Is DSC2 p.Ile342fs (c.1023dup) pathogenic?

DSC2 p.Ile342fs (c.1023dup) is classified Pathogenic in DSC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-26). Very rare (popmax 8.48e-05%, nfe); Associated with arrhythmogenic right ventricular dysplasia 11.

What condition is associated with DSC2 p.Ile342fs (c.1023dup)?

DSC2 p.Ile342fs (c.1023dup) is associated with arrhythmogenic right ventricular dysplasia 11 (ClinVar).

How common is DSC2 p.Ile342fs (c.1023dup) in the general population?

DSC2 p.Ile342fs (c.1023dup) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

DSC2 p.Ile342fs

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.1023dup · rs768389941 · VCV1429683

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

arrhythmogenic right ventricular dysplasia 11

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 8 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -2	GERP -3.4
Overall
CADD	25.3	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

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,902 alleles

Overall 0.000657% 1/152,252 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: DSC2
Protein: p.Ile342fs
Coding: c.1023dup
MANE Select: NM_024422
dbSNP: rs768389941
Type: Duplication
Location: chr18:31082979 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 342: a β-strand; the cadherin 2 domain

Full DSC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

arrhythmogenic right ventricular dysplasia 11 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

DSC2 p.Ile342Asn Uncertain significance ★★ ⚠ same residue
DSC2 p.Ile342Val Conflicting classifications of pathogenicity ★ ⚠ same residue
DSC2 p.Leu396fs Pathogenic ★★ same condition
DSC2 c.2126-15dup Likely benign ★★ same condition
DSC2 c.631-13dup Benign/Likely benign ★★ same condition
DSC2 c.70-18dup Benign/Likely benign ★★ same condition
DSC2 c.70-8dup Benign/Likely benign ★★ same condition
DSC2 c.942+13_942+15dup Benign/Likely benign ★★ 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/dsc2-p-ile342fs (accessed [today's date]).

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