Is DSP p.Arg2366Cys (c.7096C>T) pathogenic?

DSP p.Arg2366Cys (c.7096C>T) is classified Pathogenic/Likely pathogenic in DSP (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-10-06). AlphaMissense: likely pathogenic (0.9941); Very rare (popmax 0.000763%, nfe); Associated with arrhythmogenic right ventricular dysplasia 8.

What condition is associated with DSP p.Arg2366Cys (c.7096C>T)?

DSP p.Arg2366Cys (c.7096C>T) is associated with arrhythmogenic right ventricular dysplasia 8, arrhythmogenic cardiomyopathy with wooly hair and keratoderma (ClinVar).

How common is DSP p.Arg2366Cys (c.7096C>T) in the general population?

DSP p.Arg2366Cys (c.7096C>T) is very rare (popmax 0.000763%, nfe) (gnomAD).

What do computational predictors say about DSP p.Arg2366Cys (c.7096C>T)?

AlphaMissense predicts likely pathogenic (score 0.9941) — an in-silico prediction, not a clinical call.

DSP p.Arg2366Cys

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.7096C>T · rs28931610 · VCV16841

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.9941 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000763%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, REVEL

Conditions

arrhythmogenic right ventricular dysplasia 8

Computational evidence

Protein change
AlphaMissense	0.9941	likely pathogenic ✓ concordant with ClinVar · top 3% in DSP
REVEL	0.864	moderately pathogenic-leaning
⇒ AlphaMissense and REVEL both call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 696 bp · p 9.7e-06 · regional, not allelic
Overall
CADD	29.8	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 0.000763% European (non-Finnish) · 9/1,180,022 alleles

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

Overall 0.000558% 9/1,614,004 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: DSP
Protein: p.Arg2366Cys
Coding: c.7096C>T
MANE Select: NM_004415
dbSNP: rs28931610
Type: single nucleotide variant
Location: chr6:7584358 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2366: a UniProt-annotated variant site (in arvd8; uncertain significance); a UniProt-annotated variant site (in dcwhkta; uncertain significance); a UniProt-annotated variant site (in dcwhk; uncertain significance; abolishes expression in the myocardium); a UniProt-annotated variant site (in ebla; uncertain significance); a UniProt-annotated variant site (in dcwhk and dcwhkta; uncertain significance; abolishes interaction with intermediate filaments); an α-helix; the 'binds to telomeres' region; the 'globular 2' region; the '4.5 x 38 aa tandem repeats (domain b)' region; a UniProt-annotated variant site (in arvd8; likely pathogenic; results in an unstable protein that forms perinuclear aggregates); a UniProt-annotated variant site (in arvd8 and dcwhkta; uncertain significance); a UniProt-annotated variant site (in arvd8)

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

Disease context

arrhythmogenic right ventricular dysplasia 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: arrhythmogenic cardiomyopathy with wooly hair and keratoderma

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

DSP p.Arg2366His Pathogenic/Likely pathogenic ★★ same residue
DSP c.1141-2A>T Likely pathogenic ★★ same condition
DSP c.1266+2T>C Likely pathogenic ★★ same condition
DSP c.1574+1G>A Likely pathogenic ★★ same condition
DSP c.2130+1G>A Pathogenic/Likely pathogenic ★★ same condition
DSP c.2297+1G>A Likely pathogenic ★★ same condition
DSP c.2298-1G>C Likely pathogenic ★★ same condition
DSP c.2298-2A>C 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/dsp-p-arg2366cys (accessed [today's date]).

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