NOTCH2 p.Pro1335=
c.4005G>T · rs118188023 · VCV2873184
Uncertain significance
Single submitter
Classification
Uncertain significance
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.00171%, amr)
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 |
|---|---|---|
| Pangolin | Δ0.42 | loss · gain 0.01 · not in the SpliceAI release · independent |
| Constraint at this position | ||
| Conservation | phyloP -1.4 | |
| Overall | ||
| CADD | 16.31 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00171%
Admixed American · 1/58,608 alleles
Overall
0.000125%
2/1,596,700 alleles · very rare
exomes 2/1,444,460 · genomes 0/152,240 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.00171% | 58,608 |
| European (non-Finnish) | 8.55e-05% | 1,169,113 |
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.Pro1335=
- Coding
- c.4005G>T
- MANE Select
- NM_024408
- dbSNP
- rs118188023
- Type
- single nucleotide variant
- Location
- chr1:119926499 (GRCh38)
- Gene constraint
- LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 59.51 · 2 PDB
- Residue 1335
- the egf-like 34 domain
Similar variants
- NOTCH2 p.Pro1335Arg Uncertain significance ★★ ⚠ same residue
- NOTCH2 p.Pro1335Leu 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-pro1335 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown