Is CDH1 p.Ala843Asp (c.2528C>A) pathogenic?

CDH1 p.Ala843Asp (c.2528C>A) is classified Uncertain significance in CDH1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-02). AlphaMissense: ambiguous (0.5256); Very rare (popmax 0.000254%, nfe); Associated with hereditary diffuse gastric adenocarcinoma.

What condition is associated with CDH1 p.Ala843Asp (c.2528C>A)?

CDH1 p.Ala843Asp (c.2528C>A) is associated with hereditary diffuse gastric adenocarcinoma, hereditary neoplastic syndrome (ClinVar).

How common is CDH1 p.Ala843Asp (c.2528C>A) in the general population?

CDH1 p.Ala843Asp (c.2528C>A) is very rare (popmax 0.000254%, 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.Ala843Asp (c.2528C>A)?

AlphaMissense predicts ambiguous (score 0.5256) — an in-silico prediction, not a clinical call.

CDH1 p.Ala843Asp

c.2528C>A · VCV3488693

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5256 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

hereditary diffuse gastric adenocarcinoma

Computational evidence

Protein change
AlphaMissense	0.5256	ambiguous
REVEL	0.386	indeterminate
SaProt	LLR -7.82	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 25 kb · p 0.00015 · regional, not allelic
Overall
CADD	25.7	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 0.000254% European (non-Finnish) · 3/1,179,986 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,834 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.Ala843Asp
Coding: c.2528C>A
MANE Select: NM_004360
Type: single nucleotide variant
Location: chr16:68833378 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 843: the 'required for binding alpha, beta and gamma catenins' region

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

Also linked: hereditary neoplastic syndrome

For Hereditary diffuse gastric cancer (Orphanet):

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

Similar variants

CDH1 p.Ala843Thr Uncertain significance ★★ ⚠ same residue
CDH1 p.Ala843Gly Uncertain significance ★ ⚠ same residue
CDH1 p.Ala843= 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-ala843asp (accessed [today's date]).

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