Is CDH1 p.Ala289Val (c.866C>T) pathogenic?

CDH1 p.Ala289Val (c.866C>T) is classified Likely benign in CDH1 (ClinVar, Expert panel, 8 submitters; last evaluated 2023-08-17). AlphaMissense: likely benign (0.1583); Very rare (popmax 0.00446%, eas); Associated with CDH1-related diffuse gastric and lobular breast cancer syndrome.

What condition is associated with CDH1 p.Ala289Val (c.866C>T)?

CDH1 p.Ala289Val (c.866C>T) is associated with CDH1-related diffuse gastric and lobular breast cancer syndrome, hereditary diffuse gastric adenocarcinoma, hereditary neoplastic syndrome (ClinVar).

How common is CDH1 p.Ala289Val (c.866C>T) in the general population?

CDH1 p.Ala289Val (c.866C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about CDH1 p.Ala289Val (c.866C>T)?

AlphaMissense predicts likely benign (score 0.1583) — an in-silico prediction, not a clinical call.

CDH1 p.Ala289Val

c.866C>T · rs780399325 · VCV216597

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.1583 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

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.866C>T (p.Ala289Val) missense variant has a frequency of 0.00002 (6 of 251,472) in gnomAD, with a maximum allele frequency of 0.00010 (3 of 30,616) in the South Asian subpopulation (http://gnomad.broadinstitute.org). This variant has been observed in ≥10 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000669016.2, SCV000254833.6). In summary, the clinical significance of this variant is classified as of likely benign based the 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	0.1583	likely benign
REVEL	0.153	moderately benign-leaning
SaProt	LLR -11.62	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 2.1	GERP 0.89, phastCons 0.97
Regional constraint	o/e 0.87	unconstrained · MANE · 25 kb · p 0.00015 · regional, not allelic
Overall
CADD	20.2	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 0.00446% East Asian · 2/44,872 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.00109% 16/1,461,882 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,436
South Asian	0.00439%	22,769
European (non-Finnish)	0.000847%	118,001

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.Ala289Val
Coding: c.866C>T
MANE Select: NM_004360
dbSNP: rs780399325
Type: single nucleotide variant
Location: chr16:68811717 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 289: the cadherin 2 domain

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

Disease context

Also linked: hereditary diffuse gastric adenocarcinoma hereditary neoplastic syndrome

Similar variants

CDH1 p.Ala289Pro Uncertain significance ★ ⚠ same residue
CDH1 p.Ala289Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
CDH1 p.Ala289= 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
CDH1 c.1565+1G>A 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-ala289val (accessed [today's date]).

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