NOTCH3 p.Asp736=
c.2208C>T · VCV4941288
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.00267%, 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 -0.94 | GERP -2.4 |
| Overall | ||
| CADD | 7.388 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00267%
African / African-American · 2/74,884 alleles
Filtering AF
0.000443%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00026%
Overall
0.000992%
16/1,612,560 alleles · very rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.00267% | 37,442 |
| East Asian | 0.00223% | 44,840 |
| South Asian | 0.0022% | 45,523 |
| Admixed American | 0.00167% | 59,958 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,454 |
| European (non-Finnish) | 0.000763% | 131,096 |
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.Asp736=
- Coding
- c.2208C>T
- MANE Select
- NM_000435
- Type
- single nucleotide variant
- Location
- chr19:15185345 (GRCh38)
- Gene constraint
- LOEUF 0.566 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 61.79 · 6 PDB
- Residue 736
- the egf-like 19 domain; a UniProt-annotated variant site (in carasil1; likely pathogenic)
Similar variants
- NOTCH3 p.Asp736Glu 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-asp736 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown