CDH1 p.Pro30Thr
c.88C>A · rs139866691 · VCV127933
ClinGen expert panel — CDH1 VCEP
Benign for CDH1-related diffuse gastric and lobular breast cancer. Applied ACMG criteria (verbatim):
BS2 BA1
Curation rationale (ClinGen, verbatim)
The c.88C>A (p.Pro30Thr) variant has an allele frequency of 0.00249 (0.25%, 178/71372 alleles) in the European (non-Finnish) subpopulation of the gnomAD cohort (BA1). In addition to meeting stand along criteria for a benign classification, this variant has also been seen in >900 individuals 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): BA1, BS2.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.147 | likely benign |
|---|---|---|
| REVEL | 0.586 | indeterminate |
| SaProt | LLR -11.23 | damaging |
| ⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 1.4 | GERP -0.039, phastCons 0.63 |
| Regional constraint | o/e 1.05 | unconstrained · MANE · 71 kb · p 0.52 · regional, not allelic |
| Overall | ||
| CADD | 20.5 | 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 |
|---|---|---|
| European (non-Finnish)grpmax | 0.257% | 389 |
| Remaining individualsnot grpmax-eligible | 0.163% | 613 |
| Admixed American | 0.106% | 943 |
| South Asian | 0.0486% | 2,059 |
| Finnishnot grpmax-eligible | 0.0389% | 2,569 |
| African / African-American | 0.026% | 3,847 |
| Ashkenazi Jewishnot grpmax-eligible | 0.00354% | 28,278 |
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.Pro30Thr
- Coding
- c.88C>A
- MANE Select
- NM_004360
- dbSNP
- rs139866691
- Type
- single nucleotide variant
- Location
- chr16:68738336 (GRCh38)
- Gene constraint
- LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 79.13 · 22 PDB
Disease context
CDH1-related diffuse gastric and lobular breast cancer syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: orofacial cleftendometrial carcinomahereditary diffuse gastric adenocarcinomaprostate cancerhereditary neoplastic syndromehereditary breast carcinomaovarian neoplasmblepharocheilodontic syndrome 1
Similar variants
- CDH1 p.Pro30Arg Uncertain significance ★★ ⚠ same residue
- CDH1 p.Pro30Ser Uncertain significance ★★ ⚠ same residue
- CDH1 p.Pro30= Likely benign ★ same residue
- CDH1 p.Pro30fs Pathogenic ★ 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-pro30thr (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown