Is DSC2 p.Tyr545= (c.1635T>C) pathogenic?

DSC2 p.Tyr545= (c.1635T>C) is classified Likely benign in DSC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-16). Very rare (popmax 0.000763%, nfe); Associated with cardiomyopathy.

What condition is associated with DSC2 p.Tyr545= (c.1635T>C)?

DSC2 p.Tyr545= (c.1635T>C) is associated with cardiomyopathy, familial isolated arrhythmogenic right ventricular dysplasia (ClinVar).

How common is DSC2 p.Tyr545= (c.1635T>C) in the general population?

DSC2 p.Tyr545= (c.1635T>C) is very rare (popmax 0.000763%, nfe) (gnomAD).

DSC2 p.Tyr545=

c.1635T>C · rs1432185135 · VCV2775179

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Conditions

cardiomyopathy

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 0.8	GERP -0.52, phastCons 0.98
Overall
CADD	4.455	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000763% European (non-Finnish) · 9/1,179,946 alleles

Filtering AF 0.000359% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00026%

Overall 0.000558% 9/1,613,872 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.Tyr545=
Coding: c.1635T>C
MANE Select: NM_024422
dbSNP: rs1432185135
Type: single nucleotide variant
Location: chr18:31079875 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 545: a β-strand; the cadherin 4 domain

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: familial isolated arrhythmogenic right ventricular dysplasia

Similar variants

DSC3 p.Tyr545Cys Uncertain significance ★ ⚠ same residue
DSC3 p.Tyr545His 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

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-tyr545 (accessed [today's date]).

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