Is DSG2 p.Arg548His (c.1643G>A) pathogenic?

DSG2 p.Arg548His (c.1643G>A) is classified Conflicting classifications of pathogenicity in DSG2 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-27). AlphaMissense: likely benign (0.0641); Ultra-rare (popmax 0.0178%, eas); Associated with Cardiovascular phenotype.

What condition is associated with DSG2 p.Arg548His (c.1643G>A)?

DSG2 p.Arg548His (c.1643G>A) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic right ventricular dysplasia 10 (ClinVar).

How common is DSG2 p.Arg548His (c.1643G>A) in the general population?

DSG2 p.Arg548His (c.1643G>A) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about DSG2 p.Arg548His (c.1643G>A)?

AlphaMissense predicts likely benign (score 0.0641) — an in-silico prediction, not a clinical call.

DSG2 p.Arg548His

c.1643G>A · rs551034751 · VCV188453

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0641 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0641	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -8.33	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.45	GERP -3.5
Regional constraint	o/e 0.93	unconstrained · MANE · 48 kb · p 0.014 · regional, not allelic
Overall
CADD	5.858	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 0.0178% East Asian · 8/44,874 alleles

Filtering AF 0.00884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.00558% 90/1,613,214 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0178%	5,609
Middle Eastern	0.0165%	6,062
Ashkenazi Jewishnot grpmax-eligible	0.0101%	9,867
Remaining individualsnot grpmax-eligible	0.0064%	15,625
European (non-Finnish)	0.00585%	17,101
African / African-American	0.00267%	37,510
South Asian	0.0022%	45,535
Admixed American	0.00167%	60,010

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.Arg548His
Coding: c.1643G>A
MANE Select: NM_001943
dbSNP: rs551034751
Type: single nucleotide variant
Location: chr18:31536421 (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

Similar variants

DSG2 p.Arg548Cys Uncertain significance ★★ ⚠ same residue
DSG2 p.Arg548Gly Uncertain significance ★★ ⚠ same residue
DSG2 p.Arg548Leu Uncertain significance ★★ ⚠ 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-arg548his (accessed [today's date]).

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