:0001966	87.09	gold quality
superior vestibular nucleus	UBERON:0007227	87.06	gold quality
putamen	UBERON:0001874	86.99	gold quality
islet of Langerhans	UBERON:0000006	86.93	gold quality
duodenum	UBERON:0002114	86.78	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.52

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): BHLHA15, EGR2, HNF1A, HNF4A, NFIA, SOX10, SP1, SP3, YY1

miRNA regulators (miRDB)

46 targeting GJB1, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4668-3P	100.00	68.74	2635
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-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-6799-5P	99.14	65.72	2093

Literature-anchored findings (GeneRIF, showing 40)

• Voltage opens unopposed gap junction hemichannels formed by a connexin 32 mutant associated with X-linked Charcot-Marie-Tooth disease (PMID:11891346)
• Cx32 mutants that are associated with a CNS phenotype do not interact with Cx45, but may instead have other toxic effects in oligodendrocytes. (PMID:12111842)
• alpha-catenin facilitates trafficking of connexins 32 and 43 to the cell surface and induces gap junction assembly (PMID:12205082)
• A new mutation in the connexin 32 gene of a Chinese family with Charcot-Marie-Tooth disease associated with central conduction slowing (PMID:12362307)
• G/A transition (Ala40Thr)in a conserved transmembrane region of the connexin-32 gene was also found associated with X-linked Charcot-Marie-Tooth disease (PMID:12536289)
• These findings suggest that some gain of function mutations of GJB1 may be related to CNS symptoms because the patients with GJB1 deletion only had peripheral neuropathy. (PMID:12542510)
• gap junctional intercellular communication in hepatocellular carcinoma cell lines, and signal transduction mechanism of gap junction genes connexin32, connexin43 in hepatocarcinogenesis. (PMID:12717835)
• A mutation of the Cx32 gene is identified, consisting of a guanine to adenine transition at position 271 (271G-A) in a large Turkish family (N=39) with Charcot-Marie-Tooth disease. (PMID:12775342)
• Data show that connexin 32 (Cx32)-transfected HepG2 cells not only expressed a higher level of Cx32 mRNA, but also showed increased gap junctional intercellular communication. (PMID:12849984)
• Mutation (D178Y) that causes an inherited peripheral neuropathy induces a complete Ca2+ deregulation of Cx32 hemichannel activity. (PMID:14663144)
• Transgenic mice with the mutant Cx32 gene are more susceptible to diethylnitrosamine-induced hepatocarcinogenesis, developing more liver tumors with shorter latency. (PMID:14688024)
• molecular genetic analysis of the GJB1 gene in Charcot-Marie-Tooth type X1 disease (PMID:14960772)
• 10 of 22 CMTX Cx32 mutations studied in the present investigation could lead to the assembly of defective Cx32 gap junctions, which in turn may result in peripheral neuropathy (PMID:15006706)
• mRNA level correlates with cell differentiation, nd is predictive of postopoperative recurrence in hepatocellular carcinoma. (PMID:15334670)
• This study identified a large Charcot-Marie-Tooth disease family with a novel mutation in the Connexin 32 (Cx32) P2 promoter region at position -526bp. (PMID:15470753)
• Nine patients had clinical features of X-linked dominant inheritance and a moderate Charcot-Marie-Tooth neuropathy phenotype showed a G-to-A transition at position -215 of the nerve-specific promoter P2 of the Cx32 gene. (PMID:15508871)
• Cpmmexom 32 was found intracellularly in activated hepatic stellate cells. (PMID:15685554)
• Human Cx32 protein “rescued” the phenotype of cx32-null mice. The transgenic mice have less demyelinated or remyelinated axons than nontransgenic littermates. Loss of Schwann-cell-autonomous expression of Cx32 is sufficient for demyelination in CMT1X. (PMID:15703409)
• The connexin 32 were sparsely distributed In epithelial cells. (PMID:15704645)
• A Charcot-Marie-Tooth syndrome in a family with a missense mutation in GJB1. (PMID:15947997)
• Cx32 is prenylated, but that prenylation is not required for proper trafficking of Cx32 and perhaps not even for certain aspects of its function, in myelinating Schwann cells. (PMID:16079393)
• Four novel connexin 32 mutations in X-linked Charcot-Marie-Tooth disease with phenotypic variability. (PMID:16096811)
• This study identified a novel substitution T>C in the P2 promoter of GJB1 at position -529, in the SOX10 binding site S2 in a family with X-linked dominant Charcot-Marie-Tooth neuropathy. (PMID:16373087)
• In transgenic mice that express the R142W mutation in myelinating Schwann cells, the Arg142Trp mutant protein is aberrantly localized to the Golgi, indicating that it does not traffic properly. (PMID:16790356)
• We describe an Italian family with an intermediate CMTX phenotype with late onset. Mutation screening of the GJB1 gene revealed a 9-bp duplication leading to the insertion of three aminoacids. (PMID:17052905)
• Most GJB1 mutations cause neuropathy by a loss of normal connexin 32 function. (PMID:17353473)
• cytoplasmic Cx32 protein exerts effects favourable for HCC progression, such as invasion and metastasis, once the cells have acquired a malignant phenotype. (PMID:17372902)
• a cross-talk between CFTR and a variety of gap junction channels. Cytoskeletal scaffolding proteins and/or other intermediate cytoplasmic proteins are likely to play a role in CFTR-connexins interaction. (PMID:17546509)
• we refer to a new aspect of Cx32-dependent functions against cell proliferation, invasion and metastasis in RCC cells, especially in a GJIC-independent manner[review] (PMID:17565422)
• Connexin 32 may contribute to the enhancement of vinorelbine-induced cytotoxicity in A549 lung cancer cells. (PMID:17569045)
• Two novel mutations in the connexin32 gene are more severe than the majority of previously described mutations possibly due to the severe structural change of the gap junction they encode. (PMID:17620124)
• Result of DNA sequencing demonstrated that both families with X-linked Charcot-Marie-Tooth disease had a same mutation of 622G–>A, which resulted in a substitution of Glu208Lys. (PMID:17646144)
• This studies identified a L89P mutation for the first time in a CMTX1 family in China and an associated response to PMP22 in males. (PMID:17714866)
• results suggest that Cx32 inhibits hypoxia adaptation governed by HIF-2alpha, and this may help to reduce the metastasis of renal cell carcinoma cells (PMID:18058801)
• Polarized Caco-2/TC7 cells express significant amounts of Cx26, Cx32 and Cx43. (PMID:18267319)
• Increased expression of Cx32 in metastases to the lymph nodes might reflect alteration in connexin gene transcription during breast carcinogenesis and finally, it may be a sign of more malignant phenotype of cancerous cells. (PMID:18292829)
• Cx32 mutants with central nervous system manifestations are retained intracellularly in oligodendrocytes, but do not alter the co-expression of Cx31.3. (PMID:18353664)
• Charge selectivity of the Cx32*43E1 chimeric hemichannel can be determined by the combined actions of charges dispersed over the permeation pathway rather than by a defined region that acts as a charge selectivity filter. (PMID:18372303)
• identified 22 mutations in GJB1 in Italian patients with X-linked Charcot-Marie-Tooth disease (PMID:18379723)
• The decreasing expression of connexin Cx32 and Cx43 is obviously correlated with the occurrence, development and metastatic potential of stomach cancers. (PMID:18396685)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	gjb1a	ENSDARG00000035553
danio_rerio	gjb1b	ENSDARG00000058064
mus_musculus	Gjb1	ENSMUSG00000047797
rattus_norvegicus	Gjb1	ENSRNOG00000063213

Paralogs (20): GJA8 (ENSG00000121634), GJB6 (ENSG00000121742), GJA3 (ENSG00000121743), GJA9 (ENSG00000131233), GJA10 (ENSG00000135355), GJA1 (ENSG00000152661), GJD2 (ENSG00000159248), GJB7 (ENSG00000164411), GJB2 (ENSG00000165474), GJC3 (ENSG00000176402), GJD4 (ENSG00000177291), GJC1 (ENSG00000182963), GJD3 (ENSG00000183153), GJA4 (ENSG00000187513), GJB3 (ENSG00000188910), GJB5 (ENSG00000189280), GJB4 (ENSG00000189433), GJC2 (ENSG00000198835), GJE1 (ENSG00000203733), GJA5 (ENSG00000265107)

Protein

Protein identifiers

Gap junction beta-1 protein — P08034 (reviewed: P08034)

Alternative names: Connexin-32, GAP junction 28 kDa liver protein

All UniProt accessions (4): A0A2R8YD01, A0A654ICJ7, C9JWU8, P08034

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. Charcot-Marie-Tooth disease, X-linked dominant, 1 (CMTX1) [MIM:302800] A form of Charcot-Marie-Tooth disease, a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Charcot-Marie-Tooth disease is classified in two main groups on the basis of electrophysiologic properties and histopathology: primary peripheral demyelinating neuropathies characterized by severely reduced motor nerve conduction velocities (NCVs) (less than 38m/s) and segmental demyelination and remyelination, and primary peripheral axonal neuropathies characterized by normal or mildly reduced NCVs and chronic axonal degeneration and regeneration on nerve biopsy. CMTX1 has both demyelinating and axonal features. Central nervous system involvement may occur. The disease is caused by variants affecting the gene represented in this entry. Dejerine-Sottas syndrome (DSS) [MIM:145900] A severe degenerating neuropathy of the demyelinating Charcot-Marie-Tooth disease category, with onset by age 2 years. Characterized by motor and sensory neuropathy with very slow nerve conduction velocities, increased cerebrospinal fluid protein concentrations, hypertrophic nerve changes, delayed age of walking as well as areflexia. There are both autosomal dominant and autosomal recessive forms of Dejerine-Sottas syndrome. The gene represented in this entry may act as a disease modifier.

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

RefSeq proteins (2): NP_000157, NP_001091111 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000500	Connexin	Family
IPR002267	Connexin32	Family
IPR013092	Connexin_N	Domain
IPR017990	Connexin_CS	Conserved_site
IPR019570	Connexin_CCC	Domain
IPR038359	Connexin_N_sf	Homologous_superfamily

Pfam: PF00029

UniProt features (229 total): sequence variant 201, helix 6, topological domain 5, strand 5, modified residue 4, transmembrane region 4, turn 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

15 structures.

PDB	Method	Resolution (Å)
7ZXM	ELECTRON MICROSCOPY	2.14
9QND	ELECTRON MICROSCOPY	2.35
7ZXP	ELECTRON MICROSCOPY	2.39
7ZXO	ELECTRON MICROSCOPY	2.5
8QJF	ELECTRON MICROSCOPY	2.86
7ZXT	ELECTRON MICROSCOPY	2.9
8QJH	ELECTRON MICROSCOPY	2.91
7ZXN	ELECTRON MICROSCOPY	3.06
9QN9	ELECTRON MICROSCOPY	3.12
9QNF	ELECTRON MICROSCOPY	3.16
8QK6	ELECTRON MICROSCOPY	3.18
9QNT	ELECTRON MICROSCOPY	3.29
8QKI	ELECTRON MICROSCOPY	3.46
7ZXQ	ELECTRON MICROSCOPY	3.53
5KK9	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P08034-F1	80.75	0.42

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (4): 233, 258, 266, 277

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-190704	Oligomerization of connexins into connexons
R-HSA-190827	Transport of connexins along the secretory pathway
R-HSA-190861	Gap junction assembly
R-HSA-9619665	EGR2 and SOX10-mediated initiation of Schwann cell myelination

MSigDB gene sets: 289 (showing top): RNGTGGGC_UNKNOWN, MODULE_52, MODULE_92, GRUETZMANN_PANCREATIC_CANCER_DN, GNF2_GSTM1, MODULE_45, GNF2_HPN, MODULE_128, HNF1_Q6, REACTOME_MEMBRANE_TRAFFICKING, GOBP_CELL_CELL_SIGNALING, NFKB_Q6, MODULE_66, GOBP_CELL_JUNCTION_ORGANIZATION, HOSHIDA_LIVER_CANCER_SUBCLASS_S3

GO Biological Process (5): cell-cell signaling (GO:0007267), nervous system development (GO:0007399), gap junction assembly (GO:0016264), cell communication (GO:0007154), transmembrane transport (GO:0055085)

GO Molecular Function (3): gap junction channel activity (GO:0005243), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (7): endoplasmic reticulum membrane (GO:0005789), connexin complex (GO:0005922), cytoplasm (GO:0005737), plasma membrane (GO:0005886), gap junction (GO:0005921), membrane (GO:0016020), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Gap junction assembly	2
Gap junction trafficking	1
Nervous system development	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular process	2
cellular anatomical structure	2
cell communication	1
signaling	1
system development	1
cell-cell junction assembly	1
transport	1
wide pore channel activity	1
protein binding	1
binding	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
gap junction	1
plasma membrane protein complex	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
cell-cell junction	1
cell junction	1

Protein interactions and networks

STRING

1272 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GJB1	GJB2	P29033	984
GJB1	RNMT	O43148	946
GJB1	PMP22	Q01453	941
GJB1	CALM1	P02593	938
GJB1	CALML3	P27482	937
GJB1	OCLN	Q16625	936
GJB1	CALML5	Q9NZT1	935
GJB1	CALML6	Q8TD86	933
GJB1	CALML4	Q96GE6	933
GJB1	SRC	P12931	904
GJB1	CTNNB1	P35222	899
GJB1	GJB6	O95452	897
GJB1	PRX	Q9BXM0	893
GJB1	GJA1	P17302	887
GJB1	EGR2	P11161	870

IntAct

138 interactions, top by confidence:

