CADASIL: genes and variants
Explore variant evidence for CADASIL across 1 analyzed protein (NOTCH3). Linked ClinVar records include 89 pathogenic or likely pathogenic variants, 74 variants of uncertain significance and 64 with conflicting classifications.
Coverage includes proteins already analyzed in CATVariant, not every gene involved in this condition. Database links are associations, not an assessment of clinical gene–disease validity. Computable evidence prioritizes variants for expert review and does not reclassify them. Source labels are pooled across this disease family.
Data updated 2026-10-10. Automated aggregation, not a clinical review date.
Download variant evidence (CSV)
Genes linked to CADASIL
NOTCH3: Neurogenic locus notch homolog protein 3
Its signaling helps maintain vascular smooth-muscle and mural-cell identity in small arteries. Pathogenic cysteine-altering variants cause CADASIL, with migraine, recurrent ischemic strokes, white-matter disease, and progressive cognitive impairment.
89 ClinVar pathogenic / likely pathogenic and 138 uncertain variants in NOTCH3 have source records linked to CADASIL. Association strength is not clinical gene validity.
Where CADASIL variants cluster
- NOTCH3 EGF-like 1 (positions 40–77): 12 of 89 ClinVar pathogenic / likely pathogenic variants, 8.2× more than its size predicts.
- NOTCH3 EGF-like 4 (positions 158–195): 11 of 89 ClinVar pathogenic / likely pathogenic variants, 7.5× more than its size predicts.
- NOTCH3 EGF-like 3 (positions 119–156): 10 of 89 ClinVar pathogenic / likely pathogenic variants, 6.9× more than its size predicts.
- NOTCH3 EGF-like 13 (positions 507–543): 6 of 89 ClinVar pathogenic / likely pathogenic variants, 4.2× more than its size predicts.
- NOTCH3 EGF-like 5 (positions 197–234): 6 of 89 ClinVar pathogenic / likely pathogenic variants, 4.1× more than its size predicts.
ClinVar pathogenic and likely pathogenic variants linked to CADASIL
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| NOTCH3 R133C | 133 | EGF-like 3 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C146Y | 146 | EGF-like 3 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C516Y | 516 | EGF-like 13 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C516F | 516 | EGF-like 13 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C65S | 65 | EGF-like 1 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C65Y | 65 | EGF-like 1 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C146R | 146 | EGF-like 3 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C174R | 174 | EGF-like 4 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C174Y | 174 | EGF-like 4 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C183R | 183 | EGF-like 4 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C428Y | 428 | EGF-like 10 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C144F | 144 | EGF-like 3 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 R332C | 332 | EGF-like 8 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C511R | 511 | EGF-like 13 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C1015R | 1015 | EGF-like 26 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C43Y | 43 | EGF-like 1 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C49Y | 49 | EGF-like 1 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C49G | 49 | EGF-like 1 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C67F | 67 | EGF-like 1 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 R182C | 182 | EGF-like 4 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C194F | 194 | EGF-like 4 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C224Y | 224 | EGF-like 5 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C233Y | 233 | EGF-like 5 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C251R | 251 | EGF-like 6 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 R427C | 427 | EGF-like 10 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 R54C | 54 | EGF-like 1 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 R141C | 141 | EGF-like 3 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 R153C | 153 | EGF-like 3 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C55Y | 55 | EGF-like 1 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 R75P | 75 | EGF-like 1 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C82F | 82 | EGF-like 2 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 R90C | 90 | EGF-like 2 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C106G | 106 | EGF-like 2 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 R110C | 110 | EGF-like 2 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C117Y | 117 | EGF-like 2 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C123F | 123 | EGF-like 3 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 R169C | 169 | EGF-like 4 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C206Y | 206 | EGF-like 5 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C260F | 260 | EGF-like 6 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C311F | 311 | EGF-like 7 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 S396C | 396 | EGF-like 10 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C419G | 419 | EGF-like 10 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 G420C | 420 | EGF-like 10 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C455F | 455 | EGF-like 11 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 R532C | 532 | EGF-like 13 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C542R | 542 | EGF-like 13 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C559Y | 559 | EGF-like 14 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 R607C | 607 | EGF-like 15 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 R640C | 640 | EGF-like 16 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 Y710C | 710 | EGF-like 18 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 R985C | 985 | EGF-like 25 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C271F | 271 | EGF-like 6 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C504Y | 504 | EGF-like 12 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 R558C | 558 | EGF-like 14 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C568R | 568 | EGF-like 14 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 C597W | 597 | EGF-like 15 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 R1031C | 1031 | EGF-like 26 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 R1076C | 1076 | EGF-like 27 | Pathogenic / likely pathogenic (★★) |
| NOTCH3 R544C | 544 | Extracellular | Pathogenic / likely pathogenic (★★) |
| NOTCH3 R578C | 578 | EGF-like 14 | Pathogenic / likely pathogenic (★★) |
Showing 60 of 89.
Uncertain variants prioritized for review in CADASIL
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| NOTCH3 C597S | 597 | EGF-like 15 | Conflicting reports (★) | +7: C597W at the same position is pathogenic; seen in 6.8e-07 of gnomAD DNA copies; REVEL 0.962 |
Which prediction tools work for CADASIL
Observed separation of ClinVar pathogenic / likely pathogenic from benign / likely benign variants (AUROC × 100). This benchmark is not a clinical recommendation.
- MetaLR: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CATVariant: 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- REVEL: 94 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- PolyPhen-2: 89 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CADD: 82 out of 100
- SIFT: 79 out of 100
- phyloP: 61 out of 100
Same protein, different disease
- Infantile myofibromatosis also has ClinVar records linked to NOTCH3 variants; they fall mostly in different places as the CADASIL variants (12 pathogenic / likely pathogenic).
Diseases related to CADASIL
- Infantile myofibromatosis, also linked to NOTCH3
- Auditory neuropathy, also linked to NOTCH3
- Lateral meningocele syndrome, also linked to NOTCH3
- Adams-Oliver syndrome, also linked to NOTCH3
- Migraine, also linked to NOTCH3
- Ischemic stroke, also linked to NOTCH3
Frequently asked questions
Which genes have records linked to CADASIL?
This view contains 1 analyzed proteins: NOTCH3. Links come from clinical records and association databases. They do not imply that every listed gene is a validated cause, and missing genes may not yet be analyzed.
What do the clinical classifications mean?
Linked records include 89 pathogenic or likely pathogenic variants, 74 variants of uncertain significance and 64 with conflicting classifications. Labels summarize source records; multi-condition records may not make a separate assertion for this disease. Check the original record and review status.
Does the evidence score change a VUS classification?
No. 1 VUS or conflicting variants reach the likely-pathogenic points range on the computable criteria available here. This is a research prioritization signal, not a clinical classification. Patient, family and other required evidence may be missing.
Can I download the variant evidence?
Download the CSV for all 300 variants in the selected disease scope, including clinical labels, review status, evidence criteria, predictor scores, functional measurements and population frequency where available.
About this data
Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from eligible public CATVariant analyses of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.
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