Is DSC2 p.Asp682Val (c.2045A>T) pathogenic?

DSC2 p.Asp682Val (c.2045A>T) is classified Uncertain significance in DSC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-15). AlphaMissense: likely benign (0.1079); Very rare (popmax 0.000169%, nfe); Associated with arrhythmogenic right ventricular dysplasia 11.

What condition is associated with DSC2 p.Asp682Val (c.2045A>T)?

DSC2 p.Asp682Val (c.2045A>T) is associated with arrhythmogenic right ventricular dysplasia 11 (ClinVar).

How common is DSC2 p.Asp682Val (c.2045A>T) in the general population?

DSC2 p.Asp682Val (c.2045A>T) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about DSC2 p.Asp682Val (c.2045A>T)?

AlphaMissense predicts likely benign (score 0.1079) — an in-silico prediction, not a clinical call.

DSC2 p.Asp682Val

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.2045A>T · rs1364189206 · VCV3013422

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1079 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

arrhythmogenic right ventricular dysplasia 11

Computational evidence

Protein change
AlphaMissense	0.1079	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -4.73	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -5.6	GERP -3.8
Regional constraint	o/e 0.98	unconstrained · MANE · 34 kb · p 0.48 · regional, not allelic
Overall
CADD	0.286	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,180,024 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,614,018 alleles · very rare exomes 2/1,461,808 · genomes 1/152,210 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,476
European (non-Finnish)grpmax	0.000169%	590,012

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.Asp682Val
Coding: c.2045A>T
MANE Select: NM_024422
dbSNP: rs1364189206
Type: single nucleotide variant
Location: chr18:31071685 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 682: 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)

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

Disease context

arrhythmogenic right ventricular dysplasia 11 — 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

DSC2 p.Asp682= Likely benign ★★ same residue
DSC2 p.Asp682Glu 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
DSC2 p.Gln620Ter Pathogenic ★★ same condition
DSC2 p.Glu127Ter 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/dsc2-p-asp682val (accessed [today's date]).

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