Is CDH1 p.Ala408Val (c.1223C>T) pathogenic?

CDH1 p.Ala408Val (c.1223C>T) is classified Benign in CDH1 (ClinVar, Expert panel, 17 submitters; last evaluated 2023-08-10). AlphaMissense: ambiguous (0.5008); Ultra-rare (popmax 0.0955%, sas); Associated with CDH1-related diffuse gastric and lobular breast cancer syndrome.

What condition is associated with CDH1 p.Ala408Val (c.1223C>T)?

CDH1 p.Ala408Val (c.1223C>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.Ala408Val (c.1223C>T) in the general population?

CDH1 p.Ala408Val (c.1223C>T) is ultra-rare (popmax 0.0955%, sas) (gnomAD).

What do computational predictors say about CDH1 p.Ala408Val (c.1223C>T)?

AlphaMissense predicts ambiguous (score 0.5008) — an in-silico prediction, not a clinical call.

CDH1 p.Ala408Val

c.1223C>T · rs138135866 · VCV127908

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 17 submitters

AlphaMissense

ambiguous

0.5008 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0955%, sas)

Conditions

CDH1-related diffuse gastric and lobular breast cancer syndrome

ClinGen expert panel — CDH1 VCEP

Benign for CDH1-related diffuse gastric and lobular breast cancer. Applied ACMG criteria (verbatim):

BS2 BS1

Curation rationale (ClinGen, verbatim)

The c.1223C>T (p.Ala408Val) missense variant has a frequency of 0.114% (>0.1%) in South Asians (35 of 30616 alleles) in the gnomAD v2.1.1 cohort (BS1). This variant has been observed in ≥10 (122) individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000260430.7, SCV000186167.6). In summary, the clinical significance of this variant is classified as of benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS1, BS2.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.5008	ambiguous
REVEL	0.35	indeterminate
SaProt	LLR -13.38	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 25 kb · p 0.00015 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0955% South Asian · 87/91,080 alleles

Filtering AF 0.0793% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0733%

Overall 0.00905% 146/1,613,918 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0955%	1,047
African / African-American	0.0334%	2,996
East Asian	0.0178%	5,612
Remaining individualsnot grpmax-eligible	0.0112%	8,927
Finnishnot grpmax-eligible	0.00312%	32,005
European (non-Finnish)	0.00144%	69,410

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.Ala408Val
Coding: c.1223C>T
MANE Select: NM_004360
dbSNP: rs138135866
Type: single nucleotide variant
Location: chr16:68813398 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 408: the cadherin 3 domain; a turn

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.Ala408Glu Uncertain significance ★★ ⚠ same residue
CDH1 p.Ala408Gly Uncertain significance ★★ ⚠ same residue
CDH1 p.Ala408Pro Uncertain significance ★★ ⚠ same residue
CDH1 p.Ala408= Benign/Likely benign ★★ same residue
CDH1 p.Ala408Ser Uncertain significance ★ ⚠ same residue
CDH1 p.Ala408Thr Uncertain significance ★ ⚠ same residue
CDH1 p.Ala408fs Pathogenic ★ same residue
CDH1 c.1008+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-ala408val (accessed [today's date]).

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