CDH1 p.Pro42fs
c.124_126delinsT · rs876658865 · VCV230956
ClinGen expert panel — CDH1 VCEP
Pathogenic for CDH1-related diffuse gastric and lobular breast cancer. Applied ACMG criteria (verbatim):
PVS1 PM2_Supporting PS4_Supporting PM5_Supporting
Curation rationale (ClinGen, verbatim)
The c.124_126delCCCinsT (p.Pro42Serfs*16) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID 30745422). In summary, 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 (Variant Interpretation Guidelines Version 3.1): PVS1, PM2_Supporting, PS4_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 2 of 16 |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 1.3 | GERP -0.33, phastCons 1 |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Population frequency
No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.
Variant & gene context
- Gene
- CDH1
- Protein
- p.Pro42fs
- Coding
- c.124_126delinsT
- MANE Select
- NM_004360
- dbSNP
- rs876658865
- Type
- Indel
- Location
- chr16:68738372 (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.Pro42Leu Likely benign ★★★ ⚠ same residue
- CDH1 p.Pro42Ser Uncertain significance ★★ ⚠ same residue
- CDH1 p.Pro42Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
- CDH1 p.Pro42= Likely benign ★ same residue
- CDH1 p.Pro42His Likely benign ★ same residue
- CDH1 p.Asp514_Thr522delinsValTer Pathogenic/Likely pathogenic ★★ same condition
- CDH1 p.Ala137Arg Uncertain significance ★★ same condition
- CDH1 p.Asp805Ser Uncertain significance ★★ 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-pro42fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown