Is CDH1 p.Ala455Ser (c.1363G>T) pathogenic?

CDH1 p.Ala455Ser (c.1363G>T) is classified Uncertain significance in CDH1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-05). AlphaMissense: likely benign (0.0963); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

What condition is associated with CDH1 p.Ala455Ser (c.1363G>T)?

CDH1 p.Ala455Ser (c.1363G>T) is associated with hereditary neoplastic syndrome, hereditary diffuse gastric adenocarcinoma (ClinVar).

How common is CDH1 p.Ala455Ser (c.1363G>T) in the general population?

CDH1 p.Ala455Ser (c.1363G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDH1 p.Ala455Ser (c.1363G>T)?

AlphaMissense predicts likely benign (score 0.0963) — an in-silico prediction, not a clinical call.

CDH1 p.Ala455Ser

c.1363G>T · rs876659762 · VCV232433

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0963 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0963	likely benign
REVEL	0.059	moderately benign-leaning
SaProt	LLR -4.45	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.013	GERP -3.8
Regional constraint	o/e 0.87	unconstrained · MANE · 25 kb · p 0.00015 · regional, not allelic
Overall
CADD	4.141	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.Ala455Ser
Coding: c.1363G>T
MANE Select: NM_004360
dbSNP: rs876659762
Type: single nucleotide variant
Location: chr16:68815557 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 455: the cadherin 3 domain; a β-strand

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

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary diffuse gastric adenocarcinoma

Similar variants

CDH1 p.Ala455Thr Uncertain significance ★★★ ⚠ same residue
CDH1 p.Ala455Gly Uncertain significance ★ ⚠ same residue
CDH1 p.Ala455= 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-ala455ser (accessed [today's date]).

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