CDH1 p.Thr38Pro
c.112A>C · rs786203442 · VCV489846
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.112A>C (NM_004360.5) variant in CDH1 is a missense variant predicted to cause substitution in exon 2 (p.Thr38Pro). This variant was observed in seven individuals with no DGC, LBC or SRC tumours and whose families do not suggest HDGC (BS2_Supporting; Invitae). Note that this includes two individuals with a family history of stomach cancer NOS. This variant is absent from gnomAD 2.1.1 (PM2_Spporting). In summary, this variant is classified as uncertain significance for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: PM2_Supporting, BS2_supporting. (CDH1 VCEP specifications version 3.1; 04/24/2023)
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.1537 | likely benign |
|---|---|---|
| REVEL | 0.273 | benign-leaning |
| SaProt | LLR -13.46 | damaging |
| ⇒ SaProt calls this damaging; AlphaMissense and REVEL do not. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 2 | GERP 0.79, phastCons 0.96 |
| Regional constraint | o/e 1.05 | unconstrained · MANE · 71 kb · p 0.52 · regional, not allelic |
| Overall | ||
| CADD | 21.8 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- CDH1
- Protein
- p.Thr38Pro
- Coding
- c.112A>C
- MANE Select
- NM_004360
- dbSNP
- rs786203442
- Type
- single nucleotide variant
- Location
- chr16:68738360 (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.Thr38Lys Likely benign ★★★ ⚠ same residue
- CDH1 p.Thr38Met Likely benign ★★★ ⚠ same residue
- CDH1 p.Thr38= Benign/Likely benign ★★ same residue
- CDH1 p.Thr38Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
- CDH1 p.Thr38Arg Conflicting classifications of pathogenicity ★ ⚠ 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-thr38pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown