CDH1 p.Pro147fs
c.438_439del · rs1555515197 · VCV491536
ClinGen expert panel — CDH1 VCEP
Pathogenic for CDH1-related diffuse gastric and lobular breast cancer. Applied ACMG criteria (verbatim):
PVS1 PM2_Supporting PM5_Supporting
Curation rationale (ClinGen, verbatim)
The c.438_439delTC p.(Pro147Trpfs*20) variant is predicted to result in a premature stop codon that leads to nonsense mediate decay (PVS1 and PM5_supporting). The variant is absent in the gnomAD cohort (PM2_supporting; http://gnomad.broadinstitute.org). Therefore, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (CDH1 VCEP specifications version 3.1): PVS1, PM2_supporting, PM5_supporting.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Consequence | frameshift | predicted loss-of-function in a haploinsufficient gene (ClinGen) |
|---|---|---|
| NMD | predicted | premature termination codon in exon 4 of 16 |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 0.14 | GERP -2.3 |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
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.Pro147fs
- Coding
- c.438_439del
- MANE Select
- NM_004360
- dbSNP
- rs1555515197
- Type
- Microsatellite
- Location
- chr16:68808471 (GRCh38)
- Gene constraint
- LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 79.13 · 22 PDB
Similar variants
- CDH1 p.Pro147Ser Uncertain significance ★★ ⚠ same residue
- CDH1 p.Pro147= Likely benign ★★ same residue
- CDH1 p.Pro147Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
- CDH1 c.2439+5_2439+8del Likely pathogenic ★★★ same condition
- CDH1 p.Arg154fs Pathogenic ★★★ same condition
- CDH1 p.Arg492fs Pathogenic ★★★ same condition
- CDH1 p.Cys688_Glu689delinsTer Pathogenic ★★★ same condition
- CDH1 p.His632fs 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-pro147fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown