GJA1

gap junction protein alpha 1, the group of Gap junction proteins

Basic information

Region (hg38): 6:121435595-121449727

Previous symbols: [ "ODDD", "GJAL" ]

Links

ENSG00000152661 ∙ NCBI:2697 ∙ OMIM:121014 ∙ HGNC:4274 ∙ Uniprot:P17302 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Hallermann-Streiff syndrome (Limited), mode of inheritance: AR
• hypoplastic left heart syndrome 1 (Definitive), mode of inheritance: AD
• syndactyly type 3 (Limited), mode of inheritance: AD
• oculodentodigital dysplasia, autosomal recessive (Definitive), mode of inheritance: AR
• oculodentodigital dysplasia (Definitive), mode of inheritance: AD
• autosomal dominant palmoplantar keratoderma and congenital alopecia (Strong), mode of inheritance: AD
• erythrokeratodermia variabilis et progressiva 3 (Strong), mode of inheritance: AD
• oculodentodigital dysplasia (Definitive), mode of inheritance: Semidominant
• syndactyly type 3 (Limited), mode of inheritance: AD
• autosomal dominant palmoplantar keratoderma and congenital alopecia (Limited), mode of inheritance: AD
• craniometaphyseal dysplasia, autosomal recessive (Limited), mode of inheritance: AR
• erythrokeratodermia variabilis et progressiva 3 (Limited), mode of inheritance: AD
• autosomal dominant palmoplantar keratoderma and congenital alopecia (Supportive), mode of inheritance: AD
• craniometaphyseal dysplasia (Supportive), mode of inheritance: AD
• oculodentodigital dysplasia (Supportive), mode of inheritance: AD
• erythrokeratodermia variabilis (Supportive), mode of inheritance: AD
• syndactyly type 3 (Supportive), mode of inheritance: AD
• craniometaphyseal dysplasia, autosomal recessive (Limited), mode of inheritance: Unknown
• erythrokeratodermia variabilis et progressiva 3 (Strong), mode of inheritance: AD
• oculodentodigital dysplasia, autosomal recessive (Strong), mode of inheritance: AR
• oculodentodigital dysplasia (Strong), mode of inheritance: AD
• syndactyly type 3 (Limited), mode of inheritance: Unknown
• nonsyndromic genetic hearing loss (Disputed Evidence), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Oculodentodigital dysplasia; Hypoplastic left heart syndrome 1; Atrioventricular septal defect 3	AD/AR	Cardiovascular	Individuals with congenital heart anomalies may benefit from early diagnosis and intervention; Individuals with cardiac arrhythmias have been reported, and surveillance (eg, with EKG) may allow early detection and treatment	Cardiovascular; Craniofacial; Dental; Dermatologic; Endocrine; Musculoskeletal; Neurologic; Ophthalmologic	2157843; 7815444; 11470490; 12457340; 15108203; 14974090; 14729836; 14981729; 15551259; 15637728; 16709485; 16816024; 17256797; 18412120; 19338053; 21670345; 22179534; 22214631; 23951358; 25168385; 25398053

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the GJA1 gene.

• Oculodentodigital dysplasia, autosomal recessive (9 variants)
• Oculodentodigital dysplasia (6 variants)
• not provided (2 variants)
• 8 conditions (1 variants)
• Cutaneous finger syndactyly;Intellectual disability;Anteverted nares;Bilateral microphthalmos (1 variants)
• GJA1-related disorder (1 variants)
• Inborn genetic diseases (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the GJA1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			5	55		60
missense	14	15	105	1		135
nonsense	1	1	3			5
start loss						0
frameshift	1	1	3			5
inframe indel		2	5			7
splice donor/acceptor (+/-2bp)						0
splice region						0
non coding			32	3	7	42
Total	16	19	153	59	7

Variants in GJA1

This is a list of pathogenic ClinVar variants found in the GJA1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
6-121435652-T-G		Hypoplastic left heart syndrome 1 • Oculodentodigital dysplasia • Syndactyly type 3	Uncertain significance (Jan 13, 2018)
6-121435661-G-T		Hypoplastic left heart syndrome 1 • Syndactyly type 3 • Oculodentodigital dysplasia	Uncertain significance (Jan 12, 2018)
6-121435688-G-T		Syndactyly type 3 • Oculodentodigital dysplasia • Hypoplastic left heart syndrome 1	Uncertain significance (Jan 13, 2018)
6-121435714-C-T		Hypoplastic left heart syndrome 1 • Syndactyly type 3 • Oculodentodigital dysplasia	Conflicting classifications of pathogenicity (Jan 13, 2018)
6-121435762-C-T		Hypoplastic left heart syndrome 1 • Oculodentodigital dysplasia • Syndactyly type 3	Uncertain significance (Jan 12, 2018)
6-121435782-C-G		Syndactyly type 3 • Oculodentodigital dysplasia • Hypoplastic left heart syndrome 1	Conflicting classifications of pathogenicity (Feb 05, 2022)
6-121435882-C-T			Benign (May 18, 2021)
6-121435925-T-G			Benign (May 17, 2021)
6-121446820-T-A		Hypoplastic left heart syndrome 1 • Oculodentodigital dysplasia • Syndactyly type 3	Conflicting classifications of pathogenicity (Oct 28, 2019)
6-121446820-T-C			Likely benign (May 19, 2020)
6-121446862-C-T		Oculodentodigital dysplasia, autosomal recessive • not specified	Likely benign (Aug 21, 2023)
6-121446865-C-T		Oculodentodigital dysplasia, autosomal recessive	Likely benign (Mar 20, 2023)
6-121446870-G-T		Autosomal dominant palmoplantar keratoderma and congenital alopecia	Pathogenic (Jan 01, 2015)
6-121446878-C-T		Oculodentodigital dysplasia	Pathogenic (Jun 01, 2011)
6-121446879-T-A		Oculodentodigital dysplasia, autosomal recessive	Pathogenic (Jan 25, 2024)
6-121446879-T-C		Oculodentodigital dysplasia	Pathogenic (May 01, 2006)
6-121446884-A-G			Uncertain significance (Aug 02, 2022)
6-121446897-A-C		Oculodentodigital dysplasia	Pathogenic (Feb 01, 2003)
6-121446899-T-C		Oculodentodigital dysplasia	Pathogenic (Feb 01, 2003)
6-121446900-C-A		Oculodentodigital dysplasia, autosomal recessive	Pathogenic (Mar 20, 2022)
6-121446908-G-A		Oculodentodigital dysplasia	Pathogenic (Feb 01, 2003)
6-121446911-G-A		Oculodentodigital dysplasia, autosomal recessive	Pathogenic (Apr 26, 2019)
6-121446912-G-A		Oculodentodigital dysplasia • Oculodentodigital dysplasia, autosomal recessive	Pathogenic (May 06, 2022)
6-121446913-G-A		Oculodentodigital dysplasia, autosomal recessive	Likely benign (Oct 04, 2022)
6-121446922-G-C		Inborn genetic diseases	Pathogenic/Likely pathogenic (Jun 11, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
GJA1	protein_coding	protein_coding	ENST00000282561	1	14036

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.155	0.842	125735	0	13	125748	0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.28	150	201	0.746	0.0000118	2506
Missense in Polyphen		17	62.919	0.27019		862
Synonymous	-2.65	111	80.7	1.38	0.00000486	760
Loss of Function	2.58	4	14.7	0.273	0.00000117	151

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000173	0.000173
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000440	0.0000439
Middle Eastern	0.0000544	0.0000544
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Gap junction protein that acts as a regulator of bladder capacity. A 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. 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 (By similarity). May play a role in cell growth inhibition through the regulation of NOV expression and localization. Plays an essential role in gap junction communication in the ventricles (By similarity). {ECO:0000250|UniProtKB:P08050, ECO:0000250|UniProtKB:P23242}.
• Disease: DISEASE: 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. {ECO:0000269|PubMed:12457340, ECO:0000269|PubMed:14729836, ECO:0000269|PubMed:15108203, ECO:0000269|PubMed:15637728, ECO:0000269|PubMed:16219735, ECO:0000269|PubMed:16222672, ECO:0000269|PubMed:16378922, ECO:0000269|PubMed:16709485, ECO:0000269|PubMed:16813608, ECO:0000269|PubMed:16816024, ECO:0000269|PubMed:17509830, ECO:0000269|PubMed:18161618, ECO:0000269|PubMed:19338053, ECO:0000269|PubMed:21670345, ECO:0000269|PubMed:23550541, ECO:0000269|PubMed:24508941, ECO:0000269|PubMed:28258662}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:16816024}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:14729836}. Note=The disease may be caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:11470490}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. Mental retardation is present in a minority of cases. {ECO:0000269|PubMed:14974090}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Atrioventricular septal defect 3 (AVSD3) [MIM:600309]: A congenital heart malformation characterized by a common atrioventricular junction coexisting with deficient atrioventricular septation. The complete form involves underdevelopment of the lower part of the atrial septum and the upper part of the ventricular septum; the valve itself is also shared. A less severe form, known as ostium primum atrial septal defect, is characterized by separate atrioventricular valvar orifices despite a common junction. {ECO:0000269|PubMed:11470490}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:23951358}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:25398053}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: 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. {ECO:0000269|PubMed:25168385}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Arrhythmogenic right ventricular cardiomyopathy (ARVC) - Homo sapiens (human);Gap junction - Homo sapiens (human);Antiarrhythmic Pathway, Pharmacodynamics;TarBasePathway;miR-targeted genes in epithelium - TarBase;miR-targeted genes in muscle cell - TarBase;Arrhythmogenic Right Ventricular Cardiomyopathy;Corticotropin-releasing hormone signaling pathway;Spinal Cord Injury;Myometrial Relaxation and Contraction Pathways;Wnt Signaling Pathway;VEGFA-VEGFR2 Signaling Pathway;EGF-EGFR Signaling Pathway;Calcium Regulation in the Cardiac Cell;Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways;Vesicle-mediated transport;Membrane Trafficking;Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane;c-src mediated regulation of Cx43 function and closure of gap junctions;inactivation of gsk3 by akt causes accumulation of b-catenin in alveolar macrophages;EGFR1;Transport of connexins along the secretory pathway;Oligomerization of connexins into connexons;Transport of connexons to the plasma membrane;Gap junction assembly;Formation of annular gap junctions;Gap junction degradation;Gap junction trafficking;Regulation of gap junction activity;Gap junction trafficking and regulation;N-cadherin signaling events;AP-1 transcription factor network;Validated transcriptional targets of AP1 family members Fra1 and Fra2 (Consensus)

Recessive Scores

• pRec: 0.365

Intolerance Scores

• loftool: 0.108
• rvis_EVS: -0.27
• rvis_percentile_EVS: 34.32

Haploinsufficiency Scores

• pHI: 0.952
• hipred: Y
• hipred_score: 0.833
• ghis: 0.579

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.583

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium

Mouse Genome Informatics

• Gene name: Gja1
• Phenotype: immune system phenotype; skeleton phenotype; hearing/vestibular/ear phenotype; nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); limbs/digits/tail phenotype; vision/eye phenotype; reproductive system phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); normal phenotype; hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); cellular phenotype; homeostasis/metabolism phenotype; muscle phenotype; craniofacial phenotype; integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; endocrine/exocrine gland phenotype

Zebrafish Information Network

• Gene name: cx43
• Affected structure: nucleate erythrocyte
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: muscle contraction;signal transduction;cell-cell signaling;heart development;cell communication by electrical coupling;gap junction assembly;negative regulation of cell growth;ion transmembrane transport;positive regulation of I-kappaB kinase/NF-kappaB signaling;atrial cardiac muscle cell action potential;cell communication by electrical coupling involved in cardiac conduction;positive regulation of cold-induced thermogenesis
• Cellular component: Golgi membrane;nucleoplasm;mitochondrion;endoplasmic reticulum membrane;Golgi apparatus;plasma membrane;integral component of plasma membrane;gap junction;connexin complex;focal adhesion;intercalated disc;apical plasma membrane;cell junction;Golgi-associated vesicle membrane;intracellular membrane-bounded organelle;membrane raft
• Molecular function: gap junction channel activity;protein binding;ion transmembrane transporter activity;gap junction hemi-channel activity;gap junction channel activity involved in cardiac conduction electrical coupling;gap junction channel activity involved in cell communication by electrical coupling