JAG1

Chr 20AD

jagged canonical Notch ligand 1

Also known as: AGS, AGS1, AHD, AWS, CD339, CMT2HH, DCHE, HJ1

NCBI Gene: 182 ENSG00000101384 UniProt: P78504 OMIM: 601920

The jagged 1 protein functions as a ligand for Notch receptors, mediating Notch signaling pathways involved in hematopoiesis, cardiovascular development, and cell-fate decisions. Mutations cause Alagille syndrome 1 (characterized by liver, heart, eye, and skeletal abnormalities), as well as congenital heart defects, deafness with posterior embryotoxon, tetralogy of Fallot, and axonal Charcot-Marie-Tooth disease type 2HH. JAG1 follows autosomal dominant inheritance and is highly constrained against loss-of-function variants (pLI >0.99).

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The jagged 1 protein encoded by JAG1 is the human homolog of the Drosophilia jagged protein. Human jagged 1 is the ligand for the receptor notch 1, the latter is involved in signaling processes. Mutations that alter the jagged 1 protein cause Alagille syndrome. Jagged 1 signalling through notch 1 has also been shown to play a role in hematopoiesis. [provided by RefSeq, Nov 2019]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.154 OMIM phenotypes

Clinical Summary— JAG1

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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.

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Clinical Trials

3 active or recruiting trials — potential therapeutic options may be available

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

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?

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?

LoF OE?0.06 (0.03–0.15)

0≤0.351.4

Missense OE?0.65 (0.60–0.71)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 4 / 62.8Missense obs/exp: 455 / 696.0Syn Z: 0.13

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveJAG1-related Alagille syndromeLOFAD

This gene — mechanism propensity

0.3395th %ile

GOF

0.4678th %ile

LOF

0.70top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOFprediction above median · 1 literature citation · LOEUF 0.15 · ClinGen HI: Sufficient evidence for dosage pathogenicity

GOF1 literature citation

DN1 literature citation

Literature Evidence

DNAltogether, our results favor a dominant-negative mechanism of some JAGGED1 mutations in AGS.1

GOFThese data support either a relative loss-of-function or a gain-of-function pathogenetic mechanism in this family and suggest that JAG1 mutations may contribute significantly to common variants of right heart obstructive disease.2

LOFThe majority of JAG1 mutations seen in Alagille syndrome patients are null alleles, suggesting JAG1 haploinsufficiency as a primary cause of this disorder.3

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References