NOTCH2 p.Glu141=
c.423G>A · rs149906722 · VCV291154
Conflicting classifications of pathogenicity
Conflicting submitters
Classification
Conflicting classifications of pathogenicity
ClinVar
Review
Conflicting submitters ★☆☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
rare (popmax 0.168%, afr)
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 -0.16 | phastCons 0.003 |
| Overall | ||
| CADD | 6.472 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.168%
African / African-American · 126/75,054 alleles
Filtering AF
0.144%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.135%
Overall
0.0182%
294/1,613,986 alleles · rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.168% | 596 |
| Middle Eastern | 0.033% | 3,028 |
| Admixed American | 0.0233% | 4,287 |
| Remaining individualsnot grpmax-eligible | 0.0224% | 4,463 |
| European (non-Finnish) | 0.0114% | 8,740 |
| East Asian | 0.00223% | 44,882 |
| South Asian | 0.0022% | 45,541 |
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.Glu141=
- Coding
- c.423G>A
- MANE Select
- NM_024408
- dbSNP
- rs149906722
- Type
- single nucleotide variant
- Location
- chr1:119997325 (GRCh38)
- Gene constraint
- LOEUF 0.151 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 59.51 · 2 PDB
- Residue 141
- the egf-like 3 domain
Similar variants
- NOTCH2 p.Glu141Ala Uncertain significance ★ ⚠ same residue
- NOTCH2 p.Arg2003Ter Pathogenic/Likely pathogenic ★★ same type
- NOTCH2 p.Arg2400Ter Pathogenic ★★ same type
- NOTCH2 p.Gln2223Ter Pathogenic ★★ same type
- NOTCH2 p.Gln2263Ter Pathogenic ★★ same type
- NOTCH2 p.Gln2285Ter Pathogenic/Likely pathogenic ★★ same type
- NOTCH2 c.2753-8T>A Uncertain significance ★★ same type
- NOTCH2 c.5214-10A>G Uncertain significance ★★ same type
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-glu141 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown