Is DSC2 p.Ala596Val (c.1787C>T) pathogenic?

DSC2 p.Ala596Val (c.1787C>T) is classified Conflicting classifications of pathogenicity in DSC2 (ClinVar, Conflicting submitters, 20 submitters; last evaluated 2026-06-01). AlphaMissense: likely pathogenic (0.6833); Rare (popmax 0.445%, mid); Associated with Cardiovascular phenotype.

What condition is associated with DSC2 p.Ala596Val (c.1787C>T)?

DSC2 p.Ala596Val (c.1787C>T) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic right ventricular dysplasia 11 (ClinVar).

How common is DSC2 p.Ala596Val (c.1787C>T) in the general population?

DSC2 p.Ala596Val (c.1787C>T) is rare (popmax 0.445%, mid) (gnomAD).

What do computational predictors say about DSC2 p.Ala596Val (c.1787C>T)?

AlphaMissense predicts likely pathogenic (score 0.6833) — an in-silico prediction, not a clinical call.

DSC2 p.Ala596Val

c.1787C>T · rs148185335 · VCV46171

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 20 submitters

AlphaMissense

likely pathogenic

0.6833 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.445%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.6833	likely pathogenic
REVEL	0.427	indeterminate
SaProt	LLR -7.62	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 34 kb · p 0.48 · regional, not allelic
Overall
CADD	23.7	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 0.445% Middle Eastern · 27/6,062 alleles

Filtering AF 0.314% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.27%

Overall 0.0827% 1,334/1,613,922 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.445%	225
South Asian	0.284%	352
Remaining individualsnot grpmax-eligible	0.12%	833
Ashkenazi Jewishnot grpmax-eligible	0.115%	871
Admixed American	0.0833%	1,200
European (non-Finnish)	0.0725%	1,378
Finnishnot grpmax-eligible	0.0281%	3,555
African / African-American	0.02%	5,000

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.Ala596Val
Coding: c.1787C>T
MANE Select: NM_024422
dbSNP: rs148185335
Type: single nucleotide variant
Location: chr18:31074784 (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

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

Also linked: cardiomyopathy arrhythmogenic right ventricular dysplasia 11 arrhythmogenic right ventricular cardiomyopathy

Similar variants

DSC2 p.Ala596Thr Uncertain significance ★★ ⚠ same residue
DSC2 p.Ala596= Conflicting classifications of pathogenicity ★ same residue
DSC2 p.Ala596Gly Uncertain significance ★ ⚠ same residue
DSC2 p.Ala596Pro Uncertain significance ★ ⚠ same residue
DSC2 c.1521-1G>A Likely pathogenic ★★ same condition
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

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-ala596val (accessed [today's date]).

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