Benign
Multiple submitters
Classification
Benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 12 submitters
gnomAD v4.1
Common
common (popmax 87.1%, nfe) — too common for a highly-penetrant pathogenic allele
Conditions
2
lateral meningocele syndrome
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 -20 | GERP -3.8 |
| Overall | ||
| CADD | 0.014 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
87.1%
European (non-Finnish) · 999,345/1,147,074 alleles
Filtering AF
87%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 86.9%
Overall
84.5%
1,310,373/1,551,032 alleles · common
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 87.1% | 1 |
| Finnishnot grpmax-eligible | 84.8% | 1 |
| East Asian | 84.7% | 1 |
| Ashkenazi Jewishnot grpmax-eligible | 83.6% | 1 |
| Remaining individualsnot grpmax-eligible | 81.9% | 1 |
| South Asian | 80.7% | 1 |
| Middle Eastern | 78.6% | 1 |
| Amishnot grpmax-eligible | 74.2% | 1 |
| Admixed American | 69.9% | 1 |
| African / African-American | 60.4% | 2 |
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.Pro914=
- Coding
- c.2742A>G
- MANE Select
- NM_000435
- dbSNP
- rs1043997
- Type
- single nucleotide variant
- Location
- chr19:15181626 (GRCh38)
- Gene constraint
- LOEUF 0.566 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 61.79 · 6 PDB
- Residue 914
- a disulfide bond; a UniProt-annotated variant site (in carasil1; likely pathogenic); the egf-like 23; calcium-binding domain
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-pro914 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown