NOTCH2 p.Ala1986=
c.5958T>C · rs563486507 · VCV498173
Conflicting classifications of pathogenicity
Conflicting submitters
Classification
Conflicting classifications of pathogenicity
ClinVar
Review
Conflicting submitters ★☆☆☆
ClinVar · 4 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0825%, mid)
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 0.17 | phastCons 0.17 |
| Overall | ||
| CADD | 8.239 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0825%
Middle Eastern · 5/6,062 alleles
Filtering AF
0.0324%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.021%
Overall
0.00415%
67/1,613,716 alleles · ultra-rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.0825% | 1,212 |
| Admixed American | 0.01% | 10,004 |
| Remaining individualsnot grpmax-eligible | 0.0048% | 20,834 |
| European (non-Finnish) | 0.00449% | 22,258 |
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.Ala1986=
- Coding
- c.5958T>C
- MANE Select
- NM_024408
- dbSNP
- rs563486507
- Type
- single nucleotide variant
- Location
- chr1:119917734 (GRCh38)
- Gene constraint
- LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 59.51 · 2 PDB
Similar variants
- 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
- NOTCH2 c.874+4T>C 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-ala1986 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown