NOTCH3

Chr 19ADAR

notch receptor 3

Also known as: CADASIL, CADASIL1, CARASIL1, CASIL, FPLD1, IMF2, LMNS

NCBI Gene: 4854 ENSG00000074181 UniProt: Q9UM47 OMIM: 600276

The NOTCH3 protein functions as a receptor for membrane-bound ligands (Jagged1, Jagged2, and Delta1) that regulates cell-fate determination and affects differentiation, proliferation, and apoptotic programs. Mutations cause cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), lateral meningocele syndrome, infantile myofibromatosis, and familial partial lipodystrophy, with both autosomal dominant and recessive inheritance patterns reported. The gene shows high constraint against loss-of-function variants (LOEUF 0.32), indicating intolerance to protein-disrupting mutations.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes the third discovered human homologue of the Drosophilia melanogaster type I membrane protein notch. In Drosophilia, notch interaction with its cell-bound ligands (delta, serrate) establishes an intercellular signalling pathway that plays a key role in neural development. Homologues of the notch-ligands have also been identified in human, but precise interactions between these ligands and the human notch homologues remains to be determined. Mutations in NOTCH3 have been identified as the underlying cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

?Myofibromatosis, infantile 2MIM #615293

Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy 1MIM #125310

ADAR

Cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1MIM #621295

Lateral meningocele syndromeMIM #130720

Lipodystrophy, familial partial, type 1MIM #608600

Clinical highlights

Gene–disease validity (ClinGen)

Interpreting a novel variant

Gain of function is the curated mechanism (Gene2Phenotype), so a variant that simply removes the protein may not be the pathogenic class here — missense variants in functional domains often carry more weight.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

0.32

LOEUF· LoF intol.

GOF*

Mechanism· G2P

📖

GeneReview available — NOTCH3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint?

0.32LOEUF

pLI 0.408

Z-score 7.09

OE 0.23 (0.16–0.32)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

3.53Z-score

OE missense 0.74 (0.70–0.77)

1037 obs / 1410.4 exp

Constrained

Highly missense-constrained (top ~0.1%)

Observed / Expected Ratios?

LoF OE?0.23 (0.16–0.32)

0≤0.351.4

Missense OE?0.74 (0.70–0.77)

0≤0.61.4

Synonymous OE?0.92

0≤1.21.6

LoF obs/exp: 22 / 97.6Missense obs/exp: 1037 / 1410.4Syn Z: 1.51

Background carrier burden — how many people carry a rare variant somewhere in NOTCH3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 20

3,041 rare PASS variants

Rare truncating (LoF)

1 in 1,000

261 rare PASS variants

Rare synonymous (reference)

1 in 34

1,457 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for NOTCH3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 26	1 in 1,200
South Asian	~43k	1 in 17	1 in 350
Remaining (unassigned)	~30k	1 in 19	1 in 2,300
European (Finnish)	~27k	1 in 77	1 in 400
Admixed American	~22k	1 in 18	1 in 600
African / African American	~21k	1 in 18	1 in 1,300
East Asian	~20k	1 in 17	1 in 1,000
Ashkenazi Jewish	~13k	1 in 68	1 in 590
Middle Eastern	~2,884	1 in 19	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 30 of 33 coding exons well covered in gnomAD exomes; exon 1 poorly covered; exons 15, 24 marginal. Genomes: all 33.? see exons ↓