Is CDH1 p.Ala617fs (c.1849_1856del) pathogenic?

CDH1 p.Ala617fs (c.18491856del) is classified Pathogenic in CDH1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-11). Absent from gnomAD; Associated with hereditary diffuse gastric adenocarcinoma.

What condition is associated with CDH1 p.Ala617fs (c.1849_1856del)?

CDH1 p.Ala617fs (c.1849_1856del) is associated with hereditary diffuse gastric adenocarcinoma, hereditary neoplastic syndrome (ClinVar).

How common is CDH1 p.Ala617fs (c.1849_1856del) in the general population?

CDH1 p.Ala617fs (c.1849_1856del) 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.Ala617fs

c.1849_1856del · rs2152138436 · VCV1455269

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

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 12 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 11	GERP 1.8, 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.Ala617fs
Coding: c.1849_1856del
MANE Select: NM_004360
dbSNP: rs2152138436
Type: Deletion
Location: chr16:68822137 (GRCh38)
Gene constraint: LOEUF 0.514 · pLI 0.86 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 79.13 · 22 PDB
Residue 617: the cadherin 5 domain; a UniProt-annotated variant site (detected in an endometrial cancer sample; loss of heterozygosity; cells exhibited an intermediate phenotype concerning aggregation invasiveness and migration in vitro compared to cells transfected with wild-type sequence)

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

Also linked: hereditary neoplastic syndrome

For Hereditary diffuse gastric cancer (Orphanet):

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

Similar variants

CDH1 p.Ala617Thr Benign ★★★ ⚠ same residue
CDH1 p.Ala617Ser Uncertain significance ★★ ⚠ same residue
CDH1 p.Ala617Arg Uncertain significance ★ same residue
CDH1 p.Ala617Gly Conflicting classifications of pathogenicity ★ ⚠ same residue
CDH1 p.Ala617Val Conflicting classifications of pathogenicity ★ ⚠ same residue
CDH1 p.Ala617= Likely benign ★ same residue
CDH1 c.1137+1del Pathogenic ★★★ same condition
CDH1 c.1565+1del 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-ala617fs (accessed [today's date]).

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