Is DSG2 p.Cys496fs (c.1487dup) pathogenic?

DSG2 p.Cys496fs (c.1487dup) is classified Conflicting classifications of pathogenicity in DSG2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-07-14). Very rare (popmax 0.000169%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with DSG2 p.Cys496fs (c.1487dup)?

DSG2 p.Cys496fs (c.1487dup) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic right ventricular dysplasia 10 (ClinVar).

How common is DSG2 p.Cys496fs (c.1487dup) in the general population?

DSG2 p.Cys496fs (c.1487dup) is very rare (popmax 0.000169%, nfe) (gnomAD).

DSG2 p.Cys496fs

c.1487dup · rs730880347 · VCV178852

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

Cardiovascular phenotype

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 11 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.8	GERP 1.8, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,034 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,878 alleles · very rare

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: DSG2
Protein: p.Cys496fs
Coding: c.1487dup
MANE Select: NM_001943
dbSNP: rs730880347
Type: Duplication
Location: chr18:31536264 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB
Residue 496: the cadherin 4 domain

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

Disease context

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

Also linked: cardiomyopathy arrhythmogenic right ventricular dysplasia 10 arrhythmogenic right ventricular cardiomyopathy

Similar variants

DSG2 p.Cys496Tyr Uncertain significance ★★ ⚠ same residue
DSG2 p.Cys496Ser Uncertain significance ★ ⚠ same residue
DSG2 p.Leu610fs Pathogenic/Likely pathogenic ★★ same condition
DSG2 p.Thr291fs Pathogenic ★★ same condition
DSG2 p.Val271fs Pathogenic/Likely pathogenic ★★ same condition
DSG2 p.Gln1114_His1115insGln Uncertain significance ★★ same condition
DSG2 p.Glu1048_Pro1053dup Uncertain significance ★★ same condition
DSG2 p.Pro958delinsGlnGlnLysLeuProMetSerGlnGlyProLeuCysHisGlnProLeuTer 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-cys496fs (accessed [today's date]).

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