Is DSG2 p.Ala758= (c.2274C>T) pathogenic?

DSG2 p.Ala758= (c.2274C>T) is classified Likely benign in DSG2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-15). Very rare (popmax 0.00138%, afr); Associated with arrhythmogenic right ventricular dysplasia 10.

What condition is associated with DSG2 p.Ala758= (c.2274C>T)?

DSG2 p.Ala758= (c.2274C>T) is associated with arrhythmogenic right ventricular dysplasia 10 (ClinVar).

How common is DSG2 p.Ala758= (c.2274C>T) in the general population?

DSG2 p.Ala758= (c.2274C>T) is very rare (popmax 0.00138%, afr) (gnomAD).

DSG2 p.Ala758=

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.2274C>T · rs778950229 · VCV1084579

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00138%, afr)

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 -10
Overall
CADD	0.83	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00138% African / African-American · 1/72,202 alleles

Filtering AF 0.000361% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000261%

Overall 0.000688% 11/1,598,986 alleles · very rare exomes 10/1,452,296 · genomes 1/146,690 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00138%	72,202
South Asian	0.00111%	90,118
European (non-Finnish)	0.000766%	130,490

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.Ala758=
Coding: c.2274C>T
MANE Select: NM_001943
dbSNP: rs778950229
Type: single nucleotide variant
Location: chr18:31542792 (GRCh38)
Gene constraint: LOEUF 0.764 · pLI <0.01 · ClinGen HI 2/3 (gnomAD)
Structure: AlphaFold pLDDT 65.27 · 12 PDB
Residue 758: a UniProt-annotated variant site (in arvd10; uncertain significance; evidence of residual myocardium, fibrous tissue, fatty tissue, dysmetric and dysmorphic nuclei and prominent cytoplasmic vacuolization; decreases the number of desmosomes at intercalated disks also increases desmosome gap; smaller intercellular gaps, with repeating couplings, abnormally located desmosomes and pale internal plaques); a UniProt-annotated variant site (in arvd10; uncertain significance)

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

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

DSG2 p.Ala758Thr Uncertain significance ★ ⚠ same residue
DSG2 p.Ala758Val 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

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-ala758 (accessed [today's date]).

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