NOTCH3 p.Val2168=
c.6504G>C · rs546608637 · VCV447865
Benign/Likely benign
Multiple submitters
Classification
Benign/Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 4 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0886%, 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 -2.7 | GERP -3.5 |
| Overall | ||
| CADD | 0.109 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0886%
African / African-American · 65/73,378 alleles
Filtering AF
0.0713%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.065%
Overall
0.00507%
78/1,539,674 alleles · ultra-rare
exomes 45/1,387,402 · genomes 33/152,272 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.0886% | 1,129 |
| Middle Eastern | 0.0349% | 2,868 |
| Remaining individualsnot grpmax-eligible | 0.00831% | 12,029 |
| Admixed American | 0.00586% | 17,065 |
| South Asian | 0.00356% | 28,117 |
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.Val2168=
- Coding
- c.6504G>C
- MANE Select
- NM_000435
- dbSNP
- rs546608637
- Type
- single nucleotide variant
- Location
- chr19:15161124 (GRCh38)
- Gene constraint
- LOEUF 0.566 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 61.79 · 6 PDB
- Residue 2168
- a UniProt-annotated variant site (in carasil1; likely pathogenic); a UniProt-annotated variant site (in lmns; likely pathogenic)
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-val2168 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown