Is DSC2 p.Ile584Phe (c.1750A>T) pathogenic?

DSC2 p.Ile584Phe (c.1750A>T) is classified Uncertain significance in DSC2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-12-17). AlphaMissense: ambiguous (0.4636); Ultra-rare (popmax 0.0217%, amr); Associated with arrhythmogenic right ventricular dysplasia 11.

What condition is associated with DSC2 p.Ile584Phe (c.1750A>T)?

DSC2 p.Ile584Phe (c.1750A>T) is associated with arrhythmogenic right ventricular dysplasia 11 (ClinVar).

How common is DSC2 p.Ile584Phe (c.1750A>T) in the general population?

DSC2 p.Ile584Phe (c.1750A>T) is ultra-rare (popmax 0.0217%, amr) (gnomAD).

What do computational predictors say about DSC2 p.Ile584Phe (c.1750A>T)?

AlphaMissense predicts ambiguous (score 0.4636) — an in-silico prediction, not a clinical call.

DSC2 p.Ile584Phe

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.1750A>T · rs755041461 · VCV1305790

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4636 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0217%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

arrhythmogenic right ventricular dysplasia 11

Computational evidence

Protein change
AlphaMissense	0.4636	ambiguous
REVEL	0.179	moderately benign-leaning
SaProt	LLR -4.44	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.2	GERP 0.81, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 34 kb · p 0.48 · regional, not allelic
Overall
CADD	21.8	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

Grpmax group 0.0217% Admixed American · 13/59,984 alleles

Filtering AF 0.0127% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0101%

Overall 0.000991% 16/1,613,928 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0217%	4,614
Remaining individualsnot grpmax-eligible	0.0016%	62,470
European (non-Finnish)	0.000169%	589,995

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.Ile584Phe
Coding: c.1750A>T
MANE Select: NM_024422
dbSNP: rs755041461
Type: single nucleotide variant
Location: chr18:31074821 (GRCh38)
Gene constraint: LOEUF 0.743 · pLI <0.01 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 77.26 · 3 PDB
Residue 584: the cadherin 5 domain; a UniProt-annotated variant site (in arvd11; likely pathogenic; mislocalization of dsc2 to the cytoplasm within intercalated disks of the heart)

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

Disease context

arrhythmogenic right ventricular dysplasia 11 — 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.Ile584= Likely benign ★★ same residue
DSC2 p.Ile584Val Conflicting classifications of pathogenicity ★ ⚠ same residue
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
DSC2 p.Gln620Ter Pathogenic ★★ same condition
DSC2 p.Glu127Ter Pathogenic/Likely 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-ile584phe (accessed [today's date]).

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