Is DSP p.Arg2842Cys (c.8524C>T) pathogenic?

DSP p.Arg2842Cys (c.8524C>T) is classified Conflicting classifications of pathogenicity in DSP (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-10-31). AlphaMissense: ambiguous (0.4038); Very rare (popmax 0.00552%, nfe); Associated with Brugada syndrome 1.

What condition is associated with DSP p.Arg2842Cys (c.8524C>T)?

DSP p.Arg2842Cