Is CDH1 p.Glu463Ala (c.1388A>C) pathogenic?

CDH1 p.Glu463Ala (c.1388A>C) is classified Uncertain significance in CDH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-04-28). AlphaMissense: likely benign (0.0982); Absent from gnomAD v4.1; Associated with Breast and/or ovarian cancer.

What condition is associated with CDH1 p.Glu463Ala (c.1388A>C)?

CDH1 p.Glu463Ala (c.1388A>C) is associated with Breast and/or ovarian cancer (ClinVar).

How common is CDH1 p.Glu463Ala (c.1388A>C) in the general population?

CDH1 p.Glu463Ala (c.1388A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDH1 p.Glu463Ala (c.1388A>C)?

AlphaMissense predicts likely benign (score 0.0982) — an in-silico prediction, not a clinical call.

CDH1 p.Glu463Ala

c.1388A>C · rs2152134806 · VCV1329260

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0982 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Breast and/or ovarian cancer

Computational evidence

Protein change
AlphaMissense	0.0982	likely benign
REVEL	0.066	moderately benign-leaning
SaProt	LLR -4.88	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.29 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.014	GERP -3.8
Regional constraint	o/e 0.87	unconstrained · MANE · 25 kb · p 0.00015 · regional, not allelic
Overall
CADD	5.573	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDH1
Protein: p.Glu463Ala
Coding: c.1388A>C
MANE Select: NM_004360
dbSNP: rs2152134806
Type: single nucleotide variant
Location: chr16:68815582 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 463: the cadherin 3 domain; a UniProt-annotated variant site (in a gastric carcinoma sample)

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

Disease context

Breast and/or ovarian cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

CDH1 p.Glu463Lys Uncertain significance ★★ ⚠ same residue
CDH1 p.Glu463= Likely benign ★ same residue
CDH1 p.Ile192Val Uncertain significance ★★ ⚠ same condition
CDH1 p.Val475Ala Uncertain significance ★★ ⚠ same condition
CDH1 c.532-18C>T Benign/Likely benign ★★ same condition
CDH1 c.833-17T>C Likely benign ★★ same condition
CDH1 p.Ala234= Likely benign ★★ same condition
CDH1 p.Ala408= Benign/Likely benign ★★ 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-glu463ala (accessed [today's date]).

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