CDH1 p.Pro826fs
c.2474dup · rs1555518221 · VCV481178
ClinGen expert panel — CDH1 VCEP
Pathogenic for CDH1-related diffuse gastric and lobular breast cancer. Applied ACMG criteria (verbatim):
PVS1_Strong PM2_Supporting PM5_Supporting PS4
Curation rationale (ClinGen, verbatim)
The NM_004360.5:c.2474dup (p.Pro826AlafsTer3) variant in CDH1 is a frameshift variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay. However, this truncated region (removes last 57 amino acids of the protein) is critical to protein function and located upstream the most 3' well-characterized pathogenic variant c.2506G>T (pGlu836Ter) (PVS1_Strong, PM5_Supporting; PMID: 29798843, ClinVar Variation ID: 479504). This variant is absent in gnomAD 2.1.1 (PM2_Supporting). This variant has been reported in 5 families meeting HDGC criteria (PS4; NCI hereditary gastric study, Ambry, Invitae). In summary, this variant meets the criteria to be classified as pathogenic for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: PVS1_Strong, PS4, PM2_Supporting, PM5_Supporting. (CDH1 VCEP specifications version 3.1; 5/6/2022)
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 | escapes | premature termination codon in the last exon (16 of 16) — the truncated protein is likely expressed. PVS1 input, not an applied code |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP 1.9, phastCons 1 |
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.Pro826fs
- Coding
- c.2474dup
- MANE Select
- NM_004360
- dbSNP
- rs1555518221
- Type
- Duplication
- Location
- chr16:68833320 (GRCh38)
- Gene constraint
- LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 79.13 · 22 PDB
- Residue 826
- the 'required for binding alpha, beta and gamma catenins' region
Similar variants
- CDH1 p.Pro826Ser Uncertain significance ★★ ⚠ same residue
- CDH1 p.Pro826Thr Uncertain significance ★ ⚠ same residue
- CDH1 c.1565+2dup Pathogenic ★★★ same condition
- CDH1 p.Ala530fs Pathogenic ★★★ same condition
- CDH1 p.Arg796fs Likely pathogenic ★★★ same condition
- CDH1 p.Asn174fs Pathogenic ★★★ same condition
- CDH1 p.Asn531fs Pathogenic ★★★ same condition
- CDH1 p.Gln677fs 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-pro826fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown