JAG1

Chr 20AD

jagged canonical Notch ligand 1

NCBI Gene: 182ENSG00000101384UniProt: P78504

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)

Primary Disease Associations & Inheritance

?Deafness, congenital heart defects, and posterior embryotoxonMIM #617992
AD
Alagille syndrome 1MIM #118450
AD
Charcot-Marie-Tooth disease, axonal, type 2HHMIM #619574
AD
Tetralogy of FallotMIM #187500
AD
2715
ClinVar variants
53
Pathogenic / LP
1.00
pLI score· haploinsufficient
3
Active trials
Clinical Summary— JAG1
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
53 Pathogenic / Likely Pathogenic· 175 VUS of 2715 total submissions
💊
Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available
Some data sources returned errors (1)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.15LOEUF
pLI 1.000
Z-score 6.88
OE 0.06 (0.03–0.15)
Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
3.25Z-score
OE missense 0.65 (0.60–0.71)
455 obs / 696.0 exp
Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.06 (0.03–0.15)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.65 (0.60–0.71)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.99
0≤1.21.6
LoF obs/exp: 4 / 62.8Missense obs/exp: 455 / 696.0Syn Z: 0.13

ClinVar Variant Classifications

2715 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic39
Likely Pathogenic14
VUS175
Likely Benign99
Benign6
39
Pathogenic
14
Likely Pathogenic
175
VUS
99
Likely Benign
6
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
27
0
12
0
39
Likely Pathogenic
9
1
4
0
14
VUS
2
159
13
1
175
Likely Benign
0
9
38
52
99
Benign
0
2
1
3
6
Total381716856333

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

JAG1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

JAG1-related Alagille syndrome

definitive
ADLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
JAGGED 1; JAG1
MIM #601920 · *

?Deafness, congenital heart defects, and posterior embryotoxon

MIM #617992

Molecular basis of disorder known

Autosomal dominant

Alagille syndrome 1

MIM #118450

Molecular basis of disorder known

Autosomal dominant

Charcot-Marie-Tooth disease, axonal, type 2HH

MIM #619574

Molecular basis of disorder known

Autosomal dominant

Tetralogy of Fallot

MIM #187500

Molecular basis of disorder known

Autosomal dominant
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Alagille Syndrome: A Focused Review on Clinical Features, Genetics, and Treatment.
Kohut TJ et al.·Semin Liver Dis
2021Review
Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy.
Birtel J et al.·Sci Rep
2018Cohort
Alagille Syndrome.
Mitchell E et al.·Clin Liver Dis
2018Review
Management of adults with Alagille syndrome.
Ayoub MD et al.·Hepatol Int
2023Review
Alagille Syndrome: Current Understanding of Pathogenesis, and Challenges in Diagnosis and Management.
Ayoub MD et al.·Clin Liver Dis
2022Review
Endothelial upregulation of mechanosensitive channel Piezo1 in pulmonary hypertension.
Wang Z et al.·Am J Physiol Cell Physiol
2021
Human hepatic organoids for the analysis of human genetic diseases.
Guan Y et al.·JCI Insight
2017
Alagille syndrome mutation update: Comprehensive overview of JAG1 and NOTCH2 mutation frequencies and insight into missense variant classification.
Gilbert MA et al.·Hum Mutat
2019Review
Jagged2 targeting in lung cancer activates anti-tumor immunity via Notch-induced functional reprogramming of tumor-associated macrophages.
Mandula JK et al.·Immunity
2024Functional
Single cell analysis of cribriform prostate cancer reveals cell intrinsic and tumor microenvironmental pathways of aggressive disease.
Wong HY et al.·Nat Commun
2022
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
RNA‑binding protein DAZAP1 promotes gastric cancer metastasis by enhancing NOTCH1 and JAG1 mRNA stability.
Peng S et al.·Int J Oncol
2026
Oncolytic HSV-1-Mediated JAG1 Blockade Induces Glioma Senescence-Associated Secretory Phenotype to Increase Macrophage Activation and Cetuximab-Mediated Senolysis.
Rivera-Caraballo KA et al.·Cancer Res
2026
Clinical and genetic characteristics of a large cohort of children with Alagille syndrome: identification of 57 new variants in the JAG1 gene.
Gusarova EA et al.·J Hum Genet
2026Cohort
JAG1 expression in papillary thyroid cancer stem-like cells predicts poor prognosis and implicates angiogenesis.
Yoshida-Minato R et al.·Discov Oncol
2026
JAG1 of all trades, master of CKD? The role of JAG1 in autosomal dominant tubulointerstitial kidney disease.
Wiesener MS et al.·Kidney Int
2026
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Aging

Effect of Snacks on Aging

RECRUITING
NCT06879626Phase NAUniversity of California, Los AngelesStarted 2025-05-19
PecanPretzel
PFIC - Progressive Familial Intrahepatic CholestasisAlagille Syndrome (ALGS)Cholestasis, Intrahepatic

Pediatric Evaluation and Registry for Liver Cholestasis in Canada

NOT YET RECRUITING
NCT07411716Children's Hospital of Eastern OntarioStarted 2026-03
Rare DisordersUndiagnosed DisordersDisorders of Unknown Prevalence

Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford

RECRUITING
NCT01793168Sanford HealthStarted 2010-07

External Resources

Links to major genomics databases and tools