Is DSG2 p.Val440fs (c.1319_1320del) pathogenic?

DSG2 p.Val440fs (c.13191320del) is classified Pathogenic/Likely pathogenic in DSG2 (ClinVar, Multiple submitters, 10 submitters; last evaluated 2025-06-11). Ultra-rare (popmax 0.0502%, mid); Associated with arrhythmogenic right ventricular dysplasia 10.

How common is DSG2 p.Val440fs (c.1319_1320del) in the general population?

DSG2 p.Val440fs (c.1319_1320del) is ultra-rare (popmax 0.0502%, mid) (gnomAD).

DSG2 p.Val440fs

Q: What condition is associated with DSG2 p.Val440fs (c.1319_1320del)?

DSG2 p.Val440fs (c.1319_1320del) is associated with arrhythmogenic right ventricular dysplasia 10, cardiomyopathy, dilated cardiomyopathy 1BB (ClinVar).

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.1319_1320del · rs775256998 · VCV666600

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 10 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.0502%, mid)

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 10 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 2.7	GERP -0.97, phastCons 0.99

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0502% Middle Eastern · 3/5,980 alleles

Filtering AF 0.0136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00728%

Overall 0.000762% 11/1,443,624 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0502%	1,993
South Asian	0.00332%	30,095
Remaining individualsnot grpmax-eligible	0.00162%	61,876
European (non-Finnish)	0.000343%	291,151

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.Val440fs
Coding: c.1319_1320del
MANE Select: NM_001943
dbSNP: rs775256998
Type: Microsatellite
Location: chr18:31535306 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB
Residue 440: a β-strand; the cadherin 4 domain

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

Also linked: cardiomyopathy dilated cardiomyopathy 1BB

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

DSG2 p.Val440= Conflicting classifications of pathogenicity ★ same residue
DSG2 p.Thr791fs Pathogenic/Likely pathogenic ★★ same condition
DSG2 p.Glu283del Uncertain significance ★★ same condition
DSG2 p.Ser1021fs Uncertain significance ★★ same condition
DSG2 p.Ser884del Uncertain significance ★★ same condition
DSG2 c.216+14_216+15del Likely benign ★★ same condition
DSG2 c.1280+4AG[3] Conflicting classifications of pathogenicity ★ same condition
DSG2 p.Cys591_Glu592delinsTer Conflicting classifications of pathogenicity ★ 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-val440fs (accessed [today's date]).

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