Is CDH1 p.Cys686fs (c.2054dup) pathogenic?

CDH1 p.Cys686fs (c.2054dup) is classified Pathogenic in CDH1 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-09). Absent from gnomAD; Associated with hereditary diffuse gastric adenocarcinoma.

What condition is associated with CDH1 p.Cys686fs (c.2054dup)?

CDH1 p.Cys686fs (c.2054dup) is associated with hereditary diffuse gastric adenocarcinoma (ClinVar).

How common is CDH1 p.Cys686fs (c.2054dup) in the general population?

CDH1 p.Cys686fs (c.2054dup) is absent from gnomAD (gnomAD).

How is Hereditary diffuse gastric cancer inherited?

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

CDH1 p.Cys686fs

c.2054dup · rs2152139452 · VCV1455457

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

hereditary diffuse gastric adenocarcinoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 13 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.5	GERP 1.9, phastCons 1

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: CDH1
Protein: p.Cys686fs
Coding: c.2054dup
MANE Select: NM_004360
dbSNP: rs2152139452
Type: Duplication
Location: chr16:68823515 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 686: the cadherin 5 domain; a β-strand

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.Cys686Arg Uncertain significance ★ ⚠ same residue
CDH1 c.1565+2dup Pathogenic ★★★ same condition
CDH1 p.Ala530fs Pathogenic ★★★ same condition
CDH1 p.Arg796fs Likely pathogenic ★★★ same condition
CDH1 p.Asn174fs Pathogenic ★★★ same condition
CDH1 p.Asn531fs Pathogenic ★★★ same condition
CDH1 p.Gln677fs Pathogenic ★★★ same condition
CDH1 p.His121fs 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-cys686fs (accessed [today's date]).

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