Is CDH1 p.Arg224Cys (c.670C>T) pathogenic?

CDH1 p.Arg224Cys (c.670C>T) is classified Likely benign in CDH1 (ClinVar, Expert panel, 25 submitters; last evaluated 2023-08-17). AlphaMissense: likely benign (0.2082); Ultra-rare (popmax 0.0822%, mid); Associated with CDH1-related diffuse gastric and lobular breast cancer syndrome.

How common is CDH1 p.Arg224Cys (c.670C>T) in the general population?

CDH1 p.Arg224Cys (c.670C>T) is ultra-rare (popmax 0.0822%, mid) (gnomAD).

What do computational predictors say about CDH1 p.Arg224Cys (c.670C>T)?

AlphaMissense predicts likely benign (score 0.2082) — an in-silico prediction, not a clinical call.

CDH1 p.Arg224Cys

Q: What condition is associated with CDH1 p.Arg224Cys (c.670C>T)?

CDH1 p.Arg224Cys (c.670C>T) is associated with CDH1-related diffuse gastric and lobular breast cancer syndrome, endometrial carcinoma, breast cancer (ClinVar).

c.670C>T · rs200310662 · VCV127932

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 25 submitters

AlphaMissense

likely benign

0.2082 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0822%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

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.670C>T (p.Arg224Cys) 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	0.2082	likely benign
REVEL	0.207	benign-leaning
SaProt	LLR -12.93	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 -2.6	GERP -3.9
Regional constraint	o/e 0.87	unconstrained · MANE · 25 kb · p 0.00015 · regional, not allelic
Overall
CADD	11.73	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 0.0822% Middle Eastern · 5/6,082 alleles

Filtering AF 0.0436% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0423%

Overall 0.0375% 605/1,613,822 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0822%	1,216
European (non-Finnish)	0.0469%	2,134
Remaining individualsnot grpmax-eligible	0.0256%	3,904
South Asian	0.0176%	5,692
Admixed American	0.01%	9,996
African / African-American	0.00801%	12,485
Finnishnot grpmax-eligible	0.00469%	21,325

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.Arg224Cys
Coding: c.670C>T
MANE Select: NM_004360
dbSNP: rs200310662
Type: single nucleotide variant
Location: chr16:68808831 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 224: a turn; the cadherin 1 domain

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.Arg224His Benign ★★★ ⚠ same residue
CDH1 p.Arg224Ser Uncertain significance ★★ ⚠ same residue
CDH1 p.Arg224Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CDH1 p.Arg224= Likely benign ★ 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-arg224cys (accessed [today's date]).

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