NOTCH2 p.Pro551=
c.1653G>A · rs187731832 · VCV500643
Conflicting classifications of pathogenicity
Conflicting submitters
Classification
Conflicting classifications of pathogenicity
ClinVar
Review
Conflicting submitters ★☆☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
rare (popmax 0.149%, eas)
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 -16 | |
| Overall | ||
| CADD | 0.657 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.149%
East Asian · 67/44,894 alleles
Filtering AF
0.12%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.11%
Overall
0.00527%
85/1,613,868 alleles · rare
exomes 81/1,461,566 · genomes 4/152,302 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| East Asiangrpmax | 0.149% | 670 |
| Finnishnot grpmax-eligible | 0.00469% | 21,342 |
| South Asian | 0.00329% | 30,361 |
| Admixed American | 0.00167% | 60,014 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,480 |
| African / African-American | 0.00133% | 75,030 |
| European (non-Finnish) | 0.000763% | 131,085 |
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.Pro551=
- Coding
- c.1653G>A
- MANE Select
- NM_024408
- dbSNP
- rs187731832
- Type
- single nucleotide variant
- Location
- chr1:119965481 (GRCh38)
- Gene constraint
- LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 59.51 · 2 PDB
- Residue 551
- the egf-like 14; calcium-binding domain
Similar variants
- NOTCH2 p.Pro551Leu Likely benign ★ ⚠ 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-pro551 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown