Is DSC2 p.Ile565Phe (c.1693A>T) pathogenic?

DSC2 p.Ile565Phe (c.1693A>T) is classified Uncertain significance in DSC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-28). AlphaMissense: likely benign (0.3363); Absent from gnomAD v4.1; Associated with cardiomyopathy.

What condition is associated with DSC2 p.Ile565Phe (c.1693A>T)?

DSC2 p.Ile565Phe (c.1693A>T) is associated with cardiomyopathy (ClinVar).

How common is DSC2 p.Ile565Phe (c.1693A>T) in the general population?

DSC2 p.Ile565Phe (c.1693A>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DSC2 p.Ile565Phe (c.1693A>T)?

AlphaMissense predicts likely benign (score 0.3363) — an in-silico prediction, not a clinical call.

DSC2 p.Ile565Phe

c.1693A>T · VCV4076668

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.3363 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.3363	likely benign
REVEL	0.243	benign-leaning
SaProt	LLR -9.48	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 1.9	GERP -1.9, phastCons 0.99
Regional constraint	o/e 0.98	unconstrained · MANE · 34 kb · p 0.48 · regional, not allelic
Overall
CADD	18.26	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

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.Ile565Phe
Coding: c.1693A>T
MANE Select: NM_024422
Type: single nucleotide variant
Location: chr18:31074878 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 565: a UniProt-annotated variant site (in arvd11; likely pathogenic; mislocalization of dsc2 to the cytoplasm within intercalated disks of the heart); 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

Similar variants

DSC2 p.Ile565Val Conflicting classifications of pathogenicity ★ ⚠ same residue
DSC2 p.Ile565Ser Uncertain significance ★★ ⚠ same residue
DSC2 c.1077+2T>G Uncertain significance ★★ same condition
DSC2 c.1520+4C>T 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.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-ile565phe (accessed [today's date]).

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