A	B	Type	Score
GJB2	GJB1	psi-mi:“MI:0915”(physical association)	0.560
CDIPT	GJB1	psi-mi:“MI:0915”(physical association)	0.560
TF	GJB1	psi-mi:“MI:0915”(physical association)	0.560
GJB1	NDUFB11	psi-mi:“MI:0915”(physical association)	0.560
SERTM1	GJB1	psi-mi:“MI:0915”(physical association)	0.560
GJB1	LHFPL2	psi-mi:“MI:0915”(physical association)	0.560
GJB1	TEX264	psi-mi:“MI:0915”(physical association)	0.560
GJB1	CMTM3	psi-mi:“MI:0915”(physical association)	0.560
GJB1	CLEC7A	psi-mi:“MI:0915”(physical association)	0.560
GJB1	TM4SF4	psi-mi:“MI:0915”(physical association)	0.560
LAT	GJB1	psi-mi:“MI:0915”(physical association)	0.560
GJB1	YIPF6	psi-mi:“MI:0915”(physical association)	0.560
GJB1	MFF	psi-mi:“MI:0915”(physical association)	0.560
GJB1	MAL	psi-mi:“MI:0915”(physical association)	0.560
GJB1	TMEM19	psi-mi:“MI:0915”(physical association)	0.560
GJB1	CTXN3	psi-mi:“MI:0915”(physical association)	0.560
GJB1	GJB2	psi-mi:“MI:0915”(physical association)	0.560
GJB1	MAL2	psi-mi:“MI:0915”(physical association)	0.560
GJB1	ITGAM	psi-mi:“MI:0915”(physical association)	0.560
GJB1	VEGFA	psi-mi:“MI:0915”(physical association)	0.560
GJB1	IER3IP1	psi-mi:“MI:0915”(physical association)	0.560
GJB1	EMP3	psi-mi:“MI:0915”(physical association)	0.560
GJB1	MS4A13	psi-mi:“MI:0915”(physical association)	0.560
GJB1	CXCL9	psi-mi:“MI:0915”(physical association)	0.560
GJB1	TMEM14C	psi-mi:“MI:0915”(physical association)	0.560
TMEM120B	GJB1	psi-mi:“MI:0915”(physical association)	0.560
GJB1	PTPN9	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (84): GJB1 (Affinity Capture-Western), GJB1 (PCA), CANX (Affinity Capture-MS), EMC10 (Affinity Capture-MS), DLST (Affinity Capture-MS), OGDH (Affinity Capture-MS), MRPS36 (Affinity Capture-MS), MSI2 (Affinity Capture-MS), HNRNPH1 (Affinity Capture-MS), CORO1B (Affinity Capture-MS), MRPL30 (Affinity Capture-MS), DNAJB11 (Affinity Capture-MS), OGDHL (Affinity Capture-MS), MAML1 (Affinity Capture-MS), CANX (Affinity Capture-Western)

ESM2 similar proteins: A0A140LIJ0, A1L3G9, A4IFL1, B9X187, O18968, O70491, P08033, P08034, P28230, P35212, P36380, P51915, P60572, Q02738, Q059Y8, Q0V8E7, Q1LXZ7, Q28FG4, Q29559, Q4QR83, Q5E9Z5, Q5FVF4, Q5FWS4, Q5JW98, Q5R7B4, Q5T197, Q5T1A1, Q60HF7, Q640M6, Q6GMB1, Q6WGK6, Q7SY10, Q7TNJ0, Q8BXV2, Q8C2L6, Q8C9E8, Q8CE93, Q8CEG0, Q8N5C1, Q8NDZ6

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

3 interactions.

A	Effect	B	Mechanism
PRKCA	“up-regulates activity”	GJB1	phosphorylation
PRKACA	unknown	GJB1	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	141
Likely pathogenic	80
Uncertain significance	415
Likely benign	97
Benign	12

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1028587	NM_000166.6(GJB1):c.292C>T (p.Gln98Ter)	Pathogenic
10431	NM_000166.6(GJB1):c.424C>T (p.Arg142Trp)	Pathogenic
10433	NM_000166.6(GJB1):c.415G>A (p.Val139Met)	Pathogenic
10434	NM_000166.6(GJB1):c.397T>C (p.Trp133Arg)	Pathogenic
10435	NM_000166.6(GJB1):c.658C>T (p.Arg220Ter)	Pathogenic
10436	NM_000166.6(GJB1):c.89T>A (p.Ile30Asn)	Pathogenic
10438	NM_000166.6(GJB1):c.194A>G (p.Tyr65Cys)	Pathogenic
10439	NM_000166.6(GJB1):c.37G>T (p.Val13Leu)	Pathogenic
10444	NM_000166.6(GJB1):c.254C>G (p.Ser85Cys)	Pathogenic
10449	NM_001097642.3(GJB1):c.-16-511G>C	Pathogenic
10451	NM_000166.6(GJB1):c.407T>C (p.Val136Ala)	Pathogenic
1074879	NM_000166.6(GJB1):c.2T>C (p.Met1Thr)	Pathogenic
1075826	NM_000166.6(GJB1):c.461_464dup (p.Leu156fs)	Pathogenic
1256372	NM_000166.6(GJB1):c.235del (p.Leu79fs)	Pathogenic
1374888	NM_000166.6(GJB1):c.250del (p.Val84fs)	Pathogenic
1405988	NM_000166.6(GJB1):c.484del (p.Met162fs)	Pathogenic
1416909	NM_000166.6(GJB1):c.416T>G (p.Val139Gly)	Pathogenic
1436675	NM_000166.6(GJB1):c.264_280del (p.Leu89fs)	Pathogenic
1447483	NM_000166.6(GJB1):c.316_320del (p.Leu106fs)	Pathogenic
145167	GRCh38/hg38 Xq11.1-21.1(chrX:62712219-78605009)x3	Pathogenic
155724	NM_000166.6(GJB1):c.259C>G (p.Pro87Ala)	Pathogenic
155726	NM_000166.6(GJB1):c.77C>T (p.Ser26Leu)	Pathogenic
1685848	NM_000166.6(GJB1):c.395G>A (p.Trp132Ter)	Pathogenic
1685849	NM_000166.6(GJB1):c.494T>A (p.Leu165Gln)	Pathogenic
1807289	NM_000166.6(GJB1):c.462T>A (p.Tyr154Ter)	Pathogenic
2016455	NM_000166.6(GJB1):c.184A>C (p.Ser62Arg)	Pathogenic
2027099	NM_000166.6(GJB1):c.192C>A (p.Cys64Ter)	Pathogenic
2030048	NM_000166.6(GJB1):c.186C>A (p.Ser62Arg)	Pathogenic
2085595	NM_000166.6(GJB1):c.372G>T (p.Lys124Asn)	Pathogenic
21081	NM_000166.6(GJB1):c.187G>A (p.Val63Ile)	Pathogenic

SpliceAI

332 predictions. Top by Δscore:

Variant	Effect	Δscore
X:71215288:G:T	donor_gain	0.9900
X:71223691:GGT:G	acceptor_gain	0.9900
X:71215286:GGGAG:G	donor_gain	0.9800
X:71215287:GGAGG:G	donor_gain	0.9800
X:71223686:TTGCA:T	acceptor_loss	0.9800
X:71223687:TGCA:T	acceptor_loss	0.9800
X:71223689:CA:C	acceptor_loss	0.9800
X:71223690:A:AC	acceptor_loss	0.9800
X:71223690:A:AG	acceptor_gain	0.9800
X:71223691:G:GG	acceptor_gain	0.9800
X:71223691:G:T	acceptor_loss	0.9800
X:71223691:GGTGT:G	acceptor_gain	0.9800
X:71219279:T:TG	donor_gain	0.9700
X:71219279:T:G	donor_gain	0.9600
X:71223679:T:A	acceptor_gain	0.9600
X:71215288:G:GT	donor_gain	0.9500
X:71222753:TCGA:T	donor_gain	0.9500
X:71223680:G:A	acceptor_gain	0.9300
X:71223690:AG:A	acceptor_gain	0.9100
X:71223691:GG:G	acceptor_gain	0.9100
X:71215287:GGAG:G	donor_gain	0.8900
X:71222865:G:T	donor_gain	0.8900
X:71215288:GAG:G	donor_gain	0.8800
X:71215289:AG:A	donor_loss	0.8800
X:71215290:GG:G	donor_loss	0.8800
X:71222789:G:GG	donor_gain	0.8800
X:71224181:T:TA	acceptor_gain	0.8800
X:71215293:GAGGA:G	donor_loss	0.8700
X:71222788:A:AG	donor_gain	0.8700
X:71224177:ACCCT:A	acceptor_gain	0.8700

AlphaMissense

1837 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:71224245:T:C	F180L	1.000
X:71224247:C:A	F180L	1.000
X:71224247:C:G	F180L	1.000
X:71223839:G:C	W44C	0.999
X:71223839:G:T	W44C	0.999
X:71223864:T:A	C53S	0.999
X:71223865:G:A	C53Y	0.999
X:71223865:G:C	C53S	0.999
X:71223866:C:G	C53W	0.999
X:71223885:T:A	C60S	0.999
X:71223886:G:A	C60Y	0.999
X:71223886:G:C	C60S	0.999
X:71223898:G:A	C64Y	0.999
X:71223899:C:G	C64W	0.999
X:71224119:A:C	S138R	0.999
X:71224121:C:A	S138R	0.999
X:71224121:C:G	S138R	0.999
X:71224242:T:A	C179S	0.999
X:71224243:G:A	C179Y	0.999
X:71224243:G:C	C179S	0.999
X:71224244:C:G	C179W	0.999
X:71224246:T:G	F180C	0.999
X:71223837:T:A	W44R	0.998
X:71223837:T:C	W44R	0.998
X:71223859:T:G	F51C	0.998
X:71223864:T:C	C53R	0.998
X:71223865:G:T	C53F	0.998
X:71223869:C:A	N54K	0.998
X:71223869:C:G	N54K	0.998
X:71223885:T:C	C60R	0.998

dbSNP variants (sampled 300 via entrez): RS1000045652 (X:71218438 A>C), RS1000313669 (X:71220631 T>A,C), RS1001158111 (X:71213816 C>T), RS1001384749 (X:71222716 T>C), RS1001820636 (X:71221281 T>A,C), RS1001950747 (X:71213574 C>T), RS1002130577 (X:71221644 C>T), RS1002282405 (X:71214205 C>G), RS1002728687 (X:71223568 A>C,G,T), RS1003146051 (X:71216637 A>C), RS1003232768 (X:71223179 T>C,G), RS1003282204 (X:71216247 T>G), RS1004095167 (X:71219273 A>G), RS1004168767 (X:71220451 C>T), RS1004918510 (X:71215924 T>G)

Disease associations

OMIM: gene MIM:304040 | disease phenotypes: MIM:302800, MIM:302900, MIM:118220, MIM:145900, MIM:300400, MIM:214370, MIM:305450

GenCC curated gene-disease

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease X-linked dominant 1	Strong	X-linked
X-linked progressive cerebellar ataxia	Supportive	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Charcot-Marie-Tooth disease X-linked dominant 1	Definitive	XL

Mondo (10): peripheral neuropathy (MONDO:0005244), Charcot-Marie-Tooth disease X-linked dominant 1 (MONDO:0010549), Charcot-Marie-Tooth disease (MONDO:0015626), Charcot-Marie-Tooth disease type 3 (MONDO:0007790), T-B+ severe combined immunodeficiency due to gamma chain deficiency (MONDO:0010315), sensory peripheral neuropathy (MONDO:0002321), Charcot-Marie-Tooth disease-hearing loss-intellectual disability syndrome (MONDO:0008960), cerebellar ataxia (MONDO:0000437), FG syndrome 1 (MONDO:0010590), X-linked progressive cerebellar ataxia (MONDO:0010547)

Orphanet (7): X-linked Charcot-Marie-Tooth disease type 1 (Orphanet:101075), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166), Dejerine-Sottas syndrome (Orphanet:64748), T-B+ severe combined immunodeficiency due to gamma chain deficiency (Orphanet:276), Charcot-Marie-Tooth disease-deafness-intellectual disability syndrome (Orphanet:90103), Rare ataxia (Orphanet:102002), FG syndrome type 1 (Orphanet:93932)

HPO phenotypes

64 total (30 of 64 shown, HPO-id order):

HPO	Term
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000639	Nystagmus
HP:0000763	Sensory neuropathy
HP:0000764	Peripheral axonal degeneration
HP:0001152	Saccadic smooth pursuit interruptions
HP:0001251	Ataxia
HP:0001260	Dysarthria
HP:0001262	Excessive daytime somnolence
HP:0001265	Hyporeflexia
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0001284	Areflexia
HP:0001288	Gait disturbance
HP:0001310	Dysmetria
HP:0001337	Tremor
HP:0001347	Hyperreflexia
HP:0001423	X-linked dominant inheritance
HP:0001761	Pes cavus
HP:0001771	Achilles tendon contracture
HP:0002015	Dysphagia
HP:0002070	Limb ataxia
HP:0002073	Progressive cerebellar ataxia
HP:0002075	Dysdiadochokinesis
HP:0002080	Intention tremor
HP:0002311	Incoordination
HP:0002312	Clumsiness
HP:0002317	Unsteady gait
HP:0002359	Frequent falls
HP:0002378	Hand tremor

GWAS associations

0 associations (top):

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D002524	Cerebellar Ataxia	C10.228.140.252.190; C10.597.350.090.500; C23.888.592.350.090.200
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
C564446	Charcot-Marie-Tooth Peroneal Muscular Atrophy and Friedreich Ataxia, Combined (supp.)
C563134	Spinocerebellar Ataxia, X-Linked 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4879427 (SINGLE PROTEIN)

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

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	decreases expression, decreases methylation, affects localization, increases expression, affects cotreatment	5
Benzo(a)pyrene	decreases methylation, decreases expression	4
Aflatoxin B1	affects expression, decreases expression, decreases methylation	4
Acetaminophen	decreases expression, affects cotreatment	3
sodium arsenite	decreases expression	2
Tretinoin	increases reaction, increases expression, affects cotreatment, increases activity	2
FR900359	decreases phosphorylation	1
propionaldehyde	decreases expression	1
bisphenol A	affects expression	1
beta-lapachone	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
fucoxanthin	increases expression	1
benzo(e)pyrene	increases methylation	1
periodate-oxidized adenosine	affects expression	1
oleylamide	affects cotreatment, decreases reaction, increases activity, increases reaction	1
aflatoxin B2	increases methylation	1
nefazodone	affects cotreatment, decreases expression	1
cylindrospermopsin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
acetyl-aspartyl-glutamyl-valyl-aspartal	decreases reaction, increases activity, increases reaction, affects cotreatment	1
perfluoro-n-nonanoic acid	decreases expression	1
entinostat	decreases expression	1
K 7174	decreases expression	1
acetyl-leucyl-glutamyl-histidyl-aspartal	affects cotreatment, decreases reaction, increases activity, increases reaction	1
abrine	decreases expression	1
ormosil	affects binding, decreases expression	1
(+)-JQ1 compound	decreases expression	1
theaflavin-3,3’-digallate	affects expression	1
Atazanavir Sulfate	affects cotreatment, decreases expression	1
Decitabine	affects activity, affects expression, affects methylation	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4831910	Binding	Inhibition of wild type Cx32(E143) (unknown origin) expressed in Xenopus laevis oocytes assessed as at holding potential of -10 mV and stepped in 5 mV test pulses of 5 sec duration at 10 uM measured by Voltage clamp assay relative to contro	Design and synthesis of the first indole-based blockers of Panx-1 channel. — Eur J Med Chem

