Is CDH1 p.Cys163Ser (c.488G>C) pathogenic?

CDH1 p.Cys163Ser (c.488G>C) is classified Conflicting classifications of pathogenicity in CDH1 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-01-24). AlphaMissense: likely pathogenic (0.819); Ultra-rare (popmax 0.0604%, sas); Associated with blepharocheilodontic syndrome 1.

What condition is associated with CDH1 p.Cys163Ser (c.488G>C)?

CDH1 p.Cys163Ser (c.488G>C) is associated with blepharocheilodontic syndrome 1, endometrial carcinoma, hereditary diffuse gastric adenocarcinoma (ClinVar).

How common is CDH1 p.Cys163Ser (c.488G>C) in the general population?

CDH1 p.Cys163Ser (c.488G>C) is ultra-rare (popmax 0.0604%, sas) (gnomAD).

What do computational predictors say about CDH1 p.Cys163Ser (c.488G>C)?

AlphaMissense predicts likely pathogenic (score 0.819) — an in-silico prediction, not a clinical call.

CDH1 p.Cys163Ser

c.488G>C · rs748783182 · VCV239907

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

AlphaMissense

likely pathogenic

0.819 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0604%, sas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

blepharocheilodontic syndrome 1

Computational evidence

Protein change
AlphaMissense	0.819	likely pathogenic
REVEL	0.245	benign-leaning
SaProt	LLR -8.32	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.9, phastCons 1
Regional constraint	o/e 0.43	unconstrained · MANE · 256 bp · p 5.4e-05 · regional, not allelic
Overall
CADD	26.2	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

Grpmax group 0.0604% South Asian · 55/91,076 alleles

Filtering AF 0.0476% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.043%

Overall 0.00366% 59/1,613,986 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0604%	1,656
Middle Eastern	0.0329%	3,041
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	8.47e-05%	1,180,025

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.Cys163Ser
Coding: c.488G>C
MANE Select: NM_004360
dbSNP: rs748783182
Type: single nucleotide variant
Location: chr16:68808524 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 163: a β-strand; a disulfide bond; the cadherin 1 domain

Full CDH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

blepharocheilodontic syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: endometrial carcinoma hereditary diffuse gastric adenocarcinoma ovarian cancer hereditary neoplastic syndrome hereditary breast carcinoma CDH1-related diffuse gastric and lobular breast cancer syndrome

Similar variants

CDH1 p.Cys163Ter Pathogenic ★★★ same residue
CDH1 p.Cys163Arg Uncertain significance ★★ ⚠ same residue
CDH1 p.Cys163Trp Uncertain significance ★★ ⚠ same residue
CDH1 p.Cys163Tyr Uncertain significance ★★ ⚠ same residue
CDH1 p.Cys163= Benign/Likely benign ★★ same residue
CDH1 p.Cys163Gly Uncertain significance ★ ⚠ same residue
CDH1 p.Cys163Phe Uncertain significance ★ ⚠ same residue
CDH1 p.Cys163fs Pathogenic ★ same residue

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-cys163ser (accessed [today's date]).

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