NOTCH2 p.Cys427=
c.1281T>C · rs1170303070 · VCV2061658
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0104%, nfe)
Conditions
1
acroosteolysis dominant type
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 0.45 | phastCons 0.7 |
| Overall | ||
| CADD | 9.325 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0104%
European (non-Finnish) · 123/1,179,952 alleles
Filtering AF
0.00892%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00836%
Overall
0.00787%
127/1,613,984 alleles · ultra-rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.0104% | 9,593 |
| Remaining individualsnot grpmax-eligible | 0.0048% | 20,828 |
| African / African-American | 0.00133% | 74,932 |
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
- NOTCH2
- Protein
- p.Cys427=
- Coding
- c.1281T>C
- MANE Select
- NM_024408
- dbSNP
- rs1170303070
- Type
- single nucleotide variant
- Location
- chr1:119967605 (GRCh38)
- Gene constraint
- LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 59.51 · 2 PDB
- Residue 427
- a disulfide bond; the egf-like 11; calcium-binding domain; a β-strand
Similar variants
- NOTCH2 p.Cys427Tyr Uncertain significance ★★ ⚠ same residue
- NOTCH2 p.Arg2003Ter Pathogenic/Likely pathogenic ★★ same condition
- NOTCH2 p.Arg2400Ter Pathogenic ★★ same condition
- NOTCH2 p.Gln2223Ter Pathogenic ★★ same condition
- NOTCH2 p.Gln2263Ter Pathogenic ★★ same condition
- NOTCH2 p.Gln2285Ter Pathogenic/Likely pathogenic ★★ same condition
- NOTCH2 c.2753-8T>A Uncertain significance ★★ same condition
- NOTCH2 c.5214-10A>G Uncertain significance ★★ 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/notch2-p-cys427 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown