NOTCH1 p.Ser2467=
c.7401G>A · rs371306178 · VCV1125870
Likely benign
Multiple submitters
Classification
Likely benign
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 3 submitters
gnomAD v4.1
Rare
ultra-rare (popmax 0.0268%, afr)
Conditions
2
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 -13 | GERP -2.9 |
| Overall | ||
| CADD | 0.114 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0268%
African / African-American · 20/74,728 alleles
Filtering AF
0.0177%
ClinGen BA1/BS1 input
FAF95, joint · FAF99 0.0147%
Overall
0.0027%
43/1,592,414 alleles · ultra-rare
exomes 27/1,440,232 · genomes 16/152,182 · joint denominator
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.0268% | 3,736 |
| South Asian | 0.00559% | 17,880 |
| Finnishnot grpmax-eligible | 0.00171% | 58,316 |
| Remaining individualsnot grpmax-eligible | 0.00162% | 61,828 |
| European (non-Finnish) | 0.00137% | 73,171 |
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.Ser2467=
- Coding
- c.7401G>A
- MANE Select
- NM_017617
- dbSNP
- rs371306178
- Type
- single nucleotide variant
- Location
- chr9:136496338 (GRCh38)
- Gene constraint
- LOEUF 0.217 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 59.74 · 29 PDB
Similar variants
- NOTCH1 p.Ser2467Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
- NOTCH1 p.Ser2467Pro 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
- NOTCH1 p.Asp1517Asn Pathogenic/Likely 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-ser2467 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown