Is DSG2 p.Ala753fs (c.2257dup) pathogenic?

DSG2 p.Ala753fs (c.2257dup) is classified Uncertain significance in DSG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-02). Associated with cardiomyopathy.

What condition is associated with DSG2 p.Ala753fs (c.2257dup)?

DSG2 p.Ala753fs (c.2257dup) is associated with cardiomyopathy (ClinVar).

DSG2 p.Ala753fs

c.2257dup · VCV4757010

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

cardiomyopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function
NMD	predicted	premature termination codon in exon 14 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -8

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

Variant & gene context

Gene: DSG2
Protein: p.Ala753fs
Coding: c.2257dup
MANE Select: NM_001943
Type: Duplication
Location: chr18:31542771 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB
Residue 753: a UniProt-annotated variant site (in arvd10; uncertain significance; evidence of residual myocardium, fibrous tissue, fatty tissue, dysmetric and dysmorphic nuclei and prominent cytoplasmic vacuolization; decreases the number of desmosomes at intercalated disks also increases desmosome gap; smaller intercellular gaps, with repeating couplings, abnormally located desmosomes and pale internal plaques); a UniProt-annotated variant site (in arvd10; uncertain significance)

Full DSG2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DSG2 p.Ala753Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
DSG2 p.Pro958delinsGlnGlnLysLeuProMetSerGlnGlyProLeuCysHisGlnProLeuTer Uncertain significance ★★ same condition
DSG2 p.Thr1056fs Uncertain significance ★★ same condition
DSG2 c.2335-12_2335-8dup Likely benign ★★ same condition
DSG2 c.523+24dup Benign/Likely benign ★★ same condition
DSG2 c.523+2dup Uncertain significance ★ same condition
DSG2 p.Arg755_Asp756dup Uncertain significance ★ same condition
DSG2 p.Asp118fs Uncertain significance ★ 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/dsg2-p-ala753fs (accessed [today's date]).

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