JAG1

jagged canonical Notch ligand 1, the group of MicroRNA protein coding host genes|CD molecules

Basic information

Region (hg38): 20:10637683-10673999

Previous symbols: [ "AGS", "JAGL1" ]

Links

ENSG00000101384 ∙ NCBI:182 ∙ OMIM:601920 ∙ HGNC:6188 ∙ Uniprot:P78504 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Alagille syndrome due to a JAG1 point mutation (Definitive), mode of inheritance: AD
• Alagille syndrome due to a JAG1 point mutation (Strong), mode of inheritance: AD
• Alagille syndrome due to a JAG1 point mutation (Definitive), mode of inheritance: AD
• tetralogy of fallot (Supportive), mode of inheritance: AD
• Charcot-Marie-Tooth disease, axonal, Type 2HH (Limited), mode of inheritance: AD
• Alagille syndrome due to a JAG1 point mutation (Strong), mode of inheritance: AD
• Charcot-Marie-Tooth disease, axonal, Type 2HH (Strong), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Alagille syndrome; Deafness, congenital heart defects, and posterior embryotoxon	AD	Audiologic/Otolaryngologic; Cardiovascular; Gastrointestinal; Renal	For Alagille syndrome, individuals may have hepatic complications, and medications (eg, ursodeoxycholic acid, cholestyramine), and, when necessary, partial external biliary diversion may be beneficial; Other treatments, such as fat-soluble vitamin supplementation may be beneficial; Surveillance for other manifestations, including cardiac and renal manifestations, may be beneficial in order to allow early diagnosis and treatment and/or preventive measures; Contact sports should be avoided; For Deafness, congenital heart defects, and posterior embryotoxon, early recognition and treatment of hearing impairment may improve outcomes, including speech and language development	Audiologic/Otolaryngologic; Cardiovascular; Craniofacial; Gastrointestinal; Musculoskeletal; Neurologic; Ophthalmologic; Renal	803282; 9039994; 9207788; 9207787; 9585603; 9700188; 9890073; 10590916; 10213047; 11152664; 11313761; 11511567; 11139239; 12022040; 12244552; 12239725; 12509572; 14993126; 16013021; 16573599; 17286312; 19597493; 19948535; 20301450; 20437614; 22040217; 22105858; 22488849; 22521120; 22759690; 22937766; 23752887; 23801938; 23956173; 32065591
Liver transplantation has been described

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the JAG1 gene.

• Alagille syndrome due to a JAG1 point mutation (1096 variants)
• not provided (492 variants)
• Cardiovascular phenotype (291 variants)
• Isolated Nonsyndromic Congenital Heart Disease (139 variants)
• not specified (81 variants)
• JAG1-related condition (41 variants)
• Inborn genetic diseases (25 variants)
• Tetralogy of Fallot (15 variants)
• Arteriohepatic dysplasia (14 variants)
• Alagille syndrome due to a JAG1 point mutation;Tetralogy of Fallot;Deafness, congenital heart defects, and posterior embryotoxon;Charcot-Marie-Tooth disease, axonal, Type 2HH (14 variants)
• Deafness, congenital heart defects, and posterior embryotoxon;Alagille syndrome due to a JAG1 point mutation;Tetralogy of Fallot;Charcot-Marie-Tooth disease, axonal, Type 2HH (11 variants)
• Alagille syndrome due to a JAG1 point mutation;Charcot-Marie-Tooth disease, axonal, Type 2HH;Tetralogy of Fallot;Deafness, congenital heart defects, and posterior embryotoxon (8 variants)
• Alagille syndrome due to a JAG1 point mutation;Deafness, congenital heart defects, and posterior embryotoxon;Tetralogy of Fallot;Charcot-Marie-Tooth disease, axonal, Type 2HH (8 variants)
• Alagille syndrome due to a JAG1 point mutation;Deafness, congenital heart defects, and posterior embryotoxon;Charcot-Marie-Tooth disease, axonal, Type 2HH;Tetralogy of Fallot (7 variants)
• Deafness, congenital heart defects, and posterior embryotoxon;Charcot-Marie-Tooth disease, axonal, Type 2HH;Alagille syndrome due to a JAG1 point mutation;Tetralogy of Fallot (7 variants)
• Deafness, congenital heart defects, and posterior embryotoxon (6 variants)
• Tetralogy of Fallot;Alagille syndrome due to a JAG1 point mutation;Deafness, congenital heart defects, and posterior embryotoxon;Charcot-Marie-Tooth disease, axonal, Type 2HH (6 variants)
• Charcot-Marie-Tooth disease, axonal, Type 2HH;Tetralogy of Fallot;Alagille syndrome due to a JAG1 point mutation;Deafness, congenital heart defects, and posterior embryotoxon (5 variants)
• Tetralogy of Fallot;Charcot-Marie-Tooth disease, axonal, Type 2HH;Deafness, congenital heart defects, and posterior embryotoxon;Alagille syndrome due to a JAG1 point mutation (5 variants)
• Alagille syndrome due to a JAG1 point mutation;Tetralogy of Fallot;Charcot-Marie-Tooth disease, axonal, Type 2HH;Deafness, congenital heart defects, and posterior embryotoxon (5 variants)
• Alagille syndrome due to a JAG1 point mutation;Charcot-Marie-Tooth disease, axonal, Type 2HH;Deafness, congenital heart defects, and posterior embryotoxon;Tetralogy of Fallot (4 variants)
• Tetralogy of Fallot;Deafness, congenital heart defects, and posterior embryotoxon;Alagille syndrome due to a JAG1 point mutation;Charcot-Marie-Tooth disease, axonal, Type 2HH (4 variants)
• Charcot-Marie-Tooth disease, axonal, Type 2HH;Alagille syndrome due to a JAG1 point mutation;Tetralogy of Fallot;Deafness, congenital heart defects, and posterior embryotoxon (4 variants)
• Tetralogy of Fallot;Alagille syndrome due to a JAG1 point mutation;Charcot-Marie-Tooth disease, axonal, Type 2HH;Deafness, congenital heart defects, and posterior embryotoxon (4 variants)
• Tetralogy of Fallot;Deafness, congenital heart defects, and posterior embryotoxon;Charcot-Marie-Tooth disease, axonal, Type 2HH;Alagille syndrome due to a JAG1 point mutation (3 variants)
• Alagille syndrome due to a JAG1 point mutation;Tetralogy of Fallot;Deafness, congenital heart defects, and posterior embryotoxon (3 variants)
• Charcot-Marie-Tooth disease, axonal, Type 2HH;Deafness, congenital heart defects, and posterior embryotoxon;Alagille syndrome due to a JAG1 point mutation;Tetralogy of Fallot (3 variants)
• Charcot-Marie-Tooth disease, axonal, Type 2HH;Alagille syndrome due to a JAG1 point mutation;Deafness, congenital heart defects, and posterior embryotoxon;Tetralogy of Fallot (3 variants)
• Deafness, congenital heart defects, and posterior embryotoxon;Charcot-Marie-Tooth disease, axonal, Type 2HH;Tetralogy of Fallot;Alagille syndrome due to a JAG1 point mutation (2 variants)
• Tetralogy of Fallot;Charcot-Marie-Tooth disease, axonal, Type 2HH;Alagille syndrome due to a JAG1 point mutation;Deafness, congenital heart defects, and posterior embryotoxon (2 variants)
• Deafness, congenital heart defects, and posterior embryotoxon;Alagille syndrome due to a JAG1 point mutation;Charcot-Marie-Tooth disease, axonal, Type 2HH;Tetralogy of Fallot (2 variants)
• Charcot-Marie-Tooth disease, axonal, Type 2HH;Tetralogy of Fallot;Deafness, congenital heart defects, and posterior embryotoxon;Alagille syndrome due to a JAG1 point mutation (2 variants)
• Atypical coarctation of aorta (2 variants)
• JAG1-related disorders (2 variants)
• Heart, malformation of;Arteriohepatic dysplasia (1 variants)
• Familial thoracic aortic aneurysm and aortic dissection (1 variants)
• Charcot-Marie-Tooth disease, axonal, Type 2HH (1 variants)
• Aortic dilatation;Scoliosis;Pes planus (1 variants)
• Stroke disorder (1 variants)
• Congenital anomaly of kidney and urinary tract (1 variants)
• Retinal dystrophy (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the JAG1 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			17	223	14	254
missense	10	16	414	49	8	497
nonsense	83	4	4			91
start loss	2					2
frameshift	153	19	2			174
inframe indel			9			9
splice donor/acceptor (+/-2bp)	22	16				38
splice region	2	1	23	28	2	56
non coding			39	165	87	291
Total	270	55	485	437	109

Highest pathogenic variant AF is 0.00000658

Variants in JAG1

This is a list of pathogenic ClinVar variants found in the JAG1 region.

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

Position	Type	Phenotype	Significance	ClinVar
20-10637830-T-G		Isolated Nonsyndromic Congenital Heart Disease	Uncertain significance (Jan 12, 2018)
20-10637861-T-C		Isolated Nonsyndromic Congenital Heart Disease	Uncertain significance (Jan 12, 2018)
20-10637886-C-T		Isolated Nonsyndromic Congenital Heart Disease	Uncertain significance (Jan 13, 2018)
20-10637926-T-C		Isolated Nonsyndromic Congenital Heart Disease	Benign (Apr 28, 2020)
20-10637947-G-A		Isolated Nonsyndromic Congenital Heart Disease	Conflicting classifications of pathogenicity (Oct 01, 2022)
20-10637963-CCA-C		Arteriohepatic dysplasia • Isolated Nonsyndromic Congenital Heart Disease	Conflicting classifications of pathogenicity (Dec 01, 2022)
20-10637986-C-CA		Isolated Nonsyndromic Congenital Heart Disease	Likely benign (Jun 14, 2016)
20-10638005-T-C		Isolated Nonsyndromic Congenital Heart Disease	Benign (Jan 13, 2018)
20-10638058-T-C		Isolated Nonsyndromic Congenital Heart Disease	Uncertain significance (Mar 30, 2018)
20-10638274-C-T		Isolated Nonsyndromic Congenital Heart Disease	Uncertain significance (Jan 13, 2018)
20-10638283-CAGT-C		Isolated Nonsyndromic Congenital Heart Disease • Arteriohepatic dysplasia	Uncertain significance (Jun 14, 2016)
20-10638291-TA-T		Isolated Nonsyndromic Congenital Heart Disease	Benign (Jun 14, 2016)
20-10638361-AAAGT-A		Arteriohepatic dysplasia • Isolated Nonsyndromic Congenital Heart Disease	Uncertain significance (Jun 14, 2016)
20-10638366-A-C		Isolated Nonsyndromic Congenital Heart Disease	Benign (Jan 13, 2018)
20-10638400-TTGATA-T		Isolated Nonsyndromic Congenital Heart Disease • Arteriohepatic dysplasia	Uncertain significance (Jun 14, 2016)
20-10638414-C-G		Isolated Nonsyndromic Congenital Heart Disease	Benign (Jan 13, 2018)
20-10638527-AAAAC-A		Isolated Nonsyndromic Congenital Heart Disease • Arteriohepatic dysplasia	Conflicting classifications of pathogenicity (Dec 01, 2022)
20-10638528-A-G		Isolated Nonsyndromic Congenital Heart Disease	Uncertain significance (Jan 13, 2018)
20-10638584-C-T		Isolated Nonsyndromic Congenital Heart Disease	Uncertain significance (Jan 13, 2018)
20-10638617-G-A		Isolated Nonsyndromic Congenital Heart Disease	Uncertain significance (Jan 12, 2018)
20-10638641-C-CA		Isolated Nonsyndromic Congenital Heart Disease	Benign (Jun 14, 2016)
20-10638742-T-C		Isolated Nonsyndromic Congenital Heart Disease	Benign (Jan 12, 2018)
20-10638848-GATT-G		Arteriohepatic dysplasia • Isolated Nonsyndromic Congenital Heart Disease	Uncertain significance (Jun 14, 2016)
20-10638857-G-T		Isolated Nonsyndromic Congenital Heart Disease	Uncertain significance (Jan 13, 2018)
20-10638879-G-A		Isolated Nonsyndromic Congenital Heart Disease	Benign (Jan 12, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
JAG1	protein_coding	protein_coding	ENST00000254958	26	36363

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	8.28e-8	125740	0	7	125747	0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.25	455	696	0.654	0.0000426	8128
Missense in Polyphen		110	286	0.38462		3349
Synonymous	0.126	274	277	0.990	0.0000197	2158
Loss of Function	6.88	4	62.8	0.0637	0.00000330	772

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000578	0.0000578
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.0000440	0.0000352
Middle Eastern	0.0000544	0.0000544
South Asian	0.00	0.00
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Ligand for multiple Notch receptors and involved in the mediation of Notch signaling (PubMed:18660822, PubMed:20437614). May be involved in cell-fate decisions during hematopoiesis (PubMed:9462510). Seems to be involved in early and late stages of mammalian cardiovascular development. Inhibits myoblast differentiation (By similarity). Enhances fibroblast growth factor-induced angiogenesis (in vitro). {ECO:0000250, ECO:0000269|PubMed:18660822, ECO:0000269|PubMed:20437614, ECO:0000269|PubMed:9462510}.
• Disease: DISEASE: Alagille syndrome 1 (ALGS1) [MIM:118450]: A form of Alagille syndrome, an autosomal dominant multisystem disorder. It is clinically defined by hepatic bile duct paucity and cholestasis in association with cardiac, skeletal, and ophthalmologic manifestations. There are characteristic facial features and less frequent clinical involvement of the renal and vascular systems. {ECO:0000269|PubMed:10220506, ECO:0000269|PubMed:10533065, ECO:0000269|PubMed:11058898, ECO:0000269|PubMed:11139247, ECO:0000269|PubMed:11157803, ECO:0000269|PubMed:11180599, ECO:0000269|PubMed:12442286, ECO:0000269|PubMed:12497640, ECO:0000269|PubMed:15712272, ECO:0000269|PubMed:16575836, ECO:0000269|PubMed:20437614, ECO:0000269|PubMed:23801938, ECO:0000269|PubMed:9207788, ECO:0000269|PubMed:9585603}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Tetralogy of Fallot (TOF) [MIM:187500]: A congenital heart anomaly which consists of pulmonary stenosis, ventricular septal defect, dextroposition of the aorta (aorta is on the right side instead of the left) and hypertrophy of the right ventricle. In this condition, blood from both ventricles (oxygen-rich and oxygen-poor) is pumped into the body often causing cyanosis. {ECO:0000269|PubMed:11152664, ECO:0000269|PubMed:20437614}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Deafness, congenital heart defects, and posterior embryotoxon (DCHE) [MIM:617992]: An autosomal dominant disease characterized by mild to severe combined hearing loss, congenital heart defects, and posterior embryotoxon, a corneal abnormality consisting of a central collagen core surrounded by a thin layer of Descemets membrane and separated from the anterior chamber by a layer of endothelium. Congenital heart defects include tetralogy of Fallot, ventricular septal defect, or isolated peripheral pulmonic stenosis. {ECO:0000269|PubMed:12022040, ECO:0000269|PubMed:20437614}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Breast cancer - Homo sapiens (human);TNF signaling pathway - Homo sapiens (human);Apelin signaling pathway - Homo sapiens (human);Th1 and Th2 cell differentiation - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Notch signaling pathway - Homo sapiens (human);Human papillomavirus infection - Homo sapiens (human);NOTCH-Ncore;Primary Focal Segmental Glomerulosclerosis FSGS;Notch Signaling Pathway;NOTCH1 regulation of human endothelial cell calcification;Amplification and Expansion of Oncogenic Pathways as Metastatic Traits;Canonical and Non-canonical Notch signaling;VEGFA-VEGFR2 Signaling Pathway;H19 action Rb-E2F1 signaling and CDK-β-catenin activity;Transcriptional regulation by RUNX3;EMT transition in Colorectal Cancer;Notch Signaling Pathway;Notch Signaling Pathway;Notch;Disease;RUNX3 regulates NOTCH signaling;Signal Transduction;Gene expression (Transcription);Transcriptional regulation by RUNX3;Generic Transcription Pathway;GPCR signaling-G alpha q;GPCR signaling-cholera toxin;GPCR signaling-pertussis toxin;RNA Polymerase II Transcription;Receptor-ligand binding initiates the second proteolytic cleavage of Notch receptor;Notch;Signaling by NOTCH1;Signaling by NOTCH2;NOTCH3 Activation and Transmission of Signal to the Nucleus;Signaling by NOTCH3;Signaling by NOTCH4;Signaling by NOTCH;GPCR signaling-G alpha s Epac and ERK;GPCR signaling-G alpha s PKA and ERK;Validated transcriptional targets of TAp63 isoforms;NOTCH2 Activation and Transmission of Signal to the Nucleus;Notch signaling pathway;Constitutive Signaling by NOTCH1 HD Domain Mutants;Signaling by NOTCH1 HD Domain Mutants in Cancer;GPCR signaling-G alpha i;Constitutive Signaling by NOTCH1 PEST Domain Mutants;Signaling by NOTCH1 PEST Domain Mutants in Cancer;Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants;Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer;Signaling by NOTCH1 in Cancer;Diseases of signal transduction;Activated NOTCH1 Transmits Signal to the Nucleus (Consensus)

Recessive Scores

• pRec: 0.705

Intolerance Scores

• loftool: 0.00627
• rvis_EVS: -2.14
• rvis_percentile_EVS: 1.49

Haploinsufficiency Scores

• pHI: 0.663
• hipred: Y
• hipred_score: 0.825
• ghis: 0.658

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: S
• gene_indispensability_pred: E
• gene_indispensability_score: 0.983

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Jag1
• Phenotype: growth/size/body region 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); endocrine/exocrine gland phenotype; muscle phenotype; craniofacial phenotype; homeostasis/metabolism phenotype; cellular phenotype; skeleton phenotype; renal/urinary system phenotype; embryo phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary 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); 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; digestive/alimentary 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); hearing/vestibular/ear phenotype; vision/eye phenotype

Zebrafish Information Network

• Gene name: jag1b
• Affected structure: pillar of the lateral semicircular canal
• Phenotype tag: abnormal
• Phenotype quality: increased thickness

Gene ontology

• Biological process: angiogenesis;cell fate determination;negative regulation of cell-matrix adhesion;blood vessel remodeling;morphogenesis of an epithelial sheet;T cell mediated immunity;aortic valve morphogenesis;pulmonary valve morphogenesis;cardiac right ventricle morphogenesis;Notch signaling pathway;nervous system development;regulation of signaling receptor activity;negative regulation of cell-cell adhesion;hemopoiesis;keratinocyte differentiation;negative regulation of cell migration;response to muramyl dipeptide;aorta morphogenesis;regulation of cell population proliferation;inner ear auditory receptor cell differentiation;myoblast differentiation;endothelial cell differentiation;negative regulation of fat cell differentiation;negative regulation of endothelial cell differentiation;positive regulation of myeloid cell differentiation;negative regulation of neuron differentiation;positive regulation of osteoblast differentiation;positive regulation of Notch signaling pathway;positive regulation of transcription by RNA polymerase II;cardiac septum morphogenesis;ciliary body morphogenesis;pulmonary artery morphogenesis;cardiac neural crest cell development involved in outflow tract morphogenesis;Notch signaling involved in heart development;endocardial cushion cell development;positive regulation of cardiac epithelial to mesenchymal transition;nephron development;glomerular visceral epithelial cell development;distal tubule development;loop of Henle development;neuronal stem cell population maintenance;negative regulation of stem cell differentiation
• Cellular component: extracellular region;plasma membrane;integral component of plasma membrane;adherens junction;membrane;apical plasma membrane
• Molecular function: Notch binding;structural molecule activity;calcium ion binding;protein binding;phospholipid binding;growth factor activity