NOTCH1 p.Pro22=
c.66G>C · rs775812729 · VCV3003674
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
very rare (popmax 0.00215%, nfe)
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 -0.71 | GERP -3.6, phastCons 0.006 |
| Overall | ||
| CADD | 7.794 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.00215%
European (non-Finnish) · 25/1,160,166 alleles
Filtering AF
0.00148%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.00125%
Overall
0.00165%
26/1,572,540 alleles · very rare
exomes 25/1,420,334 · genomes 1/152,206 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| European (non-Finnish)grpmax | 0.00215% | 46,407 |
| Remaining individualsnot grpmax-eligible | 0.00164% | 60,832 |
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.Pro22=
- Coding
- c.66G>C
- MANE Select
- NM_017617
- dbSNP
- rs775812729
- Type
- single nucleotide variant
- Location
- chr9:136544098 (GRCh38)
- Gene constraint
- LOEUF 0.217 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 59.74 · 29 PDB
- Residue 22
- the egf-like 1 domain
Similar variants
- NOTCH1 p.Pro22Ser Benign/Likely benign ★★ same residue
- NOTCH1 p.Pro22Arg Uncertain significance ★ ⚠ same residue
- NOTCH1 p.Pro22Leu Conflicting classifications of pathogenicity ★ ⚠ 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-pro22 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown