GJA5

Summary

GJA5 (gap junction protein alpha 5, HGNC:4279) is a protein-coding gene on chromosome 1q21.2, encoding Gap junction alpha-5 protein (P36382). One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.

This gene is a member of the connexin gene family. The encoded protein is a component of gap junctions, which are composed of arrays of intercellular channels that provide a route for the diffusion of low molecular weight materials from cell to cell. Mutations in this gene may be associated with atrial fibrillation. Alternatively spliced transcript variants encoding the same isoform have been described.

Source: NCBI Gene 2702 — RefSeq curated summary.

At a glance

• Gene–disease (curated): atrial fibrillation, familial, 11 (Strong, GenCC) — +3 more curated relationships
• GWAS associations: 9
• Clinical variants (ClinVar): 327 total — 9 pathogenic
• Phenotypes (HPO): 129
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_181703

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4279
Approved symbol	GJA5
Name	gap junction protein alpha 5
Location	1q21.2
Locus type	gene with protein product
Status	Approved
Aliases	CX40
Ensembl gene	ENSG00000265107
Ensembl biotype	protein_coding
OMIM	121013
Entrez	2702

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 8 protein_coding

ENST00000430508, ENST00000579774, ENST00000621517, ENST00000863529, ENST00000922170, ENST00000955979, ENST00000955980, ENST00000955981

RefSeq mRNA: 2 — MANE Select: NM_181703 NM_005266, NM_181703

CCDS: CCDS929

Canonical transcript exons

ENST00000579774 — 2 exons

Exon	Start	End
ENSE00002715853	147756199	147759271
ENSE00003727736	147760499	147760602

Expression profiles

Bgee: expression breadth ubiquitous, 190 present calls, max score 91.79.

FANTOM5 (CAGE): breadth broad, TPM avg 1.7358 / max 193.1249, expressed in 291 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
14230	0.8204	55
14236	0.5210	191
14232	0.0906	32
14237	0.0724	37
14233	0.0556	24
14229	0.0547	17
14234	0.0536	25
14235	0.0414	16
14231	0.0146	10
14228	0.0116	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
placenta	UBERON:0001987	91.79	gold quality
right coronary artery	UBERON:0001625	89.48	gold quality
left coronary artery	UBERON:0001626	88.93	gold quality
right atrium auricular region	UBERON:0006631	88.49	gold quality
lower lobe of lung	UBERON:0008949	88.25	gold quality
cardiac atrium	UBERON:0002081	88.22	gold quality
coronary artery	UBERON:0001621	87.61	gold quality
popliteal artery	UBERON:0002250	86.91	gold quality
tibial artery	UBERON:0007610	86.91	gold quality
upper lobe of lung	UBERON:0008948	86.52	gold quality
descending thoracic aorta	UBERON:0002345	86.30	gold quality
aorta	UBERON:0000947	86.17	gold quality
upper lobe of left lung	UBERON:0008952	86.11	gold quality
cardiac muscle of right atrium	UBERON:0003379	85.96	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	85.67	gold quality
apex of heart	UBERON:0002098	85.45	gold quality
thoracic aorta	UBERON:0001515	85.43	gold quality
ascending aorta	UBERON:0001496	85.03	gold quality
omental fat pad	UBERON:0010414	83.84	gold quality
visceral pleura	UBERON:0002401	83.79	gold quality
peritoneum	UBERON:0002358	83.78	gold quality
myocardium	UBERON:0002349	83.62	silver quality
heart	UBERON:0000948	83.32	gold quality
adipose tissue of abdominal region	UBERON:0007808	82.99	gold quality
right lung	UBERON:0002167	82.95	gold quality
lung	UBERON:0002048	80.25	gold quality
heart left ventricle	UBERON:0002084	79.82	gold quality
metanephros cortex	UBERON:0010533	79.54	gold quality
cardiac ventricle	UBERON:0002082	79.45	gold quality
adult mammalian kidney	UBERON:0000082	77.64	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-135922	yes	405.73
E-MTAB-6701	yes	74.24
E-HCAD-10	yes	44.29
E-ANND-3	yes	5.63

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): APLNR, CTNNB1, GATA4, HAND2, IRX3, NKX2-1, NKX2-5, NKX2-6, SP1, SP3, TBX2, TBX3, TBX5

miRNA regulators (miRDB)

76 targeting GJA5, 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-8485	100.00	77.57	4731
HSA-MIR-3667-3P	99.99	67.17	1636
HSA-MIR-7152-3P	99.97	67.47	849
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4779	99.86	66.50	1583
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4739	99.84	65.25	1832
HSA-MIR-4756-5P	99.84	64.98	1809
HSA-MIR-6844	99.82	70.69	2423
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-7856-5P	99.75	69.99	2901
HSA-MIR-4306	99.72	70.50	3630
HSA-MIR-6892-3P	99.68	66.40	1178
HSA-MIR-466	99.67	70.85	2863
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-4756-3P	99.62	66.30	1319
HSA-MIR-7150	99.62	66.80	1322
HSA-MIR-6832-5P	99.58	64.82	1132
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-642A-5P	99.51	65.10	1152
HSA-MIR-4519	99.48	66.10	859
HSA-MIR-4688	99.48	64.68	828
HSA-MIR-4251	99.40	69.19	3363
HSA-MIR-185-5P	99.35	68.60	2497
HSA-MIR-4644	99.35	69.12	2514
HSA-MIR-155-5P	99.35	70.16	1509
HSA-MIR-7515	99.31	68.22	1795

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Data suggest that these dynamic changes of connexins 43, 40 and 45 during mouse cardiac development appear to be mirrored in the human. (PMID:12064615)
• Our data show that the presence of Cx40 does not allow GJIC and is associated with the extravillous phenotype (PMID:12397213)
• endothelial gap junction protein connexin 37 and connexin 40-mediated communication in the development and/or functional maintenance of segments of the mouse vasculature. (PMID:12435353)
• Staining for Cx43 and Cx40 along regions of intimate cell-to-cell contact between human mesenchymal stem cells. (PMID:14766937)
• 505 CHD cases were screened for the Cx40 gene to see if altered copy number associated with a cardiac phenotype. 3 cases carred deletions on chromosome 1q21.1 spanning ACPL1, Cx40, and Cx50 genes, with aortic arch anomalies being a particular feature. (PMID:15117819)
• The -44A allele & -44AA genotype were significantly more frequent in subjects with prior AF than in those without, providing strong evidence linking Cx40 polymorphisms to enhanced atrial vulnerability and increased risk of AF. (PMID:15297374)
• Coinheritance of Cx40 polymorphisms is a possible genetic factor that modifies the clinical manifestation of this inherited arrhythmia. (PMID:16188595)
• This is the first study to demonstrate that flow simultaneously and differentially regulates expression of the Cx37, Cx40, and Cx43 proteins. (PMID:16361362)
• We conclude that decidual secretion of growth factors, such as EGF, may act to prime trophoblast for migration/invasion through modulation of connexin expression and function. (PMID:16545451)
• there may be more than one conformation form of the connexin40 carboxyl tail with roles in atrial conduction and arrhythmogenesis (PMID:16600287)
• Cx40 polymorphisms are associated with enhanced spacial dispersion of refractoriness and thus with susceptibility to reentry and atrial fibrillation (PMID:16646598)
• Four novel heterozygous missense mutations were identified in 4 of the 15 patients. Mutations in GJA5 may predispose patients to idiopathic atrial fibrillation by impairing gap-junction assembly or electrical coupling. (PMID:16790700)
• The two SNPs in the promoter region of the Cx40 gene were significantly associated with atrial fibrillation and the Cx40 (-44A +71G) haplotype was associated with a higher risk for atrial fibrillation. (PMID:16814413)
• Cx40/Cx45 junctions demonstrate electrical signal transfer asymmetry that can be modulated between unidirectional and bidirectional by small changes in the difference between holding potentials of the coupled cells. (PMID:17189315)
• 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)
• This study investigates the responses of endothelial connexin 37, connexin 40, and connexin 43 (Cx37, Cx40, and Cx43) to shear stress and substrate. (PMID:17922338)
• High-frequence electromagnetic field exposure significantly and selectively increased trophoblast Cx40 and Cx43, without altering protein expression. (PMID:19490996)
• In patients with cerebral ischemic events, without prior CVD, a higher prevalence of the Cx40 gene polymorphism, as a marker of underlying idiopathic atrial fibrillation appeared to be absent. (PMID:19494781)
• analysis of intermolecular interactions between the connexin40 and connexin43 carboxyl-terminal and cytoplasmic loop domains (PMID:19808665)
• Results show that Cx40, Cx37, Cx43 and Cx45 were expressed within the glomeruli. (PMID:20530971)
• Three novel connexin40 mutations (p.V85I, p.L221I, and p.L229M) were identified which co-segregated with atrial fibrillation and were absent in the controls without atrial fibrillation. (PMID:20650941)
• There is an alternate promoter polymorphism that directly affects levels of Cx40 mRNA in vivo and is associated with early-onset lone atrial fibrillation. (PMID:21076161)
• Study shows that fusion of a V5/6-His tag (hexa moiety M r = 0.93 kDa) to the CT segment of Cx40, Cx43 and Cx45 does not prevent the cells from forming channels. (PMID:21424225)
• Association between hereditary sick sinus node syndrome and connexin 40 gene polymorphism was demonstrated. (PMID:21649591)
• Regulation of endothelial connexin40 expression by shear stress via PI3K/Akt pathway. (PMID:22021330)
• Results implicate GJA5 as the gene responsible for the congenital heart disease phenotypes observed with copy number imbalances at this locus. (PMID:22199024)
• Heteromeric cotransfection of Cx40-WT and Cx40-Q58L resulted in homogenous distribution of proteins in the plasma membrane rather than in membrane plaques in approximately 50% of cells; well-defined gap junctions were observed in other cells. (PMID:22247482)
• our study could not detect an association of Cx40 promoter polymorphisms and CAD in human (PMID:22405441)
• This is the first evidence of intrinsic differences in the Ca2+ regulatory properties of Cx43 and Cx40. (PMID:22422398)
• Presence of the Cx40 minor allele (-44 G –> A) results in a uniform down-regulation of right atrial appendage Cx40 protein which was not significantly related to development of post-operative AF. (PMID:22423256)
• Pro265Ser variant in the carboxyl-terminus of connexin 40 alters GAP junctions and increases risk for tetralogy of Fallot. (PMID:22713807)
• Genotyping of rs10465885 showed that the patients with early-onset lone AF were more likely to carry the A allele compared with controls (odds ratio = 1.30; P = 0.011). (PMID:23040431)
• Cx40 coding SNPs are uncommon in atrial fibrillation populations, although rare mutations in this gene may lead to atrial fibrillation pathogenesis. (PMID:23134779)
• 4 novel heterozygous GJA5 mutations, p.K107R, p.L223M, p.Q236H and p.I257L, were identified in 4 of 310 unrelated AF patients. (PMID:23292621)
• the germline familial mutations in Cx40 impair the gap junctions through different mechanisms, which may predispose the mutant carriers to AF. (PMID:23348765)
• Cx43 and Cx40 but not Cx37 promote apoptosis via gap junctional transfer of pro-apoptotic signals between cells. (PMID:23579271)
• 17-beta-estradiol modulates connexins and integrins as well as ER-beta expression induced by high frequency electromagnetic fields. (PMID:23819010)
• heterozygous Cx40A96S mice exhibit prolonged episodes of induced atrial fibrillation and severely reduced atrial conduction velocities similar to the corresponding human patient. (PMID:24060583)
• These findings provide evidence that the connexin 40 Q49X mutant is capable of impairing gap-junction distribution and function of key atrial connexins, which might play a role in the predisposition to and onset of atrial fibrillation. (PMID:24626989)
• This is a review summarizing atrial fibrillation-linked somatic and germline mutations in the gene encoding Cx40. Multiple impairments were observed in these mutants, including impaired gap junction function by abnormal localization or function, as well as increased hemichannel function. (PMID:24656738)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	gja5a	ENSDARG00000040065
danio_rerio	gja5b	ENSDARG00000069450
mus_musculus	Gja5	ENSMUSG00000057123
rattus_norvegicus	Gja5	ENSRNOG00000017484

Paralogs (20): GJA8 (ENSG00000121634), GJB6 (ENSG00000121742), GJA3 (ENSG00000121743), GJA9 (ENSG00000131233), GJA10 (ENSG00000135355), GJA1 (ENSG00000152661), GJD2 (ENSG00000159248), GJB7 (ENSG00000164411), GJB2 (ENSG00000165474), GJB1 (ENSG00000169562), GJC3 (ENSG00000176402), GJD4 (ENSG00000177291), GJC1 (ENSG00000182963), GJD3 (ENSG00000183153), GJA4 (ENSG00000187513), GJB3 (ENSG00000188910), GJB5 (ENSG00000189280), GJB4 (ENSG00000189433), GJC2 (ENSG00000198835), GJE1 (ENSG00000203733)

Protein

Protein identifiers

Gap junction alpha-5 protein — P36382 (reviewed: P36382)

Alternative names: Connexin-40

All UniProt accessions (3): A0A0B4J1Y3, P36382, X5D2H9

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.

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

Disease relevance. Atrial standstill 1 (ATRST1) [MIM:108770] A rare arrhythmia characterized by the absence of electrical and mechanical activity in the atria. Electrocardiographically, it is characterized by bradycardia, the absence of P waves, and a junctional narrow complex escape rhythm. The disease may be caused by variants affecting distinct genetic loci, including the gene represented in this entry. A rare GJA5 genotype has been detected in combination with a mutation in SCN5A in a large family with atrial standstill. Atrial fibrillation, familial, 11 (ATFB11) [MIM:614049] A familial form of atrial fibrillation, a common sustained cardiac rhythm disturbance. Atrial fibrillation is characterized by disorganized atrial electrical activity and ineffective atrial contraction promoting blood stasis in the atria and reduces ventricular filling. It can result in palpitations, syncope, thromboembolic stroke, and congestive heart failure. 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 (2): NP_005257, NP_859054* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000500	Connexin	Family
IPR002264	Connexin40	Family
IPR013092	Connexin_N	Domain
IPR017990	Connexin_CS	Conserved_site
IPR019570	Connexin_CCC	Domain
IPR031862	Cx40_C	Domain
IPR034634	Connexin_C	Homologous_superfamily
IPR038359	Connexin_N_sf	Homologous_superfamily

Pfam: PF00029, PF16791

UniProt features (19 total): topological domain 5, sequence variant 5, transmembrane region 4, modified residue 2, chain 1, region of interest 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P36382-F1	70.35	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 (2): 353, 357

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-190861	Gap junction assembly

MSigDB gene sets: 564 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_POTASSIUM_ION_TRANSPORT, GOBP_MEMBRANE_DEPOLARIZATION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_BUNDLE_OF_HIS_CELL_TO_PURKINJE_MYOCYTE_COMMUNICATION, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, MYOGENIN_Q6, GOBP_REGULATION_OF_SYSTEMIC_ARTERIAL_BLOOD_PRESSURE_BY_CIRCULATORY_RENIN_ANGIOTENSIN, GOBP_REGULATION_OF_BLOOD_PRESSURE, GOBP_VENTRICULAR_SEPTUM_MORPHOGENESIS, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, MODULE_255, GOBP_CARDIAC_CHAMBER_MORPHOGENESIS

GO Biological Process (58): skeletal system development (GO:0001501), angiogenesis (GO:0001525), negative regulation of glomerular filtration (GO:0003105), outflow tract morphogenesis (GO:0003151), endothelium development (GO:0003158), cardiac conduction system development (GO:0003161), mitral valve development (GO:0003174), pulmonary valve formation (GO:0003193), ventricular septum development (GO:0003281), atrial septum development (GO:0003283), septum primum development (GO:0003284), atrial ventricular junction remodeling (GO:0003294), potassium ion transport (GO:0006813), cell-cell signaling (GO:0007267), heart development (GO:0007507), cell communication by chemical coupling (GO:0010643), regulation of cell communication by electrical coupling (GO:0010649), positive regulation of cell communication by chemical coupling (GO:0010652), gap junction assembly (GO:0016264), embryonic limb morphogenesis (GO:0030326), embryonic heart tube development (GO:0035050), foramen ovale closure (GO:0035922), vasodilation (GO:0042311), negative regulation of blood pressure (GO:0045776), positive regulation of vasoconstriction (GO:0045907), artery morphogenesis (GO:0048844), regulation of cardiac muscle contraction (GO:0055117), regulation of ventricular cardiac muscle cell membrane repolarization (GO:0060307), regulation of atrial cardiac muscle cell membrane depolarization (GO:0060371), regulation of ventricular cardiac muscle cell membrane depolarization (GO:0060373), ventricular septum morphogenesis (GO:0060412), atrial septum morphogenesis (GO:0060413), ventricular cardiac muscle cell action potential (GO:0086005), SA node cell action potential (GO:0086015), SA node cell to atrial cardiac muscle cell communication by electrical coupling (GO:0086021), atrial cardiac muscle cell to AV node cell communication by electrical coupling (GO:0086044), AV node cell to bundle of His cell communication by electrical coupling (GO:0086053), bundle of His cell to Purkinje myocyte communication by electrical coupling (GO:0086054), Purkinje myocyte to ventricular cardiac muscle cell communication by electrical coupling (GO:0086055), cell communication by electrical coupling involved in cardiac conduction (GO:0086064)

GO Molecular Function (11): gap junction hemi-channel activity (GO:0055077), connexin binding (GO:0071253), gap junction channel activity involved in SA node cell-atrial cardiac muscle cell electrical coupling (GO:0086020), gap junction channel activity involved in cardiac conduction electrical coupling (GO:0086075), gap junction channel activity involved in atrial cardiac muscle cell-AV node cell electrical coupling (GO:0086076), gap junction channel activity involved in AV node cell-bundle of His cell electrical coupling (GO:0086077), gap junction channel activity involved in bundle of His cell-Purkinje myocyte electrical coupling (GO:0086078), gap junction channel activity involved in Purkinje myocyte-ventricular cardiac muscle cell electrical coupling (GO:0086079), disordered domain specific binding (GO:0097718), gap junction channel activity (GO:0005243), protein binding (GO:0005515)

GO Cellular Component (7): plasma membrane (GO:0005886), gap junction (GO:0005921), connexin complex (GO:0005922), intercalated disc (GO:0014704), cell projection (GO:0042995), membrane (GO:0016020), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Gap junction trafficking	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
gap junction channel activity involved in cardiac conduction electrical coupling	5
heart morphogenesis	2
cardiac septum development	2
cell communication	2
wide pore channel activity	2
cellular anatomical structure	2
system development	1
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
regulation of glomerular filtration	1
glomerular filtration	1
negative regulation of multicellular organismal process	1
anatomical structure morphogenesis	1
epithelium development	1
cardiac muscle tissue development	1
atrioventricular valve development	1
pulmonary valve morphogenesis	1
heart valve formation	1
cardiac ventricle development	1
cardiac atrium development	1
atrial septum development	1
tissue remodeling	1
metal ion transport	1
signaling	1
animal organ development	1
circulatory system development	1
cell communication by electrical coupling	1
regulation of cell communication	1
cell communication by chemical coupling	1
regulation of cell communication by chemical coupling	1
positive regulation of cell communication	1
cell-cell junction assembly	1
limb morphogenesis	1
embryonic appendage morphogenesis	1
gap junction channel activity	1
protein binding	1
SA node cell to atrial cardiac muscle cell communication by electrical coupling	1
cell communication by electrical coupling involved in cardiac conduction	1
gap junction channel activity involved in cell communication by electrical coupling	1
atrial cardiac muscle cell to AV node cell communication by electrical coupling	1

Protein interactions and networks

STRING

1338 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GJA5	GJC1	P36383	983
GJA5	GJA1	P17302	981
GJA5	GJA4	P35212	955
GJA5	GJB2	P29033	888
GJA5	SCN5A	Q14524	879
GJA5	NKX2-5	P52952	873
GJA5	HCN4	Q9Y3Q4	871
GJA5	NFKBIA	P25963	847
GJA5	GJB1	P08034	824
GJA5	TBX5	Q99593	805
GJA5	NPPA	P01160	778
GJA5	FMO5	P49326	724
GJA5	TBX3	O15119	722
GJA5	SP4	Q02446	720
GJA5	CLDN5	O00501	716

IntAct

100 interactions, top by confidence:

A	B	Type	Score
SLC13A4	GJA5	psi-mi:“MI:0915”(physical association)	0.560
ARLN	GJA5	psi-mi:“MI:0915”(physical association)	0.560
SLC30A2	GJA5	psi-mi:“MI:0915”(physical association)	0.560
BLCAP	GJA5	psi-mi:“MI:0915”(physical association)	0.560
GJB2	GJA5	psi-mi:“MI:0915”(physical association)	0.560
SLC41A1	GJA5	psi-mi:“MI:0915”(physical association)	0.560
MS4A13	GJA5	psi-mi:“MI:0915”(physical association)	0.560
GJA5	TREX1	psi-mi:“MI:0915”(physical association)	0.560
GJA5	SLC66A1	psi-mi:“MI:0915”(physical association)	0.560
	GJA5	psi-mi:“MI:0915”(physical association)	0.560
GJA5	SLC41A1	psi-mi:“MI:0915”(physical association)	0.560
GJA5	SLC13A4	psi-mi:“MI:0915”(physical association)	0.560
GJA5	SLC35F1	psi-mi:“MI:0915”(physical association)	0.560
IGFBP5	GJA5	psi-mi:“MI:0915”(physical association)	0.560
GJA5	RPRM	psi-mi:“MI:0915”(physical association)	0.560
GJA5	ARLN	psi-mi:“MI:0915”(physical association)	0.560
ABHD16A	GJA5	psi-mi:“MI:0915”(physical association)	0.560
GJA5	MFSD5	psi-mi:“MI:0915”(physical association)	0.560
PRAF2	GJA5	psi-mi:“MI:0915”(physical association)	0.560
GJA5	SLC30A2	psi-mi:“MI:0915”(physical association)	0.560
GJA5	BLCAP	psi-mi:“MI:0915”(physical association)	0.560
GJA5	LHFPL2	psi-mi:“MI:0915”(physical association)	0.560
GJA5	TMBIM6	psi-mi:“MI:0915”(physical association)	0.560
LEPROTL1	GJA5	psi-mi:“MI:0915”(physical association)	0.560
GJA5	PGAP2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (38): AAR2 (Two-hybrid), GJA5 (Reconstituted Complex), UBQLN4 (Affinity Capture-Western), PSMD2 (Affinity Capture-Western), GJA5 (Proximity Label-MS), GJA5 (Two-hybrid), GJA5 (Two-hybrid), GJA5 (Two-hybrid), GJA5 (Two-hybrid), GJA5 (Two-hybrid), GJA5 (Two-hybrid), GJA5 (Two-hybrid), GJA5 (Two-hybrid), GJA5 (Two-hybrid), GJA5 (Two-hybrid)

ESM2 similar proteins: A0A1B0GRQ0, A0A1B0GVT2, A2RRL7, A3KN25, A4IFL1, G1TZA0, O18968, O54851, O70610, P08033, P0DKX4, P28230, P28234, P28235, P29414, P33725, P35212, P36382, P41987, P56513, Q01231, Q03190, Q08755, Q08EA8, Q0VCR2, Q2TA35, Q3MHM8, Q58CU5, Q5HZE8, Q5M8E3, Q5RCC0, Q60HF7, Q64448, Q6WGK6, Q7TNI2, Q866T7, Q8BSD4, Q8CFA6, Q8N6S5, Q8R0I4

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

2 interactions.

A	Effect	B	Mechanism
PRKACA	“up-regulates activity”	GJA5	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	0
Uncertain significance	212
Likely benign	84
Benign	6

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
1444016	NC_000001.10:g.(?147230270)(147231346_?)del	Pathogenic
16999	NM_181703.4(GJA5):c.262C>T (p.Pro88Ser)	Pathogenic
2042319	NM_181703.4(GJA5):c.23del (p.Gly8fs)	Pathogenic
29663	NM_181703.4(GJA5):c.145C>T (p.Gln49Ter)	Pathogenic
29664	NM_181703.4(GJA5):c.253G>A (p.Val85Ile)	Pathogenic
29666	NM_181703.4(GJA5):c.685C>A (p.Leu229Met)	Pathogenic
3755327	NM_181703.4(GJA5):c.3G>A (p.Met1Ile)	Pathogenic
625769	GRCh37/hg19 1q21.2(chr1:147245049-147246661)	Pathogenic
980946	GRCh37/hg19 1q21.1-21.2(chr1:146496425-147819815)x3	Pathogenic

SpliceAI

163 predictions. Top by Δscore:

Variant	Effect	Δscore
1:147759269:CTT:C	acceptor_gain	1.0000
1:147759272:C:CC	acceptor_gain	1.0000
1:147760497:A:AC	donor_gain	1.0000
1:147760498:C:CC	donor_gain	1.0000
1:147760498:CT:C	donor_gain	1.0000
1:147760498:CTCGT:C	donor_gain	1.0000
1:147759267:AACTT:A	acceptor_gain	0.9900
1:147759270:TT:T	acceptor_gain	0.9900
1:147759270:TTCTG:T	acceptor_loss	0.9900
1:147759271:TC:T	acceptor_loss	0.9900
1:147759272:C:A	acceptor_loss	0.9900
1:147759273:T:G	acceptor_loss	0.9900
1:147759278:A:AC	acceptor_gain	0.9900
1:147759278:A:C	acceptor_gain	0.9900
1:147760492:CACT:C	donor_loss	0.9900
1:147760493:ACTT:A	donor_loss	0.9900
1:147760494:CT:C	donor_loss	0.9900
1:147760495:TTA:T	donor_loss	0.9900
1:147760496:TAC:T	donor_loss	0.9900
1:147760497:A:C	donor_loss	0.9900
1:147760497:ACT:A	donor_gain	0.9900
1:147760498:CTC:C	donor_gain	0.9900
1:147760498:CTCG:C	donor_gain	0.9900
1:147759275:C:CT	acceptor_gain	0.9800
1:147759276:A:T	acceptor_gain	0.9800
1:147760490:GACAC:G	donor_loss	0.9800
1:147760491:ACAC:A	donor_loss	0.9800
1:147759439:A:T	acceptor_gain	0.9700
1:147760449:C:A	donor_gain	0.9600
1:147759576:T:TA	donor_gain	0.9300

AlphaMissense

2347 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:147759104:C:A	W45C	0.999
1:147759104:C:G	W45C	0.999
1:147758627:C:A	K204N	0.998
1:147758627:C:G	K204N	0.998
1:147758651:A:C	C196W	0.998
1:147758738:G:C	F167L	0.998
1:147758738:G:T	F167L	0.998
1:147758740:A:G	F167L	0.998
1:147759029:G:C	F70L	0.998
1:147759029:G:T	F70L	0.998
1:147759031:A:G	F70L	0.998
1:147759078:C:G	C54S	0.998
1:147759079:A:T	C54S	0.998
1:147759084:A:C	F52C	0.998
1:147758652:C:G	C196S	0.997
1:147758653:A:T	C196S	0.997
1:147759044:G:C	C65W	0.997
1:147759045:C:T	C65Y	0.997
1:147759057:C:G	C61S	0.997
1:147759058:A:T	C61S	0.997
1:147759106:A:G	W45R	0.997
1:147759106:A:T	W45R	0.997
1:147758573:G:C	S222R	0.996
1:147758573:G:T	S222R	0.996
1:147758575:T:G	S222R	0.996
1:147758652:C:T	C196Y	0.996
1:147758976:G:C	P88R	0.996
1:147758976:G:T	P88H	0.996
1:147759030:A:C	F70C	0.996
1:147759045:C:G	C65S	0.996

dbSNP variants (sampled 300 via entrez): RS1000534810 (1:147761650 C>T), RS1000534956 (1:147772858 C>T), RS1000563749 (1:147767334 T>C), RS1000593261 (1:147767046 C>G,T), RS1000969384 (1:147773250 A>G), RS1001139713 (1:147760506 C>T), RS1001297029 (1:147761315 C>T), RS1001322312 (1:147773667 G>C,T), RS1001450655 (1:147768531 T>C), RS1001508745 (1:147760698 A>C,G), RS1001879736 (1:147772265 T>C), RS1001880387 (1:147768267 C>A,G), RS1002270027 (1:147760432 C>G,T), RS1002302690 (1:147760091 A>G), RS1002479879 (1:147766612 A>C)

Disease associations

OMIM: gene MIM:121013 | disease phenotypes: MIM:108770, MIM:614049, MIM:612474, MIM:194200

GenCC curated gene-disease

Disease	Classification	Inheritance
atrial fibrillation, familial, 11	Strong	Autosomal dominant
familial atrial fibrillation	Supportive	Autosomal dominant
heart conduction disease	Limited	Autosomal dominant
congenital heart disease	Disputed Evidence	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
congenital heart disease	Disputed	AD

Mondo (8): atrial standstill 1 (MONDO:0007171), atrial fibrillation, familial, 11 (MONDO:0013544), atrial fibrillation (MONDO:0004981), chromosome 1q21.1 deletion syndrome (MONDO:0012914), Wolff-Parkinson-White syndrome (MONDO:0008685), congenital heart disease (MONDO:0005453), heart conduction disease (MONDO:0000992), familial atrial fibrillation (MONDO:0018054)

Orphanet (3): Isolated atrial standstill (Orphanet:1344), 1q21.1 microdeletion syndrome (Orphanet:250989), NON RARE IN EUROPE: Wolff-Parkinson-White syndrome (Orphanet:907)

HPO phenotypes

129 total (30 of 129 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000179	Thick lower lip vermilion
HP:0000193	Bifid uvula
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000233	Thin vermilion border
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000262	Turricephaly
HP:0000268	Dolichocephaly
HP:0000269	Prominent occiput
HP:0000272	Malar flattening
HP:0000286	Epicanthus
HP:0000303	Mandibular prognathia
HP:0000307	Pointed chin
HP:0000311	Round face
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000325	Triangular face
HP:0000337	Broad forehead
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000369	Low-set ears
HP:0000407	Sensorineural hearing impairment
HP:0000411	Protruding ear
HP:0000414	Bulbous nose
HP:0000426	Prominent nasal bridge
HP:0000448	Prominent nose
HP:0000463	Anteverted nares

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST000579_19	Cognitive performance	9.000000e-06
GCST004358_1	Methotrexate-induced interstitial lung disease in rheumatoid arthritis	2.000000e-07
GCST006061_185	Atrial fibrillation	8.000000e-10
GCST006061_186	Atrial fibrillation	2.000000e-10
GCST006414_43	Atrial fibrillation	1.000000e-10
GCST006414_57	Atrial fibrillation	3.000000e-14
GCST010320_110	PR interval	4.000000e-15
GCST010321_177	PR interval	2.000000e-16
GCST012048_2	Triglyceride levels	3.000000e-07

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0003926	neuropsychological test
EFO:0004462	PR interval
EFO:0004530	triglyceride measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D001281	Atrial Fibrillation	C14.280.067.198; C23.550.073.198
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D014927	Wolff-Parkinson-White Syndrome	C14.280.067.780.977; C14.280.123.750.977; C16.131.240.400.980
C567291	Chromosome 1q21.1 Deletion Syndrome, 1.35-Mb (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

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

Target class: other ic — Connexins and Pannexins

CTD chemical–gene interactions

24 total (human), top 24 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Doxorubicin	decreases expression	2
fluorene-9-bisphenol	increases expression	1
titanium dioxide	affects binding, increases expression	1
sulforaphane	decreases expression	1
sodium arsenite	increases expression	1
tobacco tar	decreases expression, decreases reaction	1
potassium chromate(VI)	increases expression	1
diallyl disulfide	decreases expression, decreases reaction	1
ferrous chloride	decreases expression	1
CGP 52608	affects binding, increases reaction	1
Sunitinib	decreases expression	1
Lycopene	decreases expression, increases expression	1
Amiodarone	increases expression	1
Benzo(a)pyrene	affects methylation	1
Diethylhexyl Phthalate	increases expression	1
Estradiol	affects cotreatment, increases expression	1
Etoposide	decreases expression	1
Oxygen	increases expression	1
Plant Oils	decreases expression	1
Silicon Dioxide	increases expression	1
Tretinoin	increases expression	1
Triclosan	increases expression	1
Vitallium	affects binding, increases expression, decreases expression	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

600 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
NCT00032591	PHASE4	COMPLETED	The Home INR Study
NCT00127712	PHASE4	COMPLETED	Prevention of Atrial Fibrillation Following Noncardiac Thoracic Surgery
NCT00157781	PHASE4	COMPLETED	LEAF - Low Energy In Atrial Fibrillation
NCT00170313	PHASE4	TERMINATED	CORE: Study to Evaluate the Conducted AF-Response-Algorithm in Patients Suffering From Heart Failure and Atrial Fibrillation
NCT00189319	PHASE4	COMPLETED	To Evaluate the Impact of Oral Flecainide on Quality of Life in Patients With Paroxysmal Atrial Fibrillation
NCT00196144	PHASE4	COMPLETED	FFS - Far Field Sensing Test Study in Cardiac Dual Chamber Pacemakers
NCT00196157	PHASE4	UNKNOWN	Line Versus Spot Ablation in Persistent Atrial Fibrillation
NCT00196183	PHASE4	COMPLETED	Trigger- vs. Substrate-Ablation for Paroxysmal Atrial Fibrillation
NCT00196209	PHASE4	UNKNOWN	Cardioversion vs. Catheter Ablation for Persistent Atrial Fibrillation
NCT00227344	PHASE4	TERMINATED	CACAF2 Study: Catheter Ablation for Cure of Atrial Fibrillation
NCT00232219	PHASE4	COMPLETED	Use of Fish Oils to Reduce Recurrence of Atrial Fibrillation Following DC Cardioversion
NCT00232232	PHASE4	COMPLETED	Use of Fish Oils to Prevent Atrial Mechanical Stunning and Atrial Remodeling Due to Atrial Arrhythmia
NCT00232245	PHASE4	COMPLETED	Use of Fish Oils to Reduce the Frequency and Duration of Episodes of Atrial Fibrillation in Patients With Paroxysmal Atrial Fibrillation.
NCT00239226	PHASE4	COMPLETED	Electrophysiologically Guided PAcing Site Selection Study
NCT00247780	PHASE4	COMPLETED	Cavotricuspid Isthmusblock and Circumferential Pulmonary Vein Isolation in Patients With Atrial Fibrillation
NCT00256152	PHASE4	COMPLETED	Asymptomatic Atrial Fibrillation and Stroke Evaluation in Pacemaker Patients and the Atrial Fibrillation Reduction Atrial Pacing Trial
NCT00262119	PHASE4	COMPLETED	MINERVA: MINimizE Right Ventricular Pacing to Prevent Atrial Fibrillation and Heart Failure
NCT00287209	PHASE4	COMPLETED	Reduction of Atrial Fibrillation Study in Patients Undergoing Coronary Artery Bypass Grafting. (RASCABG 1 Study)
NCT00289042	PHASE4	COMPLETED	Assessment of Cardioversion Using Transesophageal Echocardiography II (ACUTE II)
NCT00313443	PHASE4	COMPLETED	Concentrations of Amiodarone in Fat Tissue During Chronic Treatment
NCT00340314	PHASE4	COMPLETED	A Trial of Circumferential Pulmonary Vein Ablation (CPVA) Versus Antiarrhythmic Drug Therapy in for Paroxysmal Atrial Fibrillation (AF)
NCT00343499	PHASE4	TERMINATED	The Use of DIOVAN to Reduce Post-Cardioversion Recurrence of Atrial Fibrillation Trial (the DRAFT Trial)
NCT00408473	PHASE4	TERMINATED	Comparative Study of Flecainide CR and Placebo in the Early Treatment of Atrial Fibrillation.
NCT00420017	PHASE4	COMPLETED	Prevention of Atrial Fibrillation Following Esophagectomy
NCT00438113	PHASE4	COMPLETED	Atrial Substrate Modification With Aggressive Blood Pressure Lowering to Prevent AF
NCT00446966	PHASE4	COMPLETED	Fish Oil for Reduction of Atrial Fibrillation After Cardiac Surgery
NCT00449410	PHASE4	COMPLETED	Silent Cerebrovascular Lesion and Cognitive Decline Prevention by Cholesterol Lowering in Elderly AF Patients
NCT00466973	PHASE4	WITHDRAWN	Atrial Fibrillation Ablation Device Comparison Study