Is DSG2 p.Arg46= (c.138G>T) pathogenic?

DSG2 p.Arg46= (c.138G>T) is classified Conflicting classifications of pathogenicity in DSG2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-06-23). Absent from gnomAD v4.1; Associated with arrhythmogenic right ventricular cardiomyopathy.

What condition is associated with DSG2 p.Arg46= (c.138G>T)?

DSG2 p.Arg46= (c.138G>T) is associated with arrhythmogenic right ventricular cardiomyopathy, cardiomyopathy, arrhythmogenic right ventricular dysplasia 10 (ClinVar).

How common is DSG2 p.Arg46= (c.138G>T) in the general population?

DSG2 p.Arg46= (c.138G>T) is absent from gnomAD v4.1 (gnomAD).

DSG2 p.Arg46=

c.138G>T · rs2073117347 · VCV1142707

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

arrhythmogenic right ventricular cardiomyopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.3	phastCons 1
Overall
CADD	7.931	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DSG2
Protein: p.Arg46=
Coding: c.138G>T
MANE Select: NM_001943
dbSNP: rs2073117347
Type: single nucleotide variant
Location: chr18:31519859 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB
Residue 46: a UniProt-annotated variant site (in arvd10; uncertain significance; propeptide present at intercellular junctions of cardiomyocytes; no effect on dsg2 expression at intercalated disks or at intercellular junctions; no effect on expression or localization of pkp2, jup or ctnnb1); a UniProt-annotated variant site (in arvd10; uncertain significance; propeptide present at intercellular junctions of cardiomyocytes; decrease in dsg2 protein abundance with smaller desmosome cell junctions and abnormal inter-membrane vacuoles in cardiomyocytes of both ventricles; no effect on localization of dsg2 to intercalated disks or at intercellular junctions; abnormally localized within intra-cytoplasmic vesicles in an egfr-dependent manner; reduction in incorporation into desmosomes during mechanical stress; no effect on cleavage of propeptide or ability to form homodimers; no effect on expression or localization of pkp2, jup or ctnnb1)

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

Disease context

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

Also linked: cardiomyopathy arrhythmogenic right ventricular dysplasia 10

Similar variants

DSG2 p.Arg46Gln Pathogenic/Likely pathogenic ★★ same residue
DSG2 p.Arg46Trp Pathogenic/Likely pathogenic ★★ same residue
DSG2 p.Arg46Leu Likely pathogenic ★ same residue
DSG2 c.1423+1G>T Likely pathogenic ★★ same condition
DSG2 c.1424-1G>A Likely pathogenic ★★ same condition
DSG2 c.523+1G>T Pathogenic/Likely pathogenic ★★ same condition
DSG2 c.690+1G>A Pathogenic ★★ same condition
DSG2 c.81+1G>T Likely pathogenic ★★ 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-arg46 (accessed [today's date]).

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