Is DSG2 p.Leu15= (c.45G>A) pathogenic?

DSG2 p.Leu15= (c.45G>A) is classified Conflicting classifications of pathogenicity in DSG2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-06-30). Very rare (popmax 0.0003%, nfe); Associated with arrhythmogenic right ventricular dysplasia 10.

What condition is associated with DSG2 p.Leu15= (c.45G>A)?

DSG2 p.Leu15= (c.45G>A) is associated with arrhythmogenic right ventricular dysplasia 10, cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy (ClinVar).

How common is DSG2 p.Leu15= (c.45G>A) in the general population?

DSG2 p.Leu15= (c.45G>A) is very rare (popmax 0.0003%, nfe) (gnomAD).

DSG2 p.Leu15=

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.45G>A · rs1303092705 · VCV2625494

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0003%, nfe)

Conditions

arrhythmogenic right ventricular dysplasia 10

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 2.8	GERP 0.76, phastCons 1
Overall
CADD	22.7	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0003% European (non-Finnish) · 3/998,914 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.2e-05%

Overall 0.000237% 3/1,263,840 alleles · very rare

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.Leu15=
Coding: c.45G>A
MANE Select: NM_001943
dbSNP: rs1303092705
Type: single nucleotide variant
Location: chr18:31498296 (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

arrhythmogenic right ventricular dysplasia 10 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiomyopathy arrhythmogenic right ventricular cardiomyopathy

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

DSG2 p.Leu15Gln Conflicting classifications of pathogenicity ★ same residue
DSG2 p.Leu15Val Uncertain significance ★ ⚠ same residue
DSG2 p.Leu15del 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-leu15 (accessed [today's date]).

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