CDH1 p.Glu35Asp
c.105G>C · rs876660131 · VCV422466
ClinGen expert panel — CDH1 VCEP
Uncertain Significance for CDH1-related diffuse gastric and lobular breast cancer. Applied ACMG criteria (verbatim):
PM2_Supporting BS2_Supporting
Curation rationale (ClinGen, verbatim)
The c.105G>C (NM_004360.5) variant in CDH1 is a missense variant predicted to predicted to cause substitution of Glu by Asp at amino acid 35 (p.Glu35Asp). This variant has been observed in more than 3 heterozygous individuals without GC, DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2_Supporting; Ambry, GeneDx, Invitae). This variant is absent from gnomAD 2.1.1 (PM2_Supporting). In summary, this variant meets the criteria to be classified as uncertain significance for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP (CDH1 VCEP specifications version 3.1): PM2_Supporting, BS2_Supporting.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.0926 | likely benign |
|---|---|---|
| REVEL | 0.018 | moderately benign-leaning |
| SaProt | LLR -6.80 | tolerated |
| ⇒ AlphaMissense, REVEL and SaProt all call this tolerated. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 0.94 | GERP -1.4, phastCons 1 |
| Regional constraint | o/e 1.05 | unconstrained · MANE · 71 kb · p 0.52 · regional, not allelic |
| Overall | ||
| CADD | 12.26 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
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.Glu35Asp
- Coding
- c.105G>C
- MANE Select
- NM_004360
- dbSNP
- rs876660131
- Type
- single nucleotide variant
- Location
- chr16:68738353 (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.Glu35Ter Pathogenic/Likely pathogenic ★★ same residue
- CDH1 p.Glu35Ala Uncertain significance ★ ⚠ same residue
- CDH1 p.Glu35Gln Uncertain significance ★ ⚠ same residue
- CDH1 p.Glu35Lys Conflicting classifications of pathogenicity ★ ⚠ same residue
- CDH1 p.Glu35= 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
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-glu35asp (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown