Is DSC2 p.Ile520Phe (c.1558A>T) pathogenic?

DSC2 p.Ile520Phe (c.1558A>T) is classified Conflicting classifications of pathogenicity in DSC2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-03-04). AlphaMissense: likely benign (0.2937); Absent from gnomAD v4.1; Associated with familial isolated arrhythmogenic right ventricular dysplasia.

What condition is associated with DSC2 p.Ile520Phe (c.1558A>T)?

DSC2 p.Ile520Phe (c.1558A>T) is associated with familial isolated arrhythmogenic right ventricular dysplasia (ClinVar).

How common is DSC2 p.Ile520Phe (c.1558A>T) in the general population?

DSC2 p.Ile520Phe (c.1558A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DSC2 p.Ile520Phe (c.1558A>T)?

AlphaMissense predicts likely benign (score 0.2937) — an in-silico prediction, not a clinical call.

DSC2 p.Ile520Phe

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.1558A>T · rs529156029 · VCV3069869

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2937 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

familial isolated arrhythmogenic right ventricular dysplasia

Computational evidence

Protein change
AlphaMissense	0.2937	likely benign
REVEL	0.405	indeterminate
SaProt	LLR -10.48	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2.3	GERP -4
Regional constraint	o/e 0.98	unconstrained · MANE · 34 kb · p 0.48 · regional, not allelic
Overall
CADD	14.87	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DSC2
Protein: p.Ile520Phe
Coding: c.1558A>T
MANE Select: NM_024422
dbSNP: rs529156029
Type: single nucleotide variant
Location: chr18:31079952 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 520: a β-strand; the cadherin 4 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

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

DSC2 p.Ile520= Likely benign ★★ same residue
DSC2 p.Ile520Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
DSC2 c.1077+2T>G Uncertain significance ★★ same condition
DSC2 c.1520+6T>C Uncertain significance ★★ same condition
DSC2 c.942+3A>G Uncertain significance ★★ same condition
DSC2 p.Ala138Ser Uncertain significance ★★ ⚠ same condition
DSC2 p.Ala13Val Uncertain significance ★★ ⚠ same condition
DSC2 p.Ala213Val 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-ile520phe (accessed [today's date]).

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