NOTCH3 p.Ser95Arg
c.283A>C · rs777645491 · VCV798179
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9469 | likely pathogenic |
|---|---|---|
| REVEL | 0.829 | moderately pathogenic-leaning |
| SaProt | LLR -9.15 | tolerated |
| ⇒ AlphaMissense and REVEL call this damaging; SaProt does not. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 7.8 | GERP 1.5, phastCons 1 |
| Regional constraint | o/e 0.78 | unconstrained · MANE · 14 kb · p 4.2e-11 · regional, not allelic |
| Overall | ||
| CADD | 25.5 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Ashkenazi Jewishnot grpmax-eligible | 0.206% | 485 |
| Middle Easterngrpmax | 0.0164% | 6,084 |
| Remaining individualsnot grpmax-eligible | 0.00961% | 10,408 |
| African / African-American | 0.00401% | 24,917 |
| European (non-Finnish) | 0.00297% | 33,713 |
Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- NOTCH3
- Protein
- p.Ser95Arg
- Coding
- c.283A>C
- MANE Select
- NM_000435
- dbSNP
- rs777645491
- Type
- single nucleotide variant
- Location
- chr19:15192434 (GRCh38)
- Gene constraint
- LOEUF 0.566 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 61.79 · 6 PDB
- Residue 95
- a disulfide bond; the egf-like 2 domain
Disease context
cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsFor Cerebral autosomal dominant arteriopathy-subcortical infarcts-leukoencephalopathy (Orphanet):
- Inheritance
- Autosomal dominant
- Onset
- Adult
- Prevalence
- 1-9 / 100 000 (Europe)
Similar variants
- NOTCH3 c.341-2A>T Pathogenic ★★ same condition
- NOTCH3 p.Arg1006Cys Pathogenic ★★ ⚠ same condition
- NOTCH3 p.Arg1076Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
- NOTCH3 p.Arg110Cys Pathogenic ★★ same condition
- NOTCH3 p.Arg133Cys Pathogenic/Likely pathogenic ★★ same condition
- NOTCH3 p.Arg141Cys Pathogenic ★★ same condition
- NOTCH3 p.Arg153Cys Pathogenic ★★ same condition
- NOTCH3 p.Arg169Cys Pathogenic/Likely pathogenic ★★ ⚠ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/notch3-p-ser95arg (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown