NOTCH3
Chr 19ADARnotch receptor 3
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.
Disputed — evidence questions this relationship
2 total gene-disease associations curated
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly LoF-intolerant (top ~10% of genes)
Highly missense-constrained (top ~0.1%)
This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.
ClinVar Variant Classifications
0 submitted variants in 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.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Natural History Study of CADASIL
RECRUITINGThe Myelin Disorders Biorepository Project
RECRUITINGTaiwan Associated Genetic and Nongenetic Small Vessel Disease
RECRUITINGGenotype, Clinical Features and Imaging of Neuroradiological Abnormalities in CADASIL
RECRUITINGDevelopment and Validation of a Functional MRI Biomarker of Cerebral Small Vessel Dysfunction in CADASIL
NOT YET RECRUITINGAusCADASIL: An Australian Cohort of CADASIL
RECRUITINGLong-term Prospective Study of Korean CADASIL Patients
RECRUITINGNeurogenetic And Hemodynamic Of Migraine Aura And Pfo
RECRUITINGCerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) Study
RECRUITINGExternal Resources
Links to major genomics databases and tools