Is DSC2 p.Thr251= (c.753A>G) pathogenic?

DSC2 p.Thr251= (c.753A>G) is classified Likely benign in DSC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-11-28). Very rare (popmax 0.00167%, amr); Associated with familial isolated arrhythmogenic right ventricular dysplasia.

How common is DSC2 p.Thr251= (c.753A>G) in the general population?

DSC2 p.Thr251= (c.753A>G) is very rare (popmax 0.00167%, amr) (gnomAD).

DSC2 p.Thr251=

Q: What condition is associated with DSC2 p.Thr251= (c.753A>G)?

DSC2 p.Thr251= (c.753A>G) is associated with familial isolated arrhythmogenic right ventricular dysplasia, cardiomyopathy (ClinVar).

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.753A>G · rs1987446637 · VCV927635

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

familial isolated arrhythmogenic right ventricular dysplasia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.019	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.85	GERP -4
Overall
CADD	1.427	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00167% Admixed American · 1/60,016 alleles

Overall 6.85e-05% 1/1,460,764 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.Thr251=
Coding: c.753A>G
MANE Select: NM_024422
dbSNP: rs1987446637
Type: single nucleotide variant
Location: chr18:31087691 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 251: a β-strand; the cadherin 2 domain

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

Disease context

familial isolated arrhythmogenic right ventricular dysplasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiomyopathy

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

DSC2 p.Thr251Lys Uncertain significance ★★ ⚠ same residue
DSC2 c.1077+2T>G Uncertain significance ★★ same condition
DSC2 c.1520+4C>T Uncertain significance ★★ same condition
DSC2 c.1520+6T>C Uncertain significance ★★ same condition
DSC2 c.942+3A>G Uncertain significance ★★ same condition
DSC2 c.942+6A>G Uncertain significance ★★ same condition
DSC2 p.Ala138Ser Uncertain significance ★★ ⚠ same condition
DSC2 p.Ala13Val Uncertain significance ★★ ⚠ 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-thr251 (accessed [today's date]).

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