Is CDH1 p.Trp409Arg (c.1225T>C) pathogenic?

CDH1 p.Trp409Arg (c.1225T>C) is classified Likely benign in CDH1 (ClinVar, Expert panel, 13 submitters; last evaluated 2023-08-17). AlphaMissense: likely pathogenic (0.9613); Very rare (popmax 0.00161%, nfe); Associated with CDH1-related diffuse gastric and lobular breast cancer syndrome.

How common is CDH1 p.Trp409Arg (c.1225T>C) in the general population?

CDH1 p.Trp409Arg (c.1225T>C) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about CDH1 p.Trp409Arg (c.1225T>C)?

AlphaMissense predicts likely pathogenic (score 0.9613) — an in-silico prediction, not a clinical call.

CDH1 p.Trp409Arg

Q: What condition is associated with CDH1 p.Trp409Arg (c.1225T>C)?

CDH1 p.Trp409Arg (c.1225T>C) is associated with CDH1-related diffuse gastric and lobular breast cancer syndrome, endometrial carcinoma, breast cancer (ClinVar).

c.1225T>C · rs587778176 · VCV133855

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 13 submitters

AlphaMissense

likely pathogenic

0.9613 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CDH1-related diffuse gastric and lobular breast cancer syndrome

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 c.1225T>C (p. Trp409Arg) variant has been observed in >10 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, 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	0.9613	likely pathogenic · top 10% in CDH1
REVEL	0.556	indeterminate
SaProt	LLR -10.58	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 25 kb · p 0.00015 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00161% European (non-Finnish) · 19/1,180,016 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00083%

Overall 0.0013% 21/1,613,930 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0032%	31,241
European (non-Finnish)grpmax	0.00161%	62,106

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Trp409Arg
Coding: c.1225T>C
MANE Select: NM_004360
dbSNP: rs587778176
Type: single nucleotide variant
Location: chr16:68813400 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 409: the cadherin 3 domain; a turn

Full CDH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Also linked: endometrial carcinoma breast cancer hereditary diffuse gastric adenocarcinoma prostate cancer hereditary neoplastic syndrome hereditary breast carcinoma ovarian neoplasm blepharocheilodontic syndrome 1

Similar variants

CDH1 p.Trp409Ter 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
CDH1 c.1565+1G>A Pathogenic ★★★ same condition
CDH1 c.1565+1G>C Pathogenic ★★★ same condition
CDH1 c.1565+1G>T 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-trp409arg (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown