CDH1 p.Gly2Ser
c.4G>A · rs786201212 · VCV183998
ClinGen expert panel — CDH1 VCEP
Likely Benign for CDH1-related diffuse gastric and lobular breast cancer. Applied ACMG criteria (verbatim):
BS2
Curation rationale (ClinGen, verbatim)
The CDH1 c.4G>A (p.Gly2Ser) missense variant has a frequency of 0.00002 (2 of 128,626) in gnomAD, with a maximum allele frequency of 0.00008 (2 of 24,378) in the Latino subpopulation (http://gnomad.broadinstitute.org). This variant has been observed in ≥10 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; unpublished). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.1256 | likely benign |
|---|---|---|
| REVEL | 0.048 | moderately benign-leaning |
| SaProt | LLR -6.71 | 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 2.6 | GERP 1.1, phastCons 1 |
| Regional constraint | o/e 1.05 | unconstrained · MANE · 71 kb · p 0.52 · regional, not allelic |
| Overall | ||
| CADD | 23.1 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.00392% | 25,533 |
| African / African-American | 0.00137% | 72,822 |
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.Gly2Ser
- Coding
- c.4G>A
- MANE Select
- NM_004360
- dbSNP
- rs786201212
- Type
- single nucleotide variant
- Location
- chr16:68737419 (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.Gly2Val Uncertain significance ★★★ ⚠ same residue
- CDH1 p.Gly2Asp Uncertain significance ★★ ⚠ same residue
- CDH1 p.Gly2= Benign/Likely benign ★★ same residue
- CDH1 p.Gly2Arg Uncertain significance ★ ⚠ 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
- CDH1 c.1320+1G>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-gly2ser (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown