Is CDH1 p.Ser496= (c.1488C>T) pathogenic?

CDH1 p.Ser496= (c.1488C>T) is classified Conflicting classifications of pathogenicity in CDH1 (ClinVar, Conflicting submitters, 13 submitters; last evaluated 2026-01-14). Very rare (popmax 0.00559%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CDH1 p.Ser496= (c.1488C>T)?

CDH1 p.Ser496= (c.1488C>T) is associated with hereditary neoplastic syndrome, hereditary diffuse gastric adenocarcinoma, CDH1-related diffuse gastric and lobular breast cancer syndrome (ClinVar).

How common is CDH1 p.Ser496= (c.1488C>T) in the general population?

CDH1 p.Ser496= (c.1488C>T) is very rare (popmax 0.00559%, nfe) (gnomAD).

CDH1 p.Ser496=

c.1488C>T · rs751346548 · VCV184488

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 13 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00559%, 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 -20	GERP -3.8
Overall
CADD	0.063	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00559% European (non-Finnish) · 66/1,180,038 alleles

Filtering AF 0.00451% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00411%

Overall 0.00421% 68/1,614,044 alleles · very rare exomes 65/1,461,884 · genomes 3/152,160 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00559%	17,879
African / African-American	0.00267%	37,458

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.Ser496=
Coding: c.1488C>T
MANE Select: NM_004360
dbSNP: rs751346548
Type: single nucleotide variant
Location: chr16:68815682 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 496: 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 CDH1-related diffuse gastric and lobular breast cancer syndrome

Similar variants

CDH1 p.Ser496Ala Uncertain significance ★ ⚠ same residue
CDH1 p.Ser496Pro 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-ser496 (accessed [today's date]).

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