Cellosaurus cell lines

9 cell lines: 5 finite cell line, 3 induced pluripotent stem cell, 1 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_GY21	GM04594	Finite cell line	Female
CVCL_GY22	GM04595	Finite cell line	Female
CVCL_GY23	GM04596	Finite cell line	Female
CVCL_GY24	GM04597	Finite cell line	Female
CVCL_GY25	GM04598	Finite cell line	Male
CVCL_JX03	NYSCF-AG0012-01-MR	Induced pluripotent stem cell	Male
CVCL_JX04	NYSCF-AG0013-01-MR	Induced pluripotent stem cell	Male
CVCL_QX60	KUCFRi001-A	Induced pluripotent stem cell	Female
CVCL_YL11	SZ-CMT	Embryonic stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00380965	PHASE4	COMPLETED	Evaluation of the Efficacy of Cesamet™ for the Treatment of Pain in Patients With Chemotherapy-Induced Neuropathy
NCT00487981	PHASE4	TERMINATED	Spinal Cord Stimulation for Painful Diabetic Neuropathy
NCT00904202	PHASE4	COMPLETED	A Study Of Lidocaine Patch 5% Alone, Gabapentin Alone, And Lidocaine Patch 5% And Gabapentin In Combination For The Relief Of Pain In Patients With Diverse Peripheral Neuropathic Pain Conditions
NCT01192113	PHASE4	COMPLETED	Safety and Efficacy of Mecobalamin Injection in Peripheral Neuropathies Patients (Study JGAZSY091109)
NCT01373983	PHASE4	COMPLETED	Intrathecal Bolus Doses of Ziconotide
NCT01458015	PHASE4	TERMINATED	Tapentadol Versus Oxycodone - a Mechanism-based Treatment Approach in Neuropathic Pain
NCT02074267	PHASE4	COMPLETED	Clinical Study for Assessment of the Efficacy of Gabapentin (Carbatin and Neurontin) in Patients With Neuropathy Pain
NCT02372149	PHASE4	UNKNOWN	IVIg for Demyelination in Diabetes Mellitus
NCT02670161	PHASE4	ENROLLING_BY_INVITATION	Quality Improvement and Practice Based Research in Neurology Using the EMR
NCT07022938	PHASE4	COMPLETED	Nutritional Supplement for Treating Chemotherapy Induced Neuropathy
NCT07025005	PHASE4	RECRUITING	Fenofibrate Role in the Prophylaxis From Peripheral Neuropathy Induced by Bortezomib, Lenalidomide and Dexamethasone (VRd) Protocol in the Treatment of Patients With Multiple Myeloma (MM)
NCT00058071	PHASE3	COMPLETED	Amifostine in Treating Peripheral Neuropathy in Patients Who Have Received Chemotherapy for Cancer
NCT00125268	PHASE3	TERMINATED	Near Infrared Light for the Treatment of Painful Peripheral Neuropathy
NCT00195013	PHASE3	COMPLETED	Randomized Placebo-Controlled Trial of Glutamine for Breast Cancer Patients With Peripheral Neuropathy
NCT00232141	PHASE3	COMPLETED	Study of Pregabalin Versus Placebo in the Treatment of Nerve Pain Associated With HIV Neuropathy
NCT00264875	PHASE3	COMPLETED	Open Label Safety And Efficacy Study Of Pregabalin In Subjects With Nerve Pain Asociated With Human Immunodeficiency Virus (HIV) Neuropathy
NCT00369564	PHASE3	COMPLETED	Glutamic Acid in Reducing Nerve Damage Caused by Vincristine in Young Patients With Cancer
NCT00471445	PHASE3	COMPLETED	Topical Amitriptyline and Ketamine Cream in Treating Peripheral Neuropathy Caused by Chemotherapy in Cancer Patients
NCT00489411	PHASE3	COMPLETED	Duloxetine in Treating Peripheral Neuropathy Caused by Chemotherapy in Patients With Cancer
NCT00710554	PHASE3	COMPLETED	A Study of Sativex® for Pain Relief of Peripheral Neuropathic Pain, Associated With Allodynia
NCT00711880	PHASE3	COMPLETED	A Study of Sativex® for Relief of Peripheral Neuropathic Pain Associated With Allodynia.
NCT00713323	PHASE3	COMPLETED	A Study to Compare the Safety and Tolerability of Sativex® in Patients With Neuropathic Pain.
NCT00713817	PHASE3	COMPLETED	A Study to Determine the Maintenance of Effect After Long-term Treatment of Sativex® in Subjects With Neuropathic Pain
NCT00775645	PHASE3	COMPLETED	S0715: Acetyl-L-Carnitine in Preventing Neuropathy in Women With Stage I, II, or IIIA Breast Cancer Undergoing Chemo
NCT00872352	PHASE3	UNKNOWN	Evaluation of Bortezomib Induced Peripheral Neuropathy of Multiple Myeloma (MM) Patients
NCT00998738	PHASE3	TERMINATED	Calcium and Magnesium in Preventing Peripheral Neuropathy Caused by Ixabepilone in Patients With Breast Cancer
NCT01049217	PHASE3	TERMINATED	Pregabalin Versus Placebo In The Treatment Of Neuropathic Pain Associated With HIV Neuropathy
NCT01099449	PHASE3	COMPLETED	Calcium Gluconate and Magnesium Sulfate in Preventing Neurotoxicity in Patients With Colon Cancer or Rectal Cancer Receiving Oxaliplatin-Based Combination Chemotherapy
NCT01288937	PHASE3	TERMINATED	A Placebo Controlled, Randomized, Double Blind Trial of Milnacipran for the Treatment of Idiopathic Neuropathy Pain
NCT01492920	PHASE3	WITHDRAWN	Acetyl-L-Carnitine Hydrochloride in Preventing Peripheral Neuropathy in Patients With Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cavity Cancer, or Fallopian Tube Cancer Undergoing Chemotherapy
NCT01775449	PHASE3	COMPLETED	Prevention of Oxaliplatin-induced Neuropathic Pain by a Specific Diet
NCT02024191	PHASE3	UNKNOWN	The Role of Glutamine for Preventing Oxaliplatin-Induced Peripheral Neuropathy
NCT02217267	PHASE3	COMPLETED	Long Term Outcome After Serial Lidocaine Infusion in Peripheral Neuropathic Pain
NCT02294149	PHASE3	UNKNOWN	Vit D3 and Omega 3 in Chemo Induced Neuropathy
NCT02311907	PHASE3	COMPLETED	Glutathione in Preventing Peripheral Neuropathy Caused by Paclitaxel and Carboplatin in Patients With Ovarian Cancer, Fallopian Tube Cancer, and/or Primary Peritoneal Cancer
NCT06071936	PHASE3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06071975	PHASE3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy
NCT06071988	PHASE3	UNKNOWN	Long Term Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Traumatic or Post-operative Peripheral Neuropathy
NCT06072573	PHASE3	UNKNOWN	Efficacy and Tolerability of AP707 in Patients With Chronic Pain Due to Diabetic Polyneuropathy
NCT07287592	PHASE3	NOT_YET_RECRUITING	Glutamine for the Prophylaxis of Vincristine-induced Neuropathy in Children and Adolescents With Cancer.