CDH1 p.Phe205Ser
c.614T>C · rs1567504835 · VCV599654
ClinGen expert panel — CDH1 VCEP
Uncertain Significance for CDH1-related diffuse gastric and lobular breast cancer. Applied ACMG criteria (verbatim):
PM2_Supporting PS4_Supporting
Curation rationale (ClinGen, verbatim)
The c.614T>C (p. Phe205Ser) variant is absent in the gnomAD cohort (PM2_Supporting). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; internal laboratory contributor). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, PS4_Supporting.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9987 | likely pathogenic · top 1% in CDH1 |
|---|---|---|
| REVEL | 0.929 | moderately pathogenic-leaning |
| SaProt | LLR -17.41 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 7.9 | GERP 1.9, phastCons 1 |
| Regional constraint | o/e 0.87 | unconstrained · MANE · 25 kb · p 0.00015 · regional, not allelic |
| Overall | ||
| CADD | 29.8 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- CDH1
- Protein
- p.Phe205Ser
- Coding
- c.614T>C
- MANE Select
- NM_004360
- dbSNP
- rs1567504835
- Type
- single nucleotide variant
- Location
- chr16:68808775 (GRCh38)
- Gene constraint
- LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 79.13 · 22 PDB
- Residue 205
- a β-strand; the cadherin 1 domain
Similar variants
- CDH1 p.Phe205Leu Uncertain significance ★★ ⚠ same residue
- CDH1 p.Phe205= Likely benign ★★ 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
- CDH1 c.1565+1G>C 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-phe205ser (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown