NOTCH3 p.Pro36=
c.108G>A · rs1276674466 · VCV2888956
Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.02%, afr)
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP -0.36 | GERP -1.7, phastCons 0.1 |
| Overall | ||
| CADD | 11.19 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.02%
African / African-American · 13/64,952 alleles
Filtering AF
0.0118%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00936%
Overall
0.00118%
15/1,273,886 alleles · ultra-rare
exomes 11/1,121,960 · genomes 4/151,926 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.02% | 4,996 |
| Remaining individualsnot grpmax-eligible | 0.00214% | 46,636 |
| European (non-Finnish) | 9.96e-05% | 1,003,762 |
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.Pro36=
- Coding
- c.108G>A
- MANE Select
- NM_000435
- dbSNP
- rs1276674466
- Type
- single nucleotide variant
- Location
- chr19:15200798 (GRCh38)
- Gene constraint
- LOEUF 0.566 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 61.79 · 6 PDB
Similar variants
- NOTCH3 p.Pro36Leu Uncertain significance ★★ ⚠ same residue
- NOTCH3 c.341-2A>G Pathogenic ★★ same type
- NOTCH3 c.341-2A>T Pathogenic ★★ same type
- NOTCH3 p.Arg1006Cys Pathogenic ★★ ⚠ same type
- NOTCH3 p.Arg1076Cys Pathogenic/Likely pathogenic ★★ ⚠ same type
- NOTCH3 p.Arg110Cys Pathogenic ★★ same type
- NOTCH3 p.Arg133Cys Pathogenic/Likely pathogenic ★★ same type
- NOTCH3 p.Arg141Cys Pathogenic ★★ same type
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-pro36 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown