NOTCH1 p.Val565=
c.1695G>A · VCV3694462
Likely benign
Single submitter
Classification
Likely benign
ClinVar
Review
Single submitter ★☆☆☆
ClinVar · 1 submitter
gnomAD v4.1
Rare
ultra-rare (popmax 0.0218%, mid)
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 -0.94 | GERP -0.27 |
| Overall | ||
| CADD | 4.136 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
gnomAD v4.1 · exomes + genomes
Grpmax group
0.0218%
Middle Eastern · 1/4,590 alleles
Overall
0.000258%
4/1,549,776 alleles · ultra-rare
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Middle Easterngrpmax | 0.0218% | 4,590 |
| Finnishnot grpmax-eligible | 0.00203% | 49,376 |
| African / African-American | 0.00136% | 73,398 |
| European (non-Finnish) | 8.67e-05% | 1,153,321 |
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.Val565=
- Coding
- c.1695G>A
- MANE Select
- NM_017617
- Type
- single nucleotide variant
- Location
- chr9:136515691 (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.Val565Met 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
- NOTCH1 p.Cys1496Tyr 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-val565 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown