CDH1 p.Thr560Arg
c.1679C>G · rs746481984 · VCV234554
ClinGen expert panel — CDH1 VCEP
Pathogenic for CDH1-related diffuse gastric and lobular breast cancer. Applied ACMG criteria (verbatim):
PP1_Strong PM2_Supporting PS3 PS4 PP3
Curation rationale (ClinGen, verbatim)
The c.1679C>G (p.Thr560Arg) variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There are at least 3 in silico predictors in agreement that this variant affects splicing (PP3). There is also an RNA assay demonstrating abnormal out-of-frame transcript (PS3; PMID: 27880784). Additionally, the variant was found to co-segregation with disease in multiple affected family members, with >7 meioses observed across at least 4 families (PP1_Strong; PMID: 27880784, 29769627). This variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID: 27880784, 29769627, 23709761 and SCV000580704.2). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, PP3, PS3, PP1_Strong, PS4.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.1382 | likely benign ⚠ discordant with ClinVar |
|---|---|---|
| REVEL | 0.199 | benign-leaning |
| SaProt | LLR -12.38 | damaging |
| ⇒ SaProt calls this damaging; AlphaMissense and REVEL do not. | ||
| Splicing | ||
| SpliceAI | Δ0.98 | donor gain · deltas |
| Pangolin | Δ0.71 | gain · loss 0.40 · agrees with SpliceAI · independent |
| Constraint at this position | ||
| Conservation | phyloP 4 | GERP 0.9, phastCons 1 |
| Regional constraint | o/e 0.87 | unconstrained · MANE · 25 kb · p 0.00015 · regional, not allelic |
| Overall | ||
| CADD | 29.9 | PHRED · no single calibrated threshold — expert panels disagree |
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.Thr560Arg
- Coding
- c.1679C>G
- MANE Select
- NM_004360
- dbSNP
- rs746481984
- Type
- single nucleotide variant
- Location
- chr16:68819393 (GRCh38)
- Gene constraint
- LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 79.13 · 22 PDB
- Residue 560
- the cadherin 4 domain; a β-strand
Similar variants
- CDH1 p.Thr560Met Uncertain significance ★★ ⚠ same residue
- CDH1 p.Thr560= Benign/Likely benign ★★ same residue
- CDH1 p.Thr560Lys Uncertain significance ★ ⚠ same residue
- CDH1 p.Thr560fs 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-thr560arg (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown