Is CDH1 p.Asp155Ala (c.464A>C) pathogenic?

CDH1 p.Asp155Ala (c.464A>C) is classified Uncertain significance in CDH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-26). AlphaMissense: likely pathogenic (0.6811); Very rare (popmax 0.000424%, nfe); Associated with hereditary diffuse gastric adenocarcinoma.

What condition is associated with CDH1 p.Asp155Ala (c.464A>C)?

CDH1 p.Asp155Ala (c.464A>C) is associated with hereditary diffuse gastric adenocarcinoma (ClinVar).

How common is CDH1 p.Asp155Ala (c.464A>C) in the general population?

CDH1 p.Asp155Ala (c.464A>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

How is Hereditary diffuse gastric cancer inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about CDH1 p.Asp155Ala (c.464A>C)?

AlphaMissense predicts likely pathogenic (score 0.6811) — an in-silico prediction, not a clinical call.

CDH1 p.Asp155Ala

c.464A>C · VCV4804540

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6811 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary diffuse gastric adenocarcinoma

Computational evidence

Protein change
AlphaMissense	0.6811	likely pathogenic
REVEL	0.401	indeterminate
SaProt	LLR -8.22	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 1.9, phastCons 1
Regional constraint	o/e 0.43	unconstrained · MANE · 256 bp · p 5.4e-05 · regional, not allelic
Overall
CADD	26.4	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 0.000424% European (non-Finnish) · 5/1,180,008 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000342% 5/1,461,868 alleles · very rare

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.Asp155Ala
Coding: c.464A>C
MANE Select: NM_004360
Type: single nucleotide variant
Location: chr16:68808500 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 155: the cadherin 1 domain

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

Disease context

hereditary diffuse gastric adenocarcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary diffuse gastric cancer (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

Similar variants

CDH1 p.Asp155Glu Uncertain significance ★★ ⚠ same residue
CDH1 p.Asp155= Benign/Likely benign ★★ same residue
CDH1 p.Asp155Gly Uncertain significance ★ ⚠ same residue
CDH1 p.Asp155His Uncertain significance ★ ⚠ 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-asp155ala (accessed [today's date]).

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