NOTCH3

Chr 19ADAR

notch receptor 3

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

NCBI Gene: 4854ENSG00000074181UniProt: Q9UM47OMIM: 600276

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]

GeneReviewsOMIMResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

?Myofibromatosis, infantile 2MIM #615293
AD
Cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy 1MIM #125310
ADAR
Cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1MIM #621295
AR
Lateral meningocele syndromeMIM #130720
AD
Lipodystrophy, familial partial, type 1MIM #608600
AD

Clinical highlights

Gene-disease validity (ClinGen)
pulmonary arterial hypertension · ADDisputedevidence questions this relationship4 gene-disease associations curated in total
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.
9
Active trials
356
Pubs (1 yr)
—
P/LP submissions
—
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

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

NOTCH3 · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Migraine With Aura

Neurogenetic And Hemodynamic Of Migraine Aura And Pfo

RECRUITING
NCT07349004Azienda Usl di BolognaStarted 2025-11-24
Intervention
Cerebral Small Vessel DiseasesCadasilHTRA1-Related Autosomal Dominant Cerebral Angiopathy

Taiwan Associated Genetic and Nongenetic Small Vessel Disease

RECRUITING
NCT05473637National Taiwan University HospitalStarted 2019-01-01
MRI
CADASIL

Development and Validation of a Functional MRI Biomarker of Cerebral Small Vessel Dysfunction in CADASIL

NOT YET RECRUITING
NCT06859658Assistance Publique - Hôpitaux de ParisStarted 2025-04-01
Functional MRI at 3TFunctional MRI at 3TFunctional MRI at 3T
CADASIL

Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) Study

RECRUITING
NCT05677880University of Wisconsin, MadisonStarted 2022-06-03
Study Procedures
CADASILCerebral Autosomal Dominant Arteriopatie With Subcortical Infarcts and Leukoencephalopathy

Long-term Prospective Study of Korean CADASIL Patients

RECRUITING
NCT07497867Jeju National University HospitalStarted 2023-07-10
Cadasil

AusCADASIL: An Australian Cohort of CADASIL

RECRUITING
NCT06148051Perminder SachdevStarted 2023-11-25
Cardiovascular DiseaseArterial StiffnessGermline Mutation in the NOTCH 3 Gene

Natural History Study of CADASIL

RECRUITING
NCT05072483National Heart, Lung, and Blood Institute (NHLBI)Started 2022-04-18
MRI
CADASILCADASIL (Diagnosis)

Genotype, Clinical Features and Imaging of Neuroradiological Abnormalities in CADASIL

RECRUITING
NCT06938100Fondazione I.R.C.C.S. Istituto Neurologico Carlo BestaStarted 2023-11-21
LeukodystrophyWhite Matter DiseaseLeukoencephalopathies

The Myelin Disorders Biorepository Project

RECRUITING
NCT03047369Children's Hospital of PhiladelphiaStarted 2016-12-08

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients