Is CDH1 p.Ser840= (c.2520C>T) pathogenic?

CDH1 p.Ser840= (c.2520C>T) is classified Benign/Likely benign in CDH1 (ClinVar, Multiple submitters, 24 submitters; last evaluated 2026-04-01). Rare (popmax 0.131%, afr); Associated with Breast and/or ovarian cancer.

What condition is associated with CDH1 p.Ser840= (c.2520C>T)?

CDH1 p.Ser840= (c.2520C>T) is associated with Breast and/or ovarian cancer, hereditary diffuse gastric adenocarcinoma, hereditary neoplastic syndrome (ClinVar).

How common is CDH1 p.Ser840= (c.2520C>T) in the general population?

CDH1 p.Ser840= (c.2520C>T) is rare (popmax 0.131%, afr) (gnomAD).

CDH1 p.Ser840=

c.2520C>T · rs140328601 · VCV182386

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 24 submitters

gnomAD v4.1

Rare

rare (popmax 0.131%, afr)

Conditions

Breast and/or ovarian cancer

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 -20	GERP -3.9
Overall
CADD	3.343	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.131% African / African-American · 98/75,040 alleles

Filtering AF 0.11% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.102%

Overall 0.026% 419/1,614,166 alleles · rare exomes 327/1,461,888 · genomes 92/152,278 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.131%	766
Amishnot grpmax-eligible	0.11%	912
Admixed American	0.105%	952
Middle Eastern	0.0825%	1,212
Remaining individualsnot grpmax-eligible	0.0704%	1,421
European (non-Finnish)	0.0174%	5,756
South Asian	0.00329%	30,359

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.Ser840=
Coding: c.2520C>T
MANE Select: NM_004360
dbSNP: rs140328601
Type: single nucleotide variant
Location: chr16:68833370 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 840: the 'required for binding alpha, beta and gamma catenins' region; a modified residue (phosphoserine)

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

Also linked: hereditary diffuse gastric adenocarcinoma hereditary neoplastic syndrome

Similar variants

CDH1 p.Ser840Phe Uncertain significance ★★ ⚠ same residue
CDH1 p.Ser840Pro Uncertain significance ★★ ⚠ same residue
CDH1 p.Ser840Cys 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

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-ser840 (accessed [today's date]).

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