Is DSC2 p.Thr275= (c.825G>A) pathogenic?

DSC2 p.Thr275= (c.825G>A) is classified Likely benign in DSC2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-09-28). Very rare (popmax 0.00223%, eas); Associated with Cardiovascular phenotype.

What condition is associated with DSC2 p.Thr275= (c.825G>A)?

DSC2 p.Thr275= (c.825G>A) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic right ventricular dysplasia 11 (ClinVar).

How common is DSC2 p.Thr275= (c.825G>A) in the general population?

DSC2 p.Thr275= (c.825G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

DSC2 p.Thr275=

c.825G>A · rs767301887 · VCV918777

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

Cardiovascular phenotype

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 -16	GERP -4
Overall
CADD	0.656	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,876 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000744% 12/1,613,962 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,876
South Asian	0.0022%	45,542
Remaining individualsnot grpmax-eligible	0.0016%	62,490
African / African-American	0.00134%	74,888
European (non-Finnish)	0.000593%	168,574

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.Thr275=
Coding: c.825G>A
MANE Select: NM_024422
dbSNP: rs767301887
Type: single nucleotide variant
Location: chr18:31086693 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 275: a UniProt-annotated variant site (in arvd11; can be processed into a mature form but shows a higher pro-protein to mature protein ratio; only a proportion of the partly functional mutant is incorporated into the desmosomes); the cadherin 2 domain

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 familial isolated arrhythmogenic right ventricular dysplasia

Similar variants

DSC2 p.Thr275Lys Uncertain significance ★★ ⚠ same residue
DSC2 p.Thr275Met Conflicting classifications of pathogenicity ★ ⚠ same residue
DSC3 p.Thr275= Benign ★★ 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
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-thr275 (accessed [today's date]).

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