Is DSC2 p.Pro683Thr (c.2047C>A) pathogenic?

DSC2 p.Pro683Thr (c.2047C>A) is classified Uncertain significance in DSC2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-09-10). AlphaMissense: likely benign (0.0764); Very rare (popmax 8.48e-05%, nfe); Associated with cardiomyopathy.

How common is DSC2 p.Pro683Thr (c.2047C>A) in the general population?

DSC2 p.Pro683Thr (c.2047C>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about DSC2 p.Pro683Thr (c.2047C>A)?

AlphaMissense predicts likely benign (score 0.0764) — an in-silico prediction, not a clinical call.

DSC2 p.Pro683Thr

Q: What condition is associated with DSC2 p.Pro683Thr (c.2047C>A)?

DSC2 p.Pro683Thr (c.2047C>A) is associated with cardiomyopathy, arrhythmogenic right ventricular dysplasia 11, familial isolated arrhythmogenic right ventricular dysplasia (ClinVar).

c.2047C>A · rs1386709734 · VCV575502

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0764 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.0764	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -5.97	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.9	GERP -3.8
Regional constraint	o/e 0.98	unconstrained · MANE · 34 kb · p 0.48 · regional, not allelic
Overall
CADD	0.033	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 8.48e-05% European (non-Finnish) · 1/1,179,920 alleles

Overall 0.000659% 1/151,756 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: DSC2
Protein: p.Pro683Thr
Coding: c.2047C>A
MANE Select: NM_024422
dbSNP: rs1386709734
Type: single nucleotide variant
Location: chr18:31071683 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 683: 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

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.Pro683Leu Uncertain significance ★ ⚠ same residue
DSC2 p.Pro683= Likely benign ★ 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-pro683thr (accessed [today's date]).

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