Is DSG2 p.Ser4fs (c.-11_11dup) pathogenic?

DSG2 p.Ser4fs (c.-1111dup) is classified Uncertain significance in DSG2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-05). Very rare (popmax 0.00311%, afr); Associated with arrhythmogenic right ventricular dysplasia 10.

What condition is associated with DSG2 p.Ser4fs (c.-11_11dup)?

DSG2 p.Ser4fs (c.-11_11dup) is associated with arrhythmogenic right ventricular dysplasia 10 (ClinVar).

How common is DSG2 p.Ser4fs (c.-11_11dup) in the general population?

DSG2 p.Ser4fs (c.-11_11dup) is very rare (popmax 0.00311%, afr) (gnomAD).

DSG2 p.Ser4fs

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.-11_11dup · rs1356658330 · VCV2563307

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00311%, afr)

Conditions

arrhythmogenic right ventricular dysplasia 10

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 1 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.9	GERP -0.38, phastCons 1
Overall
CADD	15.58	PHRED · no single calibrated threshold — expert panels disagree
Region caveats
Repeat context	tandem	(CGG)n simple repeat · ambiguous alignment · confidence, not pathogenicity

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00311% African / African-American · 2/64,256 alleles

Filtering AF 0.000516% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000193%

Overall 0.00016% 2/1,253,122 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.Ser4fs
Coding: c.-11_11dup
MANE Select: NM_001943
dbSNP: rs1356658330
Type: Duplication
Location: chr18:31498234 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB

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

Disease context

arrhythmogenic right ventricular dysplasia 10 — 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

DSG2 p.Ser4Asn Uncertain significance ★★ ⚠ same residue
DSG2 p.Ser4Gly Uncertain significance ★★ ⚠ same residue
DSG2 p.Ser4= Likely benign ★★ 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.Glu1048_Pro1053dup Uncertain significance ★★ same condition
DSG2 p.Thr1056fs 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-ser4fs (accessed [today's date]).

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