NOTCH1

Chr 9AD

notch receptor 1

Also known as: AOS5, AOVD1, TAN1, hN1

NCBI Gene: 4851 ENSG00000148400 UniProt: P46531 OMIM: 190198

The NOTCH1 protein functions as a transmembrane receptor for ligands including Jagged-1, Jagged-2, and Delta-1, regulating cell fate determination, differentiation, proliferation, and apoptosis across multiple developmental processes including angiogenesis, thymic maturation, cerebellar development, and left-right body symmetry. Mutations cause Adams-Oliver syndrome and aortic valve disease with autosomal dominant inheritance. This gene is extremely intolerant to loss-of-function variants (pLI ~1.0, LOEUF 0.097), reflecting its critical role in development.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

LOFmechanismADLOEUF 0.102 OMIM phenotypes

Clinical Summary— NOTCH1

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Gene-Disease Validity (ClinGen)

NOTCH1-related AOS spectrum disorder · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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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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ClinVar Variants

27 unique Pathogenic / Likely Pathogenic· 216 VUS of 500 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

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GeneReview available — NOTCH1

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

0.10LOEUF

pLI 1.000

Z-score 9.20

OE 0.05 (0.02–0.10)

Highly constrained

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

Missense Constraint

3.45Z-score

OE missense 0.76 (0.73–0.80)

1278 obs / 1674.7 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios

LoF OE0.05 (0.02–0.10)

0≤0.351.4

Missense OE0.76 (0.73–0.80)

0≤0.61.4

Synonymous OE1.17

0≤1.21.6

LoF obs/exp: 5 / 108.3Missense obs/exp: 1278 / 1674.7Syn Z: -3.79

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveNOTCH1-related Adams-Oliver syndromeOTHERAD

strongNOTCH1-related left ventricular outflow tract obstructionLOFAD

0.3991th %ile

GOF

0.5857th %ile

LOF

0.72top 10%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). 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 · 67% of P/LP variants are LoF · LOEUF 0.10

GOF1 literature citation

Literature Evidence

GOFGain-of-function mutations and copy number increases of Notch2 in diffuse large B-cell lymphomaPMID:19445024

LOFHaploinsufficiency of the NOTCH1 receptor as a cause of Adams-Oliver syndrome with variable cardiac anomaliesPMID:25963545

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