NOTCH3 p.Pro690=
c.2070A>G · rs370780913 · VCV811740
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 5 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0169%, nfe)
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 -11 | GERP -3.8 |
| Overall | ||
| CADD | 0.874 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0169%
European (non-Finnish) · 199/1,178,896 alleles
Filtering AF
0.015%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0142%
Overall
0.0127%
205/1,610,242 alleles · ultra-rare
exomes 196/1,461,446 · genomes 9/148,796 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.0169% | 5,924 |
| Remaining individualsnot grpmax-eligible | 0.00641% | 15,608 |
| Finnishnot grpmax-eligible | 0.00158% | 63,358 |
| African / African-American | 0.00136% | 73,728 |
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.Pro690=
- Coding
- c.2070A>G
- MANE Select
- NM_000435
- dbSNP
- rs370780913
- Type
- single nucleotide variant
- Location
- chr19:15185561 (GRCh38)
- Gene constraint
- LOEUF 0.566 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 61.79 · 6 PDB
- Residue 690
- the egf-like 17; calcium-binding domain
Similar variants
- 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
- NOTCH3 p.Arg153Cys 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-pro690 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown