Is CDH1 p.Cys22Ter (c.66C>A) pathogenic?

CDH1 p.Cys22Ter (c.66C>A) is classified Pathogenic in CDH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-19). Absent from gnomAD v4.1; Associated with hereditary diffuse gastric adenocarcinoma.

What condition is associated with CDH1 p.Cys22Ter (c.66C>A)?

CDH1 p.Cys22Ter (c.66C>A) is associated with hereditary diffuse gastric adenocarcinoma (ClinVar).

How common is CDH1 p.Cys22Ter (c.66C>A) in the general population?

CDH1 p.Cys22Ter (c.66C>A) is absent from gnomAD v4.1 (gnomAD).

How is Hereditary diffuse gastric cancer inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

CDH1 p.Cys22Ter

c.66C>A · rs865838543 · VCV1456385

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

hereditary diffuse gastric adenocarcinoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 2 of 16
Splicing
SpliceAI	Δ0.45	acceptor gain · deltas
Pangolin	Δ0.23	gain · loss 0.06 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 1.6	GERP -0.036, phastCons 1
Overall
CADD	37.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CDH1
Protein: p.Cys22Ter
Coding: c.66C>A
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 diffuse gastric adenocarcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary diffuse gastric cancer (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult
Prevalence: 1-9 / 100 000 (Europe)

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.Cys22= Benign/Likely benign ★★ 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-cys22ter (accessed [today's date]).

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