Is CDH1 p.Glu336Asp (c.1008G>T) pathogenic?

CDH1 p.Glu336Asp (c.1008G>T) is classified Likely pathogenic in CDH1 (ClinVar, Expert panel, 4 submitters; last evaluated 2023-08-28). AlphaMissense: likely pathogenic (0.9209); Absent from gnomAD v4.1; Associated with CDH1-related diffuse gastric and lobular breast cancer syndrome.

What condition is associated with CDH1 p.Glu336Asp (c.1008G>T)?

CDH1 p.Glu336Asp (c.1008G>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.Glu336Asp (c.1008G>T) in the general population?

CDH1 p.Glu336Asp (c.1008G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CDH1 p.Glu336Asp (c.1008G>T)?

AlphaMissense predicts likely pathogenic (score 0.9209) — an in-silico prediction, not a clinical call.

CDH1 p.Glu336Asp

c.1008G>T · rs267606712 · VCV18453

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.9209 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

CDH1-related diffuse gastric and lobular breast cancer syndrome

ClinGen expert panel — CDH1 VCEP

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

PVS1_Moderate PM2_Supporting PS3 PS4_Moderate

Curation rationale (ClinGen, verbatim)

The c.1008G>T (p.Glu336Asp) variant results in a G to non-G change at the last nucleotide of an exon (PVS1_Moderate). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is an RNA assay demonstrating an abnormal out-of-frame transcript for this variant (PS3; PMID: 9537325). Additionally, the variant has also been reported in at least two families meeting HDGC clinical criteria (PS4_Moderate; PMID: 9537325 and internal laboratory data). In summary, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Moderate, PM2_Supporting, PS3, PS4_Moderate.

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

Computational evidence

Protein change
AlphaMissense	0.9209	likely pathogenic ✓ concordant with ClinVar
REVEL	0.625	indeterminate
SaProt	LLR -13.50	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	Δ0.91	donor loss · deltas
Pangolin	Δ0.70	loss · gain 0.14 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 25 kb · p 0.00015 · regional, not allelic
Overall
CADD	35.0	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

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.Glu336Asp
Coding: c.1008G>T
MANE Select: NM_004360
dbSNP: rs267606712
Type: single nucleotide variant
Location: chr16:68811859 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 336: the cadherin 2 domain; a turn; a UniProt-annotated variant site (in dglbc; likely pathogenic)

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.Glu336= Pathogenic ★★★ same residue
CDH1 p.Glu336Gln 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
CDH1 c.1565+1G>A Pathogenic ★★★ same condition
CDH1 c.1565+1G>C 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-glu336asp (accessed [today's date]).

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