Is DSG2 p.Arg49Cys (c.145C>T) pathogenic?

DSG2 p.Arg49Cys (c.145C>T) is classified Conflicting classifications of pathogenicity in DSG2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-07-31). AlphaMissense: likely pathogenic (0.9452); Very rare (popmax 0.0011%, sas); Associated with Cardiovascular phenotype.

What condition is associated with DSG2 p.Arg49Cys (c.145C>T)?

DSG2 p.Arg49Cys (c.145C>T) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic right ventricular dysplasia 10 (ClinVar).

How common is DSG2 p.Arg49Cys (c.145C>T) in the general population?

DSG2 p.Arg49Cys (c.145C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about DSG2 p.Arg49Cys (c.145C>T)?

AlphaMissense predicts likely pathogenic (score 0.9452) — an in-silico prediction, not a clinical call.

DSG2 p.Arg49Cys

c.145C>T · rs762526848 · VCV450040

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9452 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9452	likely pathogenic · top 5% in DSG2
REVEL	0.771	pathogenic-leaning
SaProt	LLR -11.65	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 48 kb · p 0.014 · regional, not allelic
Overall
CADD	24.3	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,074 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000342% 5/1,461,872 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,074
European (non-Finnish)	0.000339%	295,003

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.Arg49Cys
Coding: c.145C>T
MANE Select: NM_001943
dbSNP: rs762526848
Type: single nucleotide variant
Location: chr18:31519866 (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.Arg49= 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-arg49cys (accessed [today's date]).

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