NOTCH1 p.Pro143=
c.429G>T · rs757406877 · VCV1541346
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.00339%, amr)
Conditions
1
Adams-Oliver syndrome 5
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 -20 | GERP -4.5 |
| Overall | ||
| CADD | 0.024 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00339%
Admixed American · 2/58,984 alleles
Filtering AF
0.000562%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.000211%
Overall
0.000125%
2/1,604,404 alleles · very rare
exomes 2/1,452,112 · genomes 0/152,292 · 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
- NOTCH1
- Protein
- p.Pro143=
- Coding
- c.429G>T
- MANE Select
- NM_017617
- dbSNP
- rs757406877
- Type
- single nucleotide variant
- Location
- chr9:136523163 (GRCh38)
- Gene constraint
- LOEUF 0.217 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 59.74 · 29 PDB
- Residue 143
- the egf-like 4 domain; an α-helix
Similar variants
- NOTCH1 p.Pro143Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
- NOTCH1 p.Pro143fs Pathogenic ★★ same residue
- NOTCH1 p.Pro143Gln Uncertain significance ★ ⚠ same residue
- NOTCH1 c.1099+1G>T Pathogenic/Likely pathogenic ★★ same condition
- NOTCH1 c.3511-1G>A Likely pathogenic ★★ same condition
- NOTCH1 p.Arg1107Ter Pathogenic ★★ same condition
- NOTCH1 p.Arg448Ter Pathogenic ★★ same condition
- NOTCH1 p.Arg56Ter Pathogenic ★★ 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/notch1-p-pro143 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown