Is DSG2 p.Val28= (c.84C>G) pathogenic?

DSG2 p.Val28= (c.84C>G) is classified Conflicting classifications of pathogenicity in DSG2 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-11-09). Ultra-rare (popmax 0.0493%, mid); Associated with Cardiovascular phenotype.

What condition is associated with DSG2 p.Val28= (c.84C>G)?

DSG2 p.Val28= (c.84C>G) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic right ventricular dysplasia 10 (ClinVar).

How common is DSG2 p.Val28= (c.84C>G) in the general population?

DSG2 p.Val28= (c.84C>G) is ultra-rare (popmax 0.0493%, mid) (gnomAD).

DSG2 p.Val28=

c.84C>G · rs397516711 · VCV44327

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 0.0493%, mid)

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 0.98	phastCons 0.5
Overall
CADD	6.466	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0493% Middle Eastern · 3/6,084 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00715%

Overall 0.00186% 30/1,613,948 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0493%	2,028
African / African-American	0.0134%	7,490
Remaining individualsnot grpmax-eligible	0.0128%	7,810
South Asian	0.0022%	45,536
European (non-Finnish)	0.000593%	168,568

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.Val28=
Coding: c.84C>G
MANE Select: NM_001943
dbSNP: rs397516711
Type: single nucleotide variant
Location: chr18:31519805 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB

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.Val28Phe 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
DSG2 c.829-2A>T Likely pathogenic ★★ same condition
DSG2 p.Arg46Gln Pathogenic/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-val28 (accessed [today's date]).

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