Is CDH1 p.Glu659= (c.1977G>A) pathogenic?

CDH1 p.Glu659= (c.1977G>A) is classified Benign/Likely benign in CDH1 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2026-01-07). Very rare (popmax 0.00153%, nfe); Associated with CDH1-related diffuse gastric and lobular breast cancer syndrome.

What condition is associated with CDH1 p.Glu659= (c.1977G>A)?

CDH1 p.Glu659= (c.1977G>A) 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.Glu659= (c.1977G>A) in the general population?

CDH1 p.Glu659= (c.1977G>A) is very rare (popmax 0.00153%, nfe) (gnomAD).

CDH1 p.Glu659=

c.1977G>A · rs368243190 · VCV184595

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00153%, nfe)

Conditions

CDH1-related diffuse gastric and lobular breast cancer 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 0.33	GERP 0.94, phastCons 0.004
Overall
CADD	7.131	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00153% European (non-Finnish) · 18/1,179,958 alleles

Filtering AF 0.000953% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.00112% 18/1,613,862 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.Glu659=
Coding: c.1977G>A
MANE Select: NM_004360
dbSNP: rs368243190
Type: single nucleotide variant
Location: chr16:68823439 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 659: the cadherin 5 domain

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.Glu659Gly Uncertain significance ★★ ⚠ same residue
CDH1 p.Glu659Asp Likely benign ★ same residue
CDH1 p.Glu659del Uncertain significance ★ same residue
CDH1 p.Glu659Gln 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

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-glu659 (accessed [today's date]).

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