Is DSG2 p.Arg49= (c.147C>T) pathogenic?

DSG2 p.Arg49= (c.147C>T) is classified Conflicting classifications of pathogenicity in DSG2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-12-03). Ultra-rare (popmax 0.02%, amr); Associated with Cardiovascular phenotype.

What condition is associated with DSG2 p.Arg49= (c.147C>T)?

DSG2 p.Arg49= (c.147C>T) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic right ventricular dysplasia 10 (ClinVar).

How common is DSG2 p.Arg49= (c.147C>T) in the general population?

DSG2 p.Arg49= (c.147C>T) is ultra-rare (popmax 0.02%, amr) (gnomAD).

DSG2 p.Arg49=

c.147C>T · rs531036279 · VCV326472

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Conditions

Cardiovascular phenotype

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 -6.1
Overall
CADD	1.626	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.02% Admixed American · 12/60,020 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.0031% 50/1,614,096 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.02%	5,002
African / African-American	0.00933%	10,715
Remaining individualsnot grpmax-eligible	0.008%	12,502
South Asian	0.0022%	45,537
European (non-Finnish)	0.00203%	49,168

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.Arg49=
Coding: c.147C>T
MANE Select: NM_001943
dbSNP: rs531036279
Type: single nucleotide variant
Location: chr18:31519868 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB
Residue 49: 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)

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.Arg49His Pathogenic/Likely pathogenic ★★ same residue
DSG2 p.Arg49Cys Conflicting classifications of pathogenicity ★ ⚠ same residue
DSG2 p.Arg49Ser Uncertain significance ★ ⚠ 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-arg49 (accessed [today's date]).

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