Is DSC2 p.Ala596= (c.1788G>A) pathogenic?

DSC2 p.Ala596= (c.1788G>A) is classified Conflicting classifications of pathogenicity in DSC2 (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2026-01-28). Ultra-rare (popmax 0.0158%, nfe); Associated with cardiomyopathy.

How common is DSC2 p.Ala596= (c.1788G>A) in the general population?

DSC2 p.Ala596= (c.1788G>A) is ultra-rare (popmax 0.0158%, nfe) (gnomAD).

DSC2 p.Ala596=

Q: What condition is associated with DSC2 p.Ala596= (c.1788G>A)?

DSC2 p.Ala596= (c.1788G>A) is associated with cardiomyopathy, arrhythmogenic right ventricular dysplasia 11, familial isolated arrhythmogenic right ventricular dysplasia (ClinVar).

c.1788G>A · rs146161960 · VCV326397

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0158%, nfe)

Conditions

cardiomyopathy

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 -2.3	GERP -4
Overall
CADD	0.746	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0158% European (non-Finnish) · 187/1,179,972 alleles

Filtering AF 0.0139% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0133%

Overall 0.0139% 225/1,613,970 alleles · ultra-rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0192%	5,208
European (non-Finnish)grpmax	0.0158%	6,310
South Asian	0.0154%	6,505
African / African-American	0.00933%	10,715
Finnishnot grpmax-eligible	0.00469%	21,336
East Asian	0.00446%	22,422

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: DSC2
Protein: p.Ala596=
Coding: c.1788G>A
MANE Select: NM_024422
dbSNP: rs146161960
Type: single nucleotide variant
Location: chr18:31074783 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 596: the cadherin 5 domain; a UniProt-annotated variant site (in arvd11; likely pathogenic; mislocalization of dsc2 to the cytoplasm within intercalated disks of the heart); a UniProt-annotated variant site (in)

Full DSC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: arrhythmogenic right ventricular dysplasia 11 familial isolated arrhythmogenic right ventricular dysplasia

Similar variants

DSC2 p.Ala596Thr Uncertain significance ★★ ⚠ same residue
DSC2 p.Ala596Pro Uncertain significance ★ ⚠ same residue
DSC2 p.Ala596Val Conflicting classifications of pathogenicity ★ ⚠ same residue
DSC2 p.Ala596Gly Uncertain significance ★ same residue
DSC2 c.1664-1G>A Likely pathogenic ★★ same condition
DSC2 c.354+2T>A Likely pathogenic ★★ same condition
DSC2 c.355-1G>A Likely pathogenic ★★ same condition
DSC2 p.Gln554Ter 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/dsc2-p-ala596 (accessed [today's date]).

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