GJA1

Summary

GJA1 (gap junction protein alpha 1, HGNC:4274) is a protein-coding gene on chromosome 6q22.31, encoding Gap junction alpha-1 protein (P17302). Structural component of the gap junction, a specialized intercellular structure consisting of a cluster of closely packed pairs of transmembrane channels, the connexons, that allow passage of small molecules and electrical signals between neighboring cells.

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. The encoded protein is the major protein of gap junctions in the heart that are thought to have a crucial role in the synchronized contraction of the heart and in embryonic development. A related intronless pseudogene has been mapped to chromosome 5. Mutations in this gene have been associated with oculodentodigital dysplasia, autosomal recessive craniometaphyseal dysplasia and heart malformations.

Source: NCBI Gene 2697 — RefSeq curated summary.

At a glance

• Gene–disease (curated): oculodentodigital dysplasia (Definitive, GenCC) — +9 more curated relationships
• GWAS associations: 84
• Clinical variants (ClinVar): 372 total — 30 pathogenic, 21 likely-pathogenic
• Phenotypes (HPO): 228
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000165

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4274
Approved symbol	GJA1
Name	gap junction protein alpha 1
Location	6q22.31
Locus type	gene with protein product
Status	Approved
Aliases	CX43, ODD, ODOD, SDTY3
Ensembl gene	ENSG00000152661
Ensembl biotype	protein_coding
OMIM	121014
Entrez	2697

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 7 protein_coding

ENST00000282561, ENST00000647564, ENST00000649003, ENST00000650427, ENST00000898933, ENST00000912060, ENST00000912061

RefSeq mRNA: 1 — MANE Select: NM_000165 NM_000165

CCDS: CCDS5123

Canonical transcript exons

ENST00000282561 — 2 exons

Exon	Start	End
ENSE00001006411	121446832	121449727
ENSE00001006412	121435646	121435832

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 99.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 62.4163 / max 1743.7381, expressed in 1267 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
69496	47.3013	1252
69497	11.4809	1180
69498	2.4569	668
69495	0.5962	260
69499	0.5810	265

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral globus pallidus	UBERON:0002476	99.92	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	99.85	gold quality
hair follicle	UBERON:0002073	99.83	gold quality
mammalian vulva	UBERON:0000997	99.82	gold quality
parietal pleura	UBERON:0002400	99.82	gold quality
penis	UBERON:0000989	99.81	gold quality
upper leg skin	UBERON:0004262	99.81	gold quality
CA1 field of hippocampus	UBERON:0003881	99.77	gold quality
globus pallidus	UBERON:0001875	99.75	gold quality
skin of hip	UBERON:0001554	99.74	gold quality
decidua	UBERON:0002450	99.73	gold quality
medial globus pallidus	UBERON:0002477	99.72	gold quality
pleura	UBERON:0000977	99.71	gold quality
upper arm skin	UBERON:0004263	99.71	gold quality
substantia nigra pars reticulata	UBERON:0001966	99.70	gold quality
vena cava	UBERON:0004087	99.69	gold quality
superior vestibular nucleus	UBERON:0007227	99.69	gold quality
seminal vesicle	UBERON:0000998	99.65	gold quality
medulla oblongata	UBERON:0001896	99.64	gold quality
substantia nigra pars compacta	UBERON:0001965	99.64	gold quality
ventral tegmental area	UBERON:0002691	99.64	gold quality
cervix squamous epithelium	UBERON:0006922	99.64	gold quality
visceral pleura	UBERON:0002401	99.63	gold quality
choroid plexus epithelium	UBERON:0003911	99.62	gold quality
tibia	UBERON:0000979	99.61	gold quality
cranial nerve II	UBERON:0000941	99.59	gold quality
pericardium	UBERON:0002407	99.57	gold quality
gingiva	UBERON:0001828	99.55	gold quality
nipple	UBERON:0002030	99.55	gold quality
cervix epithelium	UBERON:0004801	99.55	gold quality

Single-cell (SCXA)

Detected in 15 experiment(s), a significant marker in 13.

Experiment	Marker?	Max mean expression
E-MTAB-6108	yes	631.88
E-MTAB-9388	yes	524.83
E-ANND-5	yes	480.96
E-MTAB-10287	yes	113.33
E-HCAD-35	yes	74.71
E-MTAB-6701	yes	64.10
E-ANND-3	yes	31.05
E-HCAD-25	yes	23.52
E-GEOD-135922	yes	22.72
E-CURD-112	yes	17.91
E-GEOD-84465	yes	14.38
E-CURD-46	yes	10.45
E-GEOD-130148	yes	5.49
E-CURD-10	no	602.27
E-MTAB-8271	no	594.79

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
MKI67	Activation
PCNA	Activation

Upstream regulators (CollecTRI, top): ACE, AP1, CAV1, CEBPB, CTNNB1, DLX5, ESR1, EWSR1, FLI1, FOS, FOSL2, FOXC1, FOXO3, FOXP1, HNF1B, HNF4A, IRF6, IRX3, JUN, JUNB, LHX2, MYBL2, MYC, NANOG, NFATC4, NKX2-5, NONO, NR1D1, PGR, PHF5A, POU5F1, RUNX2, SFPQ, SNAI1, SP1, SP3, SP7, TBX15, TBX18, TBX2

miRNA regulators (miRDB)

184 targeting GJA1, 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-3613-3P	100.00	76.36	7965
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-432-3P	100.00	67.86	705
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-493-5P	99.96	72.47	2382
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-23A-3P	99.95	74.24	3163

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• This evidence adds Cx-43 to the list of transmembrane proteins capable of transducing survival signals in response to extracellular cues and raises the possibility that it may serve in this capacity for endogenously produced molecules or even other drugs. (PMID:11741942)
• results demonstrate a new role of Cx43 in the mediation of apoptosis under low serum conditions (PMID:11746825)
• The fast transjunctional voltage-sensitive gating mechanism of Cx43 cell-cell channel can serve as a selectivity filter, which allows electrical coupling but limits metabolic communication. (PMID:11815667)
• homocysteine (Hcy)-induced upregulation of Cx43 transcript and protein expression are associated with unaltered intercellular communication and redistribution of Cx43 in HUVEC (PMID:12003820)
• Connexin 43 suppresses human glioblastoma cell growth by down-regulation of monocyte chemotactic protein 1, as discovered using protein array technology. (PMID:12019157)
• overexpression of Cx43 or Cx26 in breast cancer cells down-regulated fibroblast growth factor receptor-3 (PMID:12042301)
• Data suggest that the dynamic changes of connexins 43, 40 and 45 during mouse cardiac development appear to be mirrored in the human. (PMID:12064615)
• Results establish a role for connexin43 hemichannels in bisphosphonate action, and a novel function of connexin43 in the regulation of survival signaling pathways. (PMID:12064622)
• Results provide evidence for Cx43 being targeted to lysosomes as a result of misfolding and aggregation, while in other cases, the delivery of wild-type Cx43 to lysosomes appears to be due to defects innate to the breast tumor cell type. (PMID:12064631)
• and expression of the transcription factor E2F1 correlated inversely with tumor grade (PMID:12203365)
• alpha-catenin facilitates trafficking of connexins 32 and 43 to the cell surface and induces gap junction assembly (PMID:12205082)
• Our data show that the presence of Cx43 allows an inter-trophoblastic GJIC and is associated with the fusion process leading to the villous syncytiotrophoblast (PMID:12397213)
• abnormal expression of connexin43 and connexin45 in nasopharynx tissues may be associated with cancerization and squamatization of human nasopharynx tissue (PMID:12452056)
• We found mutations in the GJA1 gene in all 17 families with oculodentodigital dysplasia that we screened. (PMID:12457340)
• These findings suggest that expression of Cx26 and Cx43 might be related to the differentiation of the arachnoid villi and meningiomas, and exhibit the different origin of various subtypes of meningiomas. (PMID:12484567)
• Connexin 43 in human teeth. Tooth development, Cx43 in epithelial and mesenchymal dental cells. Adult teeth, Cx43 in odontoblasts. Cx43 downregulated in mature teeth, upregulated in odontoblasts facing caries. In dental pulp Cx43 in mineralized nodules. (PMID:12489165)
• plasma membrane localization and formation of channels are not required for growth inhibition by Cx43, and nuclear localization of CT-Cx43 may exert effects on gene expression and growth (PMID:12619863)
• Focal disorganization of gap junction distribution and downregulation of Cx43 are typical of myocardial remodeling that may play an important role in the development of an arrhythmogenic substrate in human cardiomyopathies (PMID:12619876)
• connexin 43 gap junction communication induced by EGF is regulated by ERK5 (PMID:12637502)
• the transcriptional up-regulation of Cx43 by Ras-Raf-MAPK is mediated via the interaction of a novel Cx43 promoter element with a protein complex that contains both HSP90 and c-Myc. (PMID:12644583)
• gap junctional intercellular communication in hepatocellular carcinoma cell lines, and signal transduction mechanism of gap junction genes connexin32, connexin43 in hepatocarcinogenesis (PMID:12717835)
• the tyrosine-based motif of human connexin43 is a prime determinant controlling connexin43 stability, and consequently GJC, by targeting connexin43 for degradation in the endocytic/lysosomal compartment. (PMID:12730291)
• proteasomal degradation regulates the stability of phosphorylated Cx43 and appears to promote the internalization of Cx43 from the cell surface (PMID:12767974)
• Cx43 is directly involved in human trophoblast cell-cell communication, fusion and differentiation. (PMID:12840075)
• the point mutations in the second extracellular region of Cx43 do not affect the ability of the mutant proteins in vitro to suppress cell growth (PMID:12861055)
• mouse connexin43 promoter is regulated by GDF5 in osteoblasts ans embryos (PMID:12881039)
• connexin 43 is phosphorylated in ovarian tumor cells and has a role in gap junctional intercellular communication (PMID:12907686)
• examination of gating and regulation of hemichannels (PMID:13130072)
• Cx43 mRNA in adjacent normal tissue surrounding lung tumor simply detected by RT-PCR may act as a molecular marker of nodal micrometastasis in non-small cell lung cancer. (PMID:14519646)
• Heterogeneous expression of Cx 43 protein may contribute to impaired ventricular conduction. (PMID:14639017)
• mRNA levels of connexins in different sizes of luteinized normal and hyperstimulated follicles. (PMID:14667880)
• Opening of non-junctional connexin 43 (Cx43) hemichannels plays a role in cell physiology (PMID:14681024)
• Low doses of ionizing radiation induce the transcriptional upregulation of connexin 43 expression employing NFAT and AP1 sites. (PMID:14713573)
• A missense mutation in the cytoplasmic loop of GJA1 results in an atypical ophthalmological phenotype, displaying type III syndactyly but not the characteristic dental or skeletal features. (PMID:14729836)
• Staining for Cx43 and Cx40 along regions of intimate cell-to-cell contact between human mesenchymal stem cells. (PMID:14766937)
• Homozygous GJA1 point mutations in a conserver codon, one base change results in a Oculodentodigital dysplasia phenotype in one patient, another base change in the same codon resultes in a Hallermann-Streiff syndrome phenotype in another patient. (PMID:14974090)
• the downregulation of Cx43 is an important event in human wound healing. (PMID:15140236)
• Cx43 is able to regulate cell growth via an up-regulation of NOV transcription (PMID:15181016)
• mRNA level correlates with cell differentiation, nd is predictive of postoperative recurrence in hepatocellular carcinoma. (PMID:15334670)
• Laryngeal cancer presented inactivation of Cx43 gene and E-cad gene and down regulation of Cx43 and E-cad proteins. (PMID:15338868)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	gja1b	ENSDARG00000041799
danio_rerio	gja1a	ENSDARG00000071192
mus_musculus	Gja1	ENSMUSG00000050953
rattus_norvegicus	Gja1	ENSRNOG00000000805

Paralogs (20): GJA8 (ENSG00000121634), GJB6 (ENSG00000121742), GJA3 (ENSG00000121743), GJA9 (ENSG00000131233), GJA10 (ENSG00000135355), GJD2 (ENSG00000159248), GJB7 (ENSG00000164411), GJB2 (ENSG00000165474), GJB1 (ENSG00000169562), 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 alpha-1 protein — P17302 (reviewed: P17302)

Alternative names: Connexin-43, Gap junction 43 kDa heart protein

All UniProt accessions (2): P17302, A0A654IBU3

UniProt curated annotations — full annotation on UniProt →

Function. Structural component of the gap junction, a specialized intercellular structure consisting of a cluster of closely packed pairs of transmembrane channels, the connexons, that allow passage of small molecules and electrical signals between neighboring cells. Forms homotypic and heterotypic channels gated by transjunctional voltage. May play a critical role in the physiology of hearing by participating in the recycling of potassium to the cochlear endolymph. Negative regulator of bladder functional capacity: acts by enhancing intercellular electrical and chemical transmission, thus sensitizing bladder muscles to cholinergic neural stimuli and causing them to contract. May play a role in the conductive system of ventricular myocardium and heart morphogenesis. May play a role in cell growth inhibition through the regulation of NOV expression and localization. Involved in intercellular innate immune signaling. Mediates translocation of 2’,3’-cGAMP and 2’,5’-oligoadenylates (2-5A) second messengers from virus-infected cells to macrophages and uninfected neighboring cells to propagate and amplify the antiviral immune response.

Subunit / interactions. A connexon/hemichannel is composed of a hexamer of connexins. Forms functional homotypic gap junctions consisting of identical hemichannels both made of the same connexin type as well as heterotypic gap junctions consisting of two different hemichannels, each containing a different type of connexin. Assembles with GJC1 to form heterotypic gap junction channels. Interacts (via C-terminus) with TJP1. Interacts (via C-terminus) with SRC (via SH3 domain). Interacts (not ubiquitinated) with UBQLN4 (via UBA domain). Interacts with SGSM3 and CNST. Interacts with RIC1/CIP150. Interacts with CSNK1D. Interacts with NOV. Interacts with TMEM65. Interacts with ANK3/ANKG and PKP2.

Subcellular location. Cell membrane. Cell junction. Gap junction. Endoplasmic reticulum.

Tissue specificity. Expressed at intercalated disks in the heart (at protein level). Expressed in the fetal cochlea.

Post-translational modifications. Phosphorylated at Ser-368 by PRKCG; phosphorylation induces disassembly of gap junction plaques and inhibition of gap junction activity. Phosphorylation at Ser-325, Ser-328 and Ser-330 by CK1 modulates gap junction assembly. Phosphorylation at Ser-368 by PRKCD triggers its internalization into small vesicles leading to proteasome-mediated degradation. Phosphorylation by MAPK1/MAPK3 at Ser-279 and Ser-282 leads to increased ubiquitination and lysosomal degradation. Ubiquitination results in lysosomal degradation. Sumoylated with SUMO1, SUMO2 and SUMO3, which may regulate the level of functional Cx43 gap junctions at the plasma membrane. May be desumoylated by SENP1 or SENP2. S-nitrosylation at Cys-271 is enriched at the muscle endothelial gap junction in arteries, it augments channel permeability and may regulate of smooth muscle cell to endothelial cell communication. Acetylated in the developing cortex; leading to delocalization from the cell membrane.

Disease relevance. Oculodentodigital dysplasia (ODDD) [MIM:164200] A disease characterized by a typical facial appearance and variable involvement of the eyes, dentition, and fingers. Characteristic facial features include a narrow, pinched nose with hypoplastic alae nasi, prominent columella and thin anteverted nares together with a narrow nasal bridge, and prominent epicanthic folds giving the impression of hypertelorism. The teeth are usually small and carious. Typical eye findings include microphthalmia and microcornea. The characteristic digital malformation is complete syndactyly of the fourth and fifth fingers (syndactyly type III) but the third finger may be involved and associated camptodactyly is a common finding. Cardiac abnormalities are observed in rare instances. The disease is caused by variants affecting the gene represented in this entry. Oculodentodigital dysplasia, autosomal recessive (ODDD-AR) [MIM:257850] A disease characterized by a typical facial appearance and variable involvement of the eyes, dentition, and fingers. Characteristic facial features include a narrow, pinched nose with hypoplastic alae nasi, prominent columella and thin anteverted nares together with a narrow nasal bridge, and prominent epicanthic folds giving the impression of hypertelorism. The teeth are usually small and carious. Typical eye findings include microphthalmia and microcornea. The characteristic digital malformation is complete syndactyly of the fourth and fifth fingers (syndactyly type III) but the third finger may be involved and associated camptodactyly is a common finding. Cardiac abnormalities are observed in rare instances. The disease is caused by variants affecting the gene represented in this entry. Syndactyly 3 (SDTY3) [MIM:186100] A form of syndactyly, a congenital anomaly of the hand or foot marked by persistence of the webbing between adjacent digits that are more or less completely attached. In SDTY3, there is usually complete and bilateral syndactyly between the fourth and fifth fingers. Usually it is soft tissue syndactyly but occasionally the distal phalanges are fused. The fifth finger is short with absent or rudimentary middle phalanx. The feet are not affected. The disease may be caused by variants affecting the gene represented in this entry. Hypoplastic left heart syndrome 1 (HLHS1) [MIM:241550] A syndrome due to defective development of the aorta proximal to the entrance of the ductus arteriosus, and hypoplasia of the left ventricle and mitral valve. As a result of the abnormal circulation, the ductus arteriosus and foramen ovale are patent and the right atrium, right ventricle, and pulmonary artery are enlarged. The disease may be caused by variants affecting the gene represented in this entry. Hallermann-Streiff syndrome (HSS) [MIM:234100] A disorder characterized by a typical skull shape (brachycephaly with frontal bossing), hypotrichosis, microphthalmia, cataracts, beaked nose, micrognathia, skin atrophy, dental anomalies and proportionate short stature. Intellectual disability is present in a minority of cases. The disease is caused by variants affecting the gene represented in this entry. Craniometaphyseal dysplasia, autosomal recessive (CMDR) [MIM:218400] An osteochondrodysplasia characterized by hyperostosis and sclerosis of the craniofacial bones associated with abnormal modeling of the metaphyses. Sclerosis of the skull may lead to asymmetry of the mandible, as well as to cranial nerve compression, that may finally result in hearing loss and facial palsy. The disease is caused by variants affecting the gene represented in this entry. Erythrokeratodermia variabilis et progressiva 3 (EKVP3) [MIM:617525] 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. Palmoplantar keratoderma and congenital alopecia 1 (PPKCA1) [MIM:104100] A rare autosomal dominant disorder characterized by severe hyperkeratosis of the palms and soles, and congenital hypotrichosis or alopecia. Dystrophic nail changes occur in some patients. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the connexin family. Alpha-type (group II) subfamily.

RefSeq proteins (1): NP_000156* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000500	Connexin	Family
IPR002261	Connexin43	Family
IPR013092	Connexin_N	Domain
IPR013124	Connexin43_C	Domain
IPR017990	Connexin_CS	Conserved_site
IPR019570	Connexin_CCC	Domain
IPR034634	Connexin_C	Homologous_superfamily
IPR035091	Alpha_helix_dom_sf	Homologous_superfamily
IPR038359	Connexin_N_sf	Homologous_superfamily

Pfam: PF00029, PF03508

Catalyzed reactions (Rhea), 2 shown:

• 2’,3’-cGAMP(out) = 2’,3’-cGAMP(in) (RHEA:66320)
• 5’-triphosphoadenylyl-(2’->5’)-adenylyl-(2’->5’)-adenosine(out) = 5’-triphosphoadenylyl-(2’->5’)-adenylyl-(2’->5’)-adenosine(in) (RHEA:85019)

UniProt features (123 total): sequence variant 69, modified residue 19, helix 9, topological domain 5, strand 5, transmembrane region 4, region of interest 3, compositionally biased region 2, disulfide bond 2, cross-link 2, initiator methionine 1, chain 1, turn 1

Structure

Experimental structures (PDB)

19 structures.

PDB	Method	Resolution (Å)
7Z1T	ELECTRON MICROSCOPY	2.26
7XQF	ELECTRON MICROSCOPY	2.3
7XQD	ELECTRON MICROSCOPY	2.7
7Z22	ELECTRON MICROSCOPY	2.95
7XQB	ELECTRON MICROSCOPY	3
8XBM	ELECTRON MICROSCOPY	3
7F92	ELECTRON MICROSCOPY	3.1
7XQ9	ELECTRON MICROSCOPY	3.3
9INZ	ELECTRON MICROSCOPY	3.34
7F93	ELECTRON MICROSCOPY	3.6
7F94	ELECTRON MICROSCOPY	3.6
7XQI	ELECTRON MICROSCOPY	3.7
8QKO	ELECTRON MICROSCOPY	3.73
7XQG	ELECTRON MICROSCOPY	3.8
7XQH	ELECTRON MICROSCOPY	3.8
7Z23	ELECTRON MICROSCOPY	3.98
7XQJ	ELECTRON MICROSCOPY	4
9RKX	ELECTRON MICROSCOPY	14
2LL2	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P17302-F1	70.86	0.31

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 (21): 5, 247, 255, 262, 271, 275, 279, 282, 306, 314, 325, 326, 328, 330, 344, 365, 368, 369, 373, 144 …

Disulfide bonds (2): 54–192, 187–198

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-190704	Oligomerization of connexins into connexons
R-HSA-190827	Transport of connexins along the secretory pathway
R-HSA-190840	Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane
R-HSA-190861	Gap junction assembly
R-HSA-190873	Gap junction degradation
R-HSA-191650	Regulation of gap junction activity
R-HSA-196025	Formation of annular gap junctions
R-HSA-9013406	RHOQ GTPase cycle
R-HSA-9013409	RHOJ GTPase cycle
R-HSA-9705677	SARS-CoV-2 targets PDZ proteins in cell-cell junction
R-HSA-9856532	Mechanical load activates signaling by PIEZO1 and integrins in osteocytes

MSigDB gene sets: 1073 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, VERHAAK_AML_WITH_NPM1_MUTATED_DN, GOBP_ESTABLISHMENT_OF_SPINDLE_ORIENTATION, MODULE_52, MODULE_92, GOBP_NEGATIVE_REGULATION_OF_REPRODUCTIVE_PROCESS, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_GLUTAMATE_SECRETION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, MODULE_255

GO Biological Process (35): establishment of mitotic spindle orientation (GO:0000132), cardiac conduction system development (GO:0003161), signal transduction (GO:0007165), cell-cell signaling (GO:0007267), spermatogenesis (GO:0007283), heart development (GO:0007507), intracellular protein localization (GO:0008104), positive regulation of gene expression (GO:0010628), cell communication by electrical coupling (GO:0010644), glutamate secretion (GO:0014047), gap junction assembly (GO:0016264), negative regulation of cell growth (GO:0030308), negative regulation of gonadotropin secretion (GO:0032277), monoatomic ion transmembrane transport (GO:0034220), maintenance of blood-brain barrier (GO:0035633), xenobiotic transport (GO:0042908), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), bone remodeling (GO:0046849), bone development (GO:0060348), atrial cardiac muscle cell action potential (GO:0086014), cell communication by electrical coupling involved in cardiac conduction (GO:0086064), microtubule-based transport (GO:0099111), positive regulation of cold-induced thermogenesis (GO:0120162), export across plasma membrane (GO:0140115), negative regulation of trophoblast cell migration (GO:1901164), cellular response to amyloid-beta (GO:1904646), positive regulation of vascular associated smooth muscle cell proliferation (GO:1904707), positive regulation of morphogenesis of an epithelium (GO:1905332), positive regulation of mesodermal cell differentiation (GO:1905772), positive regulation of stem cell proliferation (GO:2000648), cell communication (GO:0007154), glutathione transmembrane transport (GO:0034775), cell-cell junction organization (GO:0045216), transmembrane transport (GO:0055085), regulation of blood circulation (GO:1903522)

GO Molecular Function (12): gap junction channel activity (GO:0005243), beta-catenin binding (GO:0008013), monoatomic ion transmembrane transporter activity (GO:0015075), efflux transmembrane transporter activity (GO:0015562), tubulin binding (GO:0015631), glutathione transmembrane transporter activity (GO:0034634), alpha-tubulin binding (GO:0043014), gap junction hemi-channel activity (GO:0055077), gap junction channel activity involved in cardiac conduction electrical coupling (GO:0086075), gap junction channel activity involved in cell communication by electrical coupling (GO:1903763), protein binding (GO:0005515), transmembrane transporter activity (GO:0022857)

GO Cellular Component (21): Golgi membrane (GO:0000139), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), mitochondrion (GO:0005739), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), gap junction (GO:0005921), connexin complex (GO:0005922), focal adhesion (GO:0005925), intercalated disc (GO:0014704), apical plasma membrane (GO:0016324), cell junction (GO:0030054), Golgi-associated vesicle membrane (GO:0030660), cell-cell contact zone (GO:0044291), membrane raft (GO:0045121), tight junction (GO:0070160), endoplasmic reticulum (GO:0005783), membrane (GO:0016020), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Gap junction assembly	2
Gap junction trafficking	2
RHO GTPase cycle	2
Transport of connexons to the plasma membrane	1
Gap junction trafficking and regulation	1
Gap junction degradation	1
SARS-CoV-2-host interactions	1
Cellular responses to mechanical stimuli	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	4
cellular anatomical structure	4
cell communication	3
cytoplasm	3
cell-cell junction	3
signaling	2
animal organ development	2
transmembrane transport	2
wide pore channel activity	2
transmembrane transporter activity	2
gap junction channel activity	2
bounding membrane of organelle	2
endomembrane system	2
mitotic cell cycle	1
establishment of mitotic spindle localization	1
establishment of spindle orientation	1
cardiac muscle tissue development	1
cellular process	1
regulation of cellular process	1
cellular response to stimulus	1
developmental process involved in reproduction	1
male gamete generation	1
circulatory system development	1
macromolecule localization	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
dicarboxylic acid transport	1
acidic amino acid transport	1
secretion by cell	1
nitrogen compound transport	1
cell-cell junction assembly	1
regulation of cell growth	1
cell growth	1
negative regulation of growth	1
negative regulation of cellular process	1
gonadotropin secretion	1
regulation of gonadotropin secretion	1
negative regulation of hormone secretion	1
negative regulation of multicellular organismal process	1

Protein interactions and networks

STRING

3978 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GJA1	TJP1	Q07157	994
GJA1	GJC1	P36383	984
GJA1	GJA5	P36382	981
GJA1	SRC	P12931	975
GJA1	PKP2	Q99959	972
GJA1	GJB6	O95452	971
GJA1	CDH2	P19022	941
GJA1	PCDH7	O60245	921
GJA1	CAV1	Q03135	909
GJA1	TJP2	Q9UDY2	907
GJA1	GJA4	P35212	900
GJA1	DBN1	Q16643	898
GJA1	GJB1	P08034	887
GJA1	SCN5A	Q14524	868
GJA1	GJB2	P29033	864

IntAct

282 interactions, top by confidence:

A	B	Type	Score
GJA1	TJP1	psi-mi:“MI:0915”(physical association)	0.740
GJA1	TJP1	psi-mi:“MI:0407”(direct interaction)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
GJA1	CREB3	psi-mi:“MI:0915”(physical association)	0.670
GPR156	PLD2	psi-mi:“MI:0914”(association)	0.640
GJA1	PLPP4	psi-mi:“MI:0915”(physical association)	0.560
GJA1	NINJ2	psi-mi:“MI:0915”(physical association)	0.560
GJA1	TMEM128	psi-mi:“MI:0915”(physical association)	0.560
GJA1	TMEM86B	psi-mi:“MI:0915”(physical association)	0.560
GJA1	CSNK1D	psi-mi:“MI:0915”(physical association)	0.560
GJA1	ARFGAP3	psi-mi:“MI:0915”(physical association)	0.560
GJA1	C1orf216	psi-mi:“MI:0915”(physical association)	0.560
GPR21	TMEM120B	psi-mi:“MI:0914”(association)	0.530
ADGRG5	KLRG2	psi-mi:“MI:0914”(association)	0.530
FSHR	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
NT5E	SCAMP1	psi-mi:“MI:0914”(association)	0.530
ZACN	GPAA1	psi-mi:“MI:0914”(association)	0.530
STS	GJA1	psi-mi:“MI:0914”(association)	0.530

BioGRID (682): GJA1 (Affinity Capture-MS), GJA1 (Affinity Capture-MS), GJA1 (Affinity Capture-MS), GJA1 (Affinity Capture-MS), GJA1 (Affinity Capture-MS), STXBP2 (Affinity Capture-MS), NDUFA7 (Affinity Capture-MS), STXBP1 (Affinity Capture-MS), EEF1A2 (Affinity Capture-MS), GJA1 (Affinity Capture-MS), GJA1 (Affinity Capture-MS), GJA1 (Affinity Capture-MS), GJA1 (Reconstituted Complex), CREB3 (Two-hybrid), GJA1 (Affinity Capture-MS)

ESM2 similar proteins: A4GG66, A4GVD1, A6XKM2, O54851, O57474, O70610, P08050, P14154, P16863, P16864, P17302, P18246, P18860, P18861, P23242, P28228, P28229, P28234, P28235, P28236, P29414, P29415, P33725, P36381, P36382, P36383, P48165, P51914, P69998, P69999, Q01231, Q03190, Q0V990, Q0VCR2, Q29101, Q2HJ66, Q4R4S7, Q64448, Q6NZH5, Q6PYT3

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

25 interactions.

A	Effect	B	Mechanism
PRKCA	down-regulates	GJA1	phosphorylation
PRKCE	up-regulates	GJA1	phosphorylation
SRC	down-regulates	GJA1	phosphorylation
PTPN2	up-regulates	GJA1	dephosphorylation
MAPK1	“down-regulates activity”	GJA1	phosphorylation
MAPK3	“down-regulates activity”	GJA1	phosphorylation
MAPK7	“down-regulates activity”	GJA1	phosphorylation
Gbeta	“down-regulates activity”	GJA1	phosphorylation
ERK1/2	“down-regulates activity”	GJA1	phosphorylation
IRX3	“down-regulates quantity by repression”	GJA1	“transcriptional regulation”
PRKCE	“down-regulates activity”	GJA1	phosphorylation
PRKCA	“down-regulates activity”	GJA1	phosphorylation
PRKCB	“down-regulates activity”	GJA1	phosphorylation
PRKCG	“down-regulates activity”	GJA1	phosphorylation
CSNK1D	“up-regulates activity”	GJA1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 190 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Ras activation upon Ca2+ influx through NMDA receptor	7	33.9×	4e-07
Metal ion SLC transporters	6	30.6×	5e-06
Neurexins and neuroligins	9	15.0×	2e-06
Protein-protein interactions at synapses	6	13.5×	4e-04
Assembly and cell surface presentation of NMDA receptors	6	12.9×	5e-04
G alpha (s) signalling events	8	5.0×	4e-03
Neuronal System	11	4.1×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
protein localization to synapse	5	22.7×	4e-04
zinc ion transmembrane transport	5	20.8×	6e-04
establishment or maintenance of epithelial cell apical/basal polarity	6	20.6×	2e-04
receptor clustering	5	18.5×	9e-04
intracellular zinc ion homeostasis	6	17.1×	3e-04
regulation of postsynaptic membrane neurotransmitter receptor levels	5	14.7×	2e-03
adenylate cyclase-activating G protein-coupled receptor signaling pathway	9	6.0×	2e-03
chemical synaptic transmission	13	6.0×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	30
Likely pathogenic	21
Uncertain significance	210
Likely benign	71
Benign	7

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
16982	NM_000165.5(GJA1):c.50A>C (p.Tyr17Ser)	Pathogenic
16983	NM_000165.5(GJA1):c.52T>C (p.Ser18Pro)	Pathogenic
16984	NM_000165.5(GJA1):c.61G>A (p.Gly21Arg)	Pathogenic
16986	NM_000165.5(GJA1):c.154_156dup (p.Phe52dup)	Pathogenic
16987	NM_000165.5(GJA1):c.427G>A (p.Gly143Ser)	Pathogenic
16988	NM_000165.5(GJA1):c.286G>A (p.Val96Met)	Pathogenic
16989	NM_000165.5(GJA1):c.780_781del (p.Cys260fs)	Pathogenic
16992	NM_000165.5(GJA1):c.581A>C (p.His194Pro)	Pathogenic
16993	NM_000165.5(GJA1):c.32T>C (p.Leu11Pro)	Pathogenic
16994	NM_000165.5(GJA1):c.689_690del (p.Tyr230fs)	Pathogenic
16995	NM_000165.5(GJA1):c.97C>T (p.Arg33Ter)	Pathogenic
16996	NM_000165.5(GJA1):c.227G>A (p.Arg76His)	Pathogenic
1715214	NM_000165.5(GJA1):c.187A>G (p.Asn63Asp)	Pathogenic
203467	NM_000165.5(GJA1):c.23G>T (p.Gly8Val)	Pathogenic
2136231	NM_000165.5(GJA1):c.461C>T (p.Thr154Ile)	Pathogenic
2628335	NM_000165.5(GJA1):c.602C>T (p.Ser201Phe)	Pathogenic
2705428	NM_000165.5(GJA1):c.32T>A (p.Leu11His)	Pathogenic
29668	NM_000165.5(GJA1):c.31C>T (p.Leu11Phe)	Pathogenic
3099928	NM_000165.5(GJA1):c.460A>G (p.Thr154Ala)	Pathogenic
3647870	NM_000165.5(GJA1):c.679G>C (p.Glu227Gln)	Pathogenic
374068	NM_000165.5(GJA1):c.440T>C (p.Met147Thr)	Pathogenic
435323	NM_000165.5(GJA1):c.119C>T (p.Ala40Val)	Pathogenic
435325	NM_000165.5(GJA1):c.646G>T (p.Val216Leu)	Pathogenic
470215	NM_000165.5(GJA1):c.389T>C (p.Ile130Thr)	Pathogenic
470216	NM_000165.5(GJA1):c.413G>A (p.Gly138Asp)	Pathogenic
537755	NM_000165.5(GJA1):c.306G>C (p.Lys102Asn)	Pathogenic
844190	NM_000165.5(GJA1):c.64G>A (p.Gly22Arg)	Pathogenic
88726	NM_000165.5(GJA1):c.617A>G (p.Lys206Arg)	Pathogenic
941060	NM_000165.5(GJA1):c.53C>A (p.Ser18Ter)	Pathogenic
989202	NM_000165.5(GJA1):c.93T>G (p.Ile31Met)	Pathogenic

SpliceAI

240 predictions. Top by Δscore:

Variant	Effect	Δscore
6:121446820:T:TA	acceptor_gain	1.0000
6:121446828:TCAG:T	acceptor_loss	1.0000
6:121446830:A:AG	acceptor_gain	1.0000
6:121446830:AG:A	acceptor_gain	1.0000
6:121446830:AGGT:A	acceptor_gain	1.0000
6:121446830:AGGTG:A	acceptor_gain	1.0000
6:121446831:G:GA	acceptor_gain	1.0000
6:121446831:GG:G	acceptor_gain	1.0000
6:121446831:GGT:G	acceptor_gain	1.0000
6:121446831:GGTG:G	acceptor_gain	1.0000
6:121446831:GGTGG:G	acceptor_gain	1.0000
6:121435831:GA:G	donor_gain	0.9900
6:121435833:G:GG	donor_gain	0.9900
6:121435828:AAAGA:A	donor_gain	0.9800
6:121435829:AAGA:A	donor_gain	0.9800
6:121446828:TCAGG:T	acceptor_gain	0.9800
6:121446829:CAGGT:C	acceptor_gain	0.9800
6:121446830:A:C	acceptor_gain	0.9700
6:121446831:G:T	acceptor_gain	0.9700
6:121435830:AGA:A	donor_gain	0.9600
6:121435831:GAG:G	donor_gain	0.9600
6:121446827:TTCAG:T	acceptor_gain	0.9500
6:121435743:GTC:G	donor_gain	0.9200
6:121435744:TCT:T	donor_gain	0.9200
6:121435830:AGAG:A	donor_loss	0.9200
6:121435832:AGT:A	donor_loss	0.9200
6:121435833:GT:G	donor_loss	0.9200
6:121435834:TAA:T	donor_loss	0.9200
6:121435835:AA:A	donor_loss	0.9200
6:121437908:G:GT	donor_gain	0.9000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000066531 (6:121448571 G>A), RS1000270907 (6:121435644 A>G), RS1000400582 (6:121448993 G>C), RS1000484925 (6:121441433 G>A,C), RS1000725697 (6:121435867 T>C), RS1000893834 (6:121442548 C>T), RS1001018748 (6:121450103 C>T), RS1001373038 (6:121442187 T>C), RS1001432357 (6:121435937 T>C), RS1001639341 (6:121442303 C>G), RS1001781325 (6:121435920 G>A), RS1001942095 (6:121441953 G>A), RS1002233673 (6:121436232 A>C,G), RS1002413748 (6:121445832 CT>C), RS1002792788 (6:121437564 G>C,T)

Disease associations

OMIM: gene MIM:121014 | disease phenotypes: MIM:257850, MIM:164200, MIM:104100, MIM:186100, MIM:218400, MIM:241550, MIM:617525, MIM:186300

GenCC curated gene-disease

Disease	Classification	Inheritance
oculodentodigital dysplasia	Definitive	Autosomal dominant
autosomal dominant palmoplantar keratoderma and congenital alopecia	Strong	Autosomal dominant
oculodentodigital dysplasia, autosomal recessive	Strong	Autosomal recessive
erythrokeratodermia variabilis et progressiva 3	Strong	Autosomal dominant
syndactyly type 3	Supportive	Autosomal dominant
craniometaphyseal dysplasia	Supportive	Autosomal dominant
erythrokeratodermia variabilis	Supportive	Autosomal dominant
craniometaphyseal dysplasia, autosomal recessive	Limited	Autosomal recessive
congenital heart disease	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
congenital heart disease	Limited	UD
nonsyndromic genetic hearing loss	Disputed	AD

Mondo (15): oculodentodigital dysplasia, autosomal recessive (MONDO:0009768), oculodentodigital dysplasia (MONDO:0008111), autosomal dominant palmoplantar keratoderma and congenital alopecia (MONDO:0007083), syndactyly type 3 (MONDO:0008514), craniometaphyseal dysplasia, autosomal recessive (MONDO:0009035), hypoplastic left heart syndrome 1 (MONDO:0009433), erythrokeratodermia variabilis et progressiva 3 (MONDO:0033013), cleft palate (MONDO:0016064), intellectual disability (MONDO:0001071), isolated cleft lip (MONDO:0016043), syndactyly type 5 (MONDO:0008516), congenital heart disease (MONDO:0005453), nonsyndromic genetic hearing loss (MONDO:0019497), craniometaphyseal dysplasia (MONDO:0015465), erythrokeratodermia variabilis (MONDO:0017851)

Orphanet (9): Oculodentodigital dysplasia (Orphanet:2710), Autosomal dominant palmoplantar keratoderma and congenital alopecia (Orphanet:1010), Craniometaphyseal dysplasia (Orphanet:1522), Hypoplastic left heart syndrome (Orphanet:2248), Syndactyly type 3 (Orphanet:93404), Cleft palate (Orphanet:2014), Isolated cleft lip (Orphanet:199302), Syndactyly type 5 (Orphanet:93406), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

228 total (30 of 228 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000011	Neurogenic bladder
HP:0000035	Abnormal testis morphology
HP:0000160	Narrow mouth
HP:0000161	Median cleft upper lip
HP:0000175	Cleft palate
HP:0000187	Broad alveolar ridges
HP:0000204	Cleft upper lip
HP:0000218	High palate
HP:0000233	Thin vermilion border
HP:0000239	Large fontanelles
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000303	Mandibular prognathia
HP:0000316	Hypertelorism
HP:0000327	Hypoplasia of the maxilla
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000365	Hearing impairment
HP:0000366	Abnormality of the nose
HP:0000369	Low-set ears
HP:0000377	Abnormal pinna morphology
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000410	Mixed hearing impairment

GWAS associations

84 associations (top):

Study	Trait	p-value
GCST000189_39	Protein quantitative trait loci	2.000000e-06
GCST000731_10	Resting heart rate	7.000000e-08
GCST000731_8	Resting heart rate	4.000000e-15
GCST001748_1	Resting heart rate	5.000000e-15
GCST001969_27	Heart rate	7.000000e-12
GCST001969_29	Heart rate	1.000000e-08
GCST001969_8	Heart rate	1.000000e-33
GCST002948_1	Peak creatinine levels in vancomycin therapy	1.000000e-07
GCST003720_44	Migraine	7.000000e-09
GCST003807_3	Systolic blood pressure response to hydrochlorothiazide in hypertension	8.000000e-06
GCST003818_22	Resting heart rate	1.000000e-64
GCST004278_26	Pulse pressure	1.000000e-10
GCST004295_5	Atrial fibrillation	1.000000e-08
GCST004297_13	Atrial fibrillation	2.000000e-08
GCST004373_15	Atrial fibrillation	4.000000e-08
GCST005359_12	Disease progression in age-related macular degeneration	9.000000e-07
GCST005789_11	Resting heart rate	1.000000e-24
GCST006061_130	Atrial fibrillation	9.000000e-21
GCST006061_194	Atrial fibrillation	2.000000e-16
GCST006979_379	Heel bone mineral density	6.000000e-16
GCST007096_170	Pulse pressure	1.000000e-12
GCST007217_1	RR interval (heart rate)	1.000000e-13
GCST007217_8	RR interval (heart rate)	3.000000e-09
GCST007325_189	General risk tolerance (MTAG)	2.000000e-08
GCST007350_2	Focal epilepsy (with hippocampal sclerosis)	7.000000e-09
GCST009002_1	Tendinopathy	1.000000e-06
GCST009724_7	Vertical cup-disc ratio (multi-trait analysis)	7.000000e-14
GCST010242_395	HDL cholesterol levels	6.000000e-10
GCST010321_117	PR interval	5.000000e-17
GCST010796_4587	Electrocardiogram morphology (amplitude at temporal datapoints)	8.000000e-10

EFO canonical traits (11, from GWAS)

EFO ID	Trait name
EFO:0004532	serum gamma-glutamyl transferase measurement
EFO:0006944	systolic blood pressure change measurement
EFO:0005763	pulse pressure measurement
EFO:0008336	disease progression measurement
EFO:0009270	heel bone mineral density
EFO:0004831	RR interval
EFO:0008579	risk-taking behaviour
EFO:0006939	cup-to-disc ratio measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0004462	PR interval
EFO:0004327	electrocardiography

MeSH disease descriptors (11)

Descriptor	Name	Tree numbers
D002972	Cleft Palate	C05.500.460.185; C05.660.207.540.460.185; C07.320.440.185; C07.465.525.185; C07.650.500.460.185; C07.650.525.185; C16.131.621.207.540.460.185; C16.131.850.500.460.185; C16.131.850.525.185
D056266	Erythrokeratodermia Variabilis	C16.320.850.337; C17.800.229.606; C17.800.428.304; C17.800.827.337
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
C536570	Craniometaphyseal dysplasia, autosomal recessive type (supp.)
C536154	Keratoderma palmoplantaris transgrediens (supp.)
C580334	Nonsyndromic Deafness (supp.)
C563160	Oculodentodigital Dysplasia (supp.)
C567605	Oculodentodigital Dysplasia, Autosomal Recessive (supp.)
C538154	Syndactyly, type 3 (supp.)
C538155	Syndactyly, type v (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4680024 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 257,519 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1384	KANAMYCIN	4	257,519

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3805787	GJA1		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: other ic — Connexins and Pannexins

ChEMBL bioactivities

8 potent at pChembl≥5 of 12 total, top 8 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.51	IC50	3100	nM	CHEMBL4794431
5.39	IC50	4100	nM	CHEMBL4793190
5.26	IC50	5500	nM	CHEMBL4778380
5.21	IC50	6200	nM	CHEMBL4784426
5.21	IC50	6200	nM	CHEMBL4790312
5.07	IC50	8600	nM	CHEMBL4799209
5.05	IC50	8900	nM	CHEMBL4776897
5.05	IC50	8900	nM	CHEMBL4785499

PubChem BioAssay actives

8 with measured affinity, of 92 total; 8 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2R,3S,4S,5R,6R)-2-(aminomethyl)-6-[(1R,2R,3S,4R,6S)-4,6-diamino-3-[(2S,3R,4R,5S,6R)-4-amino-3-hydroxy-5-[(4-methylphenyl)methoxy]-6-[(4-methylphenyl)methoxymethyl]oxan-2-yl]oxy-2-hydroxycyclohexyl]oxyoxane-3,4,5-triol	1740923: Inhibition of human Cx43 expressed in Escherichia coli LB2003 cells in medium containing 8 mM K+ and 10 uM IPTG by measuring cell growth after 18 hrs by plate reader	ic50	3.1000	uM
(2R,3S,4S,5R,6R)-2-(aminomethyl)-6-[(1R,2R,3S,4R,6S)-4,6-diamino-3-[(2S,3R,4R,5S,6R)-4-amino-3-hydroxy-5-[(4-methoxyphenyl)methoxy]-6-[(4-methoxyphenyl)methoxymethyl]oxan-2-yl]oxy-2-hydroxycyclohexyl]oxyoxane-3,4,5-triol	1740923: Inhibition of human Cx43 expressed in Escherichia coli LB2003 cells in medium containing 8 mM K+ and 10 uM IPTG by measuring cell growth after 18 hrs by plate reader	ic50	4.1000	uM
(2R,3S,4S,5R,6R)-2-(aminomethyl)-6-[(1R,2R,3S,4R,6S)-4,6-diamino-3-[(2S,3R,4R,5S,6R)-4-amino-3-hydroxy-5-[(3-phenylphenyl)methoxy]-6-[(3-phenylphenyl)methoxymethyl]oxan-2-yl]oxy-2-hydroxycyclohexyl]oxyoxane-3,4,5-triol	1740923: Inhibition of human Cx43 expressed in Escherichia coli LB2003 cells in medium containing 8 mM K+ and 10 uM IPTG by measuring cell growth after 18 hrs by plate reader	ic50	5.5000	uM
(2R,3S,4S,5R,6R)-2-(aminomethyl)-6-[(1R,2R,3S,4R,6S)-4,6-diamino-3-[(2S,3R,4R,5S,6R)-4-amino-3-hydroxy-5-(naphthalen-2-ylmethoxy)-6-(naphthalen-2-ylmethoxymethyl)oxan-2-yl]oxy-2-hydroxycyclohexyl]oxyoxane-3,4,5-triol	1740923: Inhibition of human Cx43 expressed in Escherichia coli LB2003 cells in medium containing 8 mM K+ and 10 uM IPTG by measuring cell growth after 18 hrs by plate reader	ic50	6.2000	uM
(2R,3S,4S,5R,6R)-2-(aminomethyl)-6-[(1R,2R,3S,4R,6S)-4,6-diamino-3-[(2S,3R,4S,5S,6R)-4-amino-3,5-dihydroxy-6-[(4-methylphenoxy)methyl]oxan-2-yl]oxy-2-hydroxycyclohexyl]oxyoxane-3,4,5-triol	1740923: Inhibition of human Cx43 expressed in Escherichia coli LB2003 cells in medium containing 8 mM K+ and 10 uM IPTG by measuring cell growth after 18 hrs by plate reader	ic50	6.2000	uM
N-[[(2R,3S,4S,5R,6R)-6-[(1R,2R,3S,4R,6S)-4,6-diamino-3-[(2S,3R,4S,5S,6R)-4-amino-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-3,4,5-trihydroxyoxan-2-yl]methyl]-4-pyren-2-ylbutanamide	1740923: Inhibition of human Cx43 expressed in Escherichia coli LB2003 cells in medium containing 8 mM K+ and 10 uM IPTG by measuring cell growth after 18 hrs by plate reader	ic50	8.6000	uM
(2R,3S,4S,5R,6R)-2-(aminomethyl)-6-[(1R,2R,3S,4R,6S)-4,6-diamino-3-[(2S,3R,4S,5S,6R)-4-amino-6-[(4-chlorophenoxy)methyl]-3,5-dihydroxyoxan-2-yl]oxy-2-hydroxycyclohexyl]oxyoxane-3,4,5-triol	1740923: Inhibition of human Cx43 expressed in Escherichia coli LB2003 cells in medium containing 8 mM K+ and 10 uM IPTG by measuring cell growth after 18 hrs by plate reader	ic50	8.9000	uM
N-[[(2R,3S,4S,5R,6R)-6-[(1R,2R,3S,4R,6S)-4,6-diamino-3-[(2S,3R,4S,5S,6R)-4-amino-3,5-dihydroxy-6-(hydroxymethyl)oxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-3,4,5-trihydroxyoxan-2-yl]methyl]-2-(3-hydroxy-6-oxoxanthen-9-yl)benzamide	1740923: Inhibition of human Cx43 expressed in Escherichia coli LB2003 cells in medium containing 8 mM K+ and 10 uM IPTG by measuring cell growth after 18 hrs by plate reader	ic50	8.9000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression, decreases activity, decreases expression	7
bisphenol A	affects expression, affects reaction, affects cotreatment, decreases expression, decreases methylation (+3 more)	5
Particulate Matter	decreases reaction, increases abundance, increases expression, decreases expression	5
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	4
Estradiol	affects cotreatment, decreases expression, increases expression	4
Resveratrol	affects cotreatment, decreases expression, decreases reaction, increases degradation, increases expression	3
Arsenic Trioxide	decreases expression, decreases reaction	3
Air Pollutants	decreases reaction, increases abundance, increases expression, decreases expression	3
Tobacco Smoke Pollution	decreases expression, increases expression	3
Tretinoin	increases expression, decreases expression	3
Aflatoxin B1	affects expression, increases methylation	3
cobaltous chloride	decreases expression	2
perfluorooctanoic acid	affects expression, decreases expression, affects cotreatment	2
S-(1,2-dichlorovinyl)cysteine	decreases expression, affects cotreatment	2
perfluorooctane sulfonic acid	affects cotreatment, decreases expression, affects expression	2
Fulvestrant	affects cotreatment, affects expression, affects reaction, affects binding, increases reaction (+3 more)	2
Acetylcysteine	increases expression, affects reaction, affects cotreatment, affects expression, decreases reaction (+1 more)	2
Cadmium	increases abundance, increases expression, increases phosphorylation, decreases expression, decreases reaction (+1 more)	2
Diethylhexyl Phthalate	affects expression, increases expression	2
Doxorubicin	decreases reaction, decreases expression, increases expression, increases phosphorylation, affects cotreatment	2
Oxygen	decreases reaction, increases expression, decreases expression, increases phosphorylation	2
Plant Extracts	affects cotreatment, decreases expression, decreases reaction, increases expression	2
Tetrachlorodibenzodioxin	increases phosphorylation, affects cotreatment, decreases expression, decreases activity	2
Tetradecanoylphorbol Acetate	decreases reaction, increases expression, increases phosphorylation	2
Valproic Acid	decreases reaction, decreases expression	2
Cadmium Chloride	increases abundance, increases expression, increases phosphorylation, decreases reaction, affects phosphorylation (+4 more)	2
tert-Butylhydroperoxide	decreases response to substance, decreases expression	2
FR900359	decreases phosphorylation	1
ammonium 2,3,3,3-tetrafluoro-2-(heptafluoropropoxy)-propanoate	affects cotreatment, affects expression	1
pirinixic acid	affects expression	1

ChEMBL screening assays

4 unique, capped per target: 4 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4673569	Binding	Inhibition of Cx43 in hypoxic-acidic ion-shifted ringers solution-induced human cerebral microvascular endothelial cell model of ischaemic injury assessed as ATP release at 10 uM measured after 2 hrs by luciferin-luciferase based luminescen	Synthesis and biological evaluation of S-lipidated lipopeptides of a connexin 43 channel inhibitory peptide — RSC Med Chem

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B1AX	Abcam HEK293 GJA1 KO	Transformed cell line	Female
CVCL_D1SS	Abcam U-87MG GJA1 KO	Cancer cell line	Male
CVCL_E9CB	HT29-Cx43	Cancer cell line	Female
CVCL_E9CC	HT29-Cx43TK	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00668824	PHASE4	UNKNOWN	Improved Diagnosis of Congenital Heart Disease by Magnetic Resonance Imaging Using Vasovist
NCT01368705	PHASE4	COMPLETED	Nitrogen Balance in Infants After Post Cardiothoracic Surgery
NCT01619982	PHASE4	COMPLETED	Pre-operative Prophylaxis With Vancomycin and Cefazolin in Pediatric Cardiovascular Surgery Patients
NCT02122679	PHASE4	WITHDRAWN	Tranexamic Acid Effect on Platelet Aggregation Following Infant Cardiopulmonary Bypass
NCT02527811	PHASE4	UNKNOWN	Ulinastatin Injection in in Pediatric Patients Undergoing Open Heart Surgery
NCT03014700	PHASE4	COMPLETED	Fibrinogen Concentrate vs Cryoprecipitate
NCT03408340	PHASE4	TERMINATED	Paravertebral Nerve Blocks in Neonates
NCT03630796	PHASE4	UNKNOWN	Effect of Sevoflurane in Postoperative Troponin I Levels in Children Undergoing Congenital Heart Defects Surgery
NCT03667703	PHASE4	COMPLETED	Stress Ulcer Prophylaxis Versus Placebo in Critically Ill Infants With Congenital Heart Disease
NCT04453761	PHASE4	UNKNOWN	Thiamine Influenced on Substrate Energy Effectiveness in Indonesian Children Undergoing Cardiopulmonary Bypass
NCT06668389	PHASE4	RECRUITING	Sodium-Glucose Cotransporter 2 Inhibitors for Repaired Tetralogy of Fallot Patients for Enhancement of Cardio-Pulmonary Status Trial
NCT07499154	PHASE4	NOT_YET_RECRUITING	Perioperative Lidocaine for Lung Protection in Infants Undergoing Cardiac Surgery
NCT02422056	PHASE4	COMPLETED	Acid Tranexamic Effectiveness in Reducing the Intraoperative Bleeding in Palatoplasty
NCT02915042	PHASE4	WITHDRAWN	Dexmedetomidine vs Placebo for Pediatric Cleft Palate Repair
NCT02953145	PHASE4	WITHDRAWN	The Use of Fibrin Sealant to Reduce Post Operative Pain in Cleft Palate Surgery
NCT03632044	PHASE4	ACTIVE_NOT_RECRUITING	Evaluation of Trigeminal Nerve Blockade
NCT06962306	PHASE4	RECRUITING	Optimizing Perioperative Analgesia to Lower Pain Following Cleft Palate Surgery
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00000470	PHASE3	COMPLETED	Infant Heart Surgery: Central Nervous System Sequelae of Circulatory Arrest
NCT00000494	PHASE3	COMPLETED	Management of Patent Ductus in Premature Infants
NCT01134302	PHASE3	UNKNOWN	Hybrid Versus Norwood Management Strategies in Infants Undergoing Single Ventricle Palliation
NCT01607983	PHASE3	WITHDRAWN	Effects of Pulmonary Vasodilation Upon VA Coupling in Fontan Patients
NCT01662011	PHASE3	UNKNOWN	Application of Neurally Adjusted Ventilatory Assist to Children After Congenital Cardiac Surgery
NCT02320669	PHASE3	COMPLETED	Phase 3 Triiodothyronine Supplementation for Infants After Cardiopulmonary Bypass
NCT02615262	PHASE3	COMPLETED	Intraoperative Dexamethasone in Pediatric Cardiac Surgery
NCT03153137	PHASE3	COMPLETED	Clinical Study Assessing the Efficacy and Safety of Macitentan in Fontan-palliated Subjects
NCT03154476	PHASE3	COMPLETED	Role of Sildenafil for Fontan Associated Liver Disease (SiFALD) Study
NCT04536194	PHASE3	COMPLETED	Dopamine Versus Norepinephrine Under General Anesthesia
NCT04702373	PHASE3	ACTIVE_NOT_RECRUITING	Training in Exercise Activities and Motion for Growth (TEAM 4 Growth) RCT
NCT05049590	PHASE3	COMPLETED	Acute Normovolemic Hemodilution in Complex Cardiac Surgery
NCT06406517	PHASE3	UNKNOWN	Comparative Effectiveness of Gadopiclenol for Evaluation of Adult Congenital Heart Anatomy and Hemodynamics
NCT06693674	PHASE3	RECRUITING	Effect of Sacubitril-Valsartan on Cardiac Structure and Function
NCT06955260	PHASE3	NOT_YET_RECRUITING	SGLT2 Inhibition With Empagliflozin in Fontan Circulatory Failure
NCT00098319	PHASE3	COMPLETED	Oral Cleft Prevention Trial in Brazil
NCT00397917	PHASE3	COMPLETED	Oral Cleft Prevention Program
NCT04928352	PHASE3	RECRUITING	Nebulized Bupivacaine Analgesia for Cleft Palate Repair
NCT04928391	PHASE3	COMPLETED	A Single Bolus of Dexmedetomidine Versus Normal Saline in Postoperative Agitation