Is CDH1 p.Cys22= (c.66C>T) pathogenic?

CDH1 p.Cys22= (c.66C>T) is classified Benign/Likely benign in CDH1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-05-05). Very rare (popmax 0.00196%, amr); Associated with hereditary neoplastic syndrome.

What condition is associated with CDH1 p.Cys22= (c.66C>T)?

CDH1 p.Cys22= (c.66C>T) is associated with hereditary neoplastic syndrome, hereditary diffuse gastric adenocarcinoma (ClinVar).

How common is CDH1 p.Cys22= (c.66C>T) in the general population?

CDH1 p.Cys22= (c.66C>T) is very rare (popmax 0.00196%, amr) (gnomAD).

CDH1 p.Cys22=

c.66C>T · rs865838543 · VCV232158

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00196%, amr)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.45 · evaluated, not missing
Constraint at this position
Conservation	phyloP 1.6	GERP -0.036, phastCons 1
Overall
CADD	12.65	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00196% Admixed American · 1/50,996 alleles

Overall 6.45e-05% 1/1,550,642 alleles · very rare exomes 1/1,398,352 · genomes 0/152,290 · joint denominator

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.Cys22=
Coding: c.66C>T
MANE Select: NM_004360
dbSNP: rs865838543
Type: single nucleotide variant
Location: chr16:68738314 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB

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.Cys22Phe Uncertain significance ★★ ⚠ same residue
CDH1 p.Cys22Trp Uncertain significance ★★ ⚠ same residue
CDH1 p.Cys22Tyr Uncertain significance ★★ ⚠ same residue
CDH1 p.Cys22Ter Pathogenic ★ same residue
CDH1 p.Cys22fs Pathogenic ★ 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

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-cys22 (accessed [today's date]).

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