Is DSG2 p.Arg548Cys (c.1642C>T) pathogenic?

DSG2 p.Arg548Cys (c.1642C>T) is classified Uncertain significance in DSG2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-10-22). AlphaMissense: likely benign (0.1629); Very rare (popmax 0.00446%, eas); Associated with Cardiovascular phenotype.

What condition is associated with DSG2 p.Arg548Cys (c.1642C>T)?

DSG2 p.Arg548Cys (c.1642C>T) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic right ventricular dysplasia 10 (ClinVar).

How common is DSG2 p.Arg548Cys (c.1642C>T) in the general population?

DSG2 p.Arg548Cys (c.1642C>T) is very rare (popmax 0.00446%, eas) (gnomAD).

What do computational predictors say about DSG2 p.Arg548Cys (c.1642C>T)?

AlphaMissense predicts likely benign (score 0.1629) — an in-silico prediction, not a clinical call.

DSG2 p.Arg548Cys

c.1642C>T · rs550400909 · VCV466332

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1629 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.1629	likely benign
REVEL	0.176	moderately benign-leaning
SaProt	LLR -13.95	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.8, phastCons 0.24
Regional constraint	o/e 0.93	unconstrained · MANE · 48 kb · p 0.014 · regional, not allelic
Overall
CADD	21.4	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 0.00446% East Asian · 2/44,876 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000539%

Overall 0.00124% 20/1,613,352 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,438
African / African-American	0.004%	25,007
Admixed American	0.00167%	60,020
European (non-Finnish)	0.00119%	84,285

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.Arg548Cys
Coding: c.1642C>T
MANE Select: NM_001943
dbSNP: rs550400909
Type: single nucleotide variant
Location: chr18:31536420 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB
Residue 548: a β-strand

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.Arg548Gly Uncertain significance ★★ ⚠ same residue
DSG2 p.Arg548Leu Uncertain significance ★★ ⚠ same residue
DSG2 p.Arg548His Conflicting classifications of pathogenicity ★ ⚠ same residue
DSG2 p.Arg548Ser 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

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-arg548cys (accessed [today's date]).

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