NOTCH3 p.Pro68=
c.204G>A · rs772468516 · VCV804625
Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0521%, amr)
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 -8.4 | GERP -3.7 |
| Overall | ||
| CADD | 0.639 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0521%
Admixed American · 29/55,616 alleles
Filtering AF
0.0372%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0323%
Overall
0.00385%
61/1,586,284 alleles · ultra-rare
exomes 56/1,434,120 · genomes 5/152,164 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.0521% | 1,918 |
| South Asian | 0.0137% | 7,310 |
| Remaining individualsnot grpmax-eligible | 0.00488% | 20,481 |
| African / African-American | 0.00269% | 37,142 |
| East Asian | 0.0023% | 43,462 |
| European (non-Finnish) | 0.0012% | 83,353 |
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.Pro68=
- Coding
- c.204G>A
- MANE Select
- NM_000435
- dbSNP
- rs772468516
- Type
- single nucleotide variant
- Location
- chr19:15192513 (GRCh38)
- Gene constraint
- LOEUF 0.566 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 61.79 · 6 PDB
- Residue 68
- the egf-like 1 domain
Similar variants
- NOTCH3 p.Pro68Leu Conflicting classifications of pathogenicity ★ ⚠ 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-pro68 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown