CDH1 p.Ala843fs
c.2526del · rs1961538047 · VCV981224
ClinGen expert panel — CDH1 VCEP
Uncertain Significance for CDH1-related diffuse gastric and lobular breast cancer. Applied ACMG criteria (verbatim):
PVS1_Moderate PM2_Supporting PS4_Supporting
Curation rationale (ClinGen, verbatim)
The c.2526del (p.Ala843LeufsTer3) variant results in a premature stop codon that leads to a truncated protein. It is located within the nonsense mediated decay resistant zone, and downstream of codon 836 where the most 3' pathogenic variant in CDH1 terminates (PVS1_Moderate, PMID: 29798843). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). One family meets the HDGC criteria (PS4_Supporting; Internal lab contributor). In summary, the clinical significance of this variant is uncertain based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Moderate, PM2_Supporting, PS4_Supporting. This VUS variant is trending to the pathogenic side. The CDH1 VCEP will re-evaluate it, if more evidence emerge in the future.
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 6 | GERP 1.9, 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.Ala843fs
- Coding
- c.2526del
- MANE Select
- NM_004360
- dbSNP
- rs1961538047
- Type
- Deletion
- Location
- chr16:68833376 (GRCh38)
- Gene constraint
- LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 79.13 · 22 PDB
- Residue 843
- the 'required for binding alpha, beta and gamma catenins' region
Similar variants
- CDH1 c.1137+1del Pathogenic ★★★ same condition
- CDH1 c.1565+1del Likely pathogenic ★★★ same condition
- CDH1 c.1711+2_1711+7del Likely pathogenic ★★★ same condition
- CDH1 p.Ala546fs Pathogenic ★★★ same condition
- CDH1 p.Arg800fs Pathogenic ★★★ same condition
- CDH1 p.Asn369fs Pathogenic ★★★ same condition
- CDH1 p.Asn390fs Pathogenic ★★★ same condition
- CDH1 p.Asn481fs 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-ala843fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown