NOTCH2 p.Pro1334=
c.4002C>G · rs1390174762 · VCV595890
Conflicting classifications of pathogenicity
Conflicting submitters
Classification
Conflicting classifications of pathogenicity
ClinVar
Review
Conflicting submitters ★☆☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
very rare (popmax 0.00401%, afr)
Conditions
1
acroosteolysis dominant type
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 0.019 | phastCons 0.28 |
| Overall | ||
| CADD | 6.623 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00401%
African / African-American · 3/74,764 alleles
Filtering AF
0.00107%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.000495%
Overall
0.000188%
3/1,598,508 alleles · very rare
exomes 1/1,446,368 · genomes 2/152,140 · joint denominator
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.Pro1334=
- Coding
- c.4002C>G
- MANE Select
- NM_024408
- dbSNP
- rs1390174762
- Type
- single nucleotide variant
- Location
- chr1:119926502 (GRCh38)
- Gene constraint
- LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 59.51 · 2 PDB
- Residue 1334
- the egf-like 34 domain
Similar variants
- NOTCH2 p.Pro1334Arg Uncertain significance ★★ ⚠ same residue
- NOTCH2 p.Pro1334Ser 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
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-pro1334 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown