CDH1 p.Val473Ile
c.1417G>A · rs36087757 · VCV127914
ClinGen expert panel — CDH1 VCEP
Likely Benign for CDH1-related diffuse gastric and lobular breast cancer. Applied ACMG criteria (verbatim):
BS2
Curation rationale (ClinGen, verbatim)
The c.1417G>A (p.Val473Ile) variant results in a conservative missense change in the Cadherin 3 domain of CDH1. This variant was observed in 5 of 152,172 alleles in the gnomAD v3.1.2 population database. However, this variants has also been observed in more than 10 individuals without GC, DGC, gastric SRC tumours or LBC and whose families do not suggest HDGC (BS2). In summary, this variant meets criteria to be classified as Likely Benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 05/22/2023)
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.0728 | likely benign |
|---|---|---|
| REVEL | 0.172 | moderately benign-leaning |
| SaProt | LLR -9.43 | tolerated |
| ⇒ AlphaMissense, REVEL and SaProt all call this tolerated. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 0.85 | GERP -1.7, phastCons 0.86 |
| Regional constraint | o/e 0.87 | unconstrained · MANE · 25 kb · p 0.00015 · regional, not allelic |
| Overall | ||
| CADD | 16.45 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| East Asiangrpmax | 0.0223% | 4,488 |
| Middle Eastern | 0.0165% | 6,062 |
| European (non-Finnish) | 0.00737% | 13,564 |
| Remaining individualsnot grpmax-eligible | 0.0048% | 20,837 |
| Admixed American | 0.00167% | 60,020 |
| African / African-American | 0.00133% | 75,048 |
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
- CDH1
- Protein
- p.Val473Ile
- Coding
- c.1417G>A
- MANE Select
- NM_004360
- dbSNP
- rs36087757
- Type
- single nucleotide variant
- Location
- chr16:68815611 (GRCh38)
- Gene constraint
- LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 79.13 · 22 PDB
- Residue 473
- the cadherin 3 domain; a β-strand; a UniProt-annotated variant site (in a diffuse gastric cancer sample); a UniProt-annotated variant site (in)
Disease context
CDH1-related diffuse gastric and lobular breast cancer syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: hereditary breast ovarian cancer syndromehereditary diffuse gastric adenocarcinomahereditary neoplastic syndromehereditary breast carcinoma
Similar variants
- CDH1 p.Val473= Likely benign ★ same residue
- CDH1 p.Val473fs Pathogenic ★ same residue
- CDH1 p.Val473_Thr474insIle Uncertain significance ★ same residue
- CDH1 c.1008+2T>C Likely pathogenic ★★★ same condition
- CDH1 c.1137+1G>A Pathogenic ★★★ same condition
- CDH1 c.1137+2T>C Likely pathogenic ★★★ same condition
- CDH1 c.1320+1G>C Likely pathogenic ★★★ same condition
- CDH1 c.1565+1G>A 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/cdh1-p-val473ile (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown