Is CDH1 p.Glu504= (c.1512A>G) pathogenic?

CDH1 p.Glu504= (c.1512A>G) is classified Conflicting classifications of pathogenicity in CDH1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2022-08-01). Very rare (popmax 0.000254%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CDH1 p.Glu504= (c.1512A>G)?

CDH1 p.Glu504= (c.1512A>G) is associated with hereditary neoplastic syndrome, hereditary diffuse gastric adenocarcinoma (ClinVar).

How common is CDH1 p.Glu504= (c.1512A>G) in the general population?

CDH1 p.Glu504= (c.1512A>G) is very rare (popmax 0.000254%, nfe) (gnomAD).

CDH1 p.Glu504=

c.1512A>G · rs748906857 · VCV819429

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.91	GERP -3.5, phastCons 0.98
Overall
CADD	8.032	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,180,058 alleles

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

Overall 0.000205% 3/1,461,892 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.Glu504=
Coding: c.1512A>G
MANE Select: NM_004360
dbSNP: rs748906857
Type: single nucleotide variant
Location: chr16:68815706 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 504: the cadherin 4 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.Glu504Lys Conflicting classifications of pathogenicity ★ ⚠ 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
CDH1 c.1565+1G>T 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-glu504 (accessed [today's date]).

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