CDH1 p.Arg63Gln
c.188G>A · rs587780117 · VCV127919
ClinGen expert panel — CDH1 VCEP
Benign for CDH1-related diffuse gastric and lobular breast cancer. Applied ACMG criteria (verbatim):
BS2 BS1
Curation rationale (ClinGen, verbatim)
The c.188G>A (p.Arg63Gln) variant has an allele frequency of 0.00109 (0.11%, 6/5486 alleles) in the “Other” subpopulation of the gnomAD cohort (BS1). This variant has also been observed in >10 without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS1, BS2.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.0823 | likely benign |
|---|---|---|
| REVEL | 0.053 | moderately benign-leaning |
| SaProt | LLR -7.33 | 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 0.42 | GERP -2.1 |
| Regional constraint | o/e 1.05 | unconstrained · MANE · 71 kb · p 0.52 · regional, not allelic |
| Overall | ||
| CADD | 5.898 | 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 |
|---|---|---|
| Middle Easterngrpmax | 0.181% | 553 |
| South Asian | 0.0187% | 5,357 |
| Remaining individualsnot grpmax-eligible | 0.008% | 12,496 |
| African / African-American | 0.00401% | 24,965 |
| European (non-Finnish) | 0.0022% | 45,384 |
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.Arg63Gln
- Coding
- c.188G>A
- MANE Select
- NM_004360
- dbSNP
- rs587780117
- Type
- single nucleotide variant
- Location
- chr16:68801694 (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.Arg63Ter Pathogenic ★★★ same residue
- CDH1 p.Arg63Gly Uncertain significance ★★ ⚠ same residue
- CDH1 p.Arg63= Benign/Likely benign ★★ same residue
- CDH1 p.Arg63Pro Uncertain significance ★ ⚠ same residue
- CDH1 p.Arg63Leu 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
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-arg63gln (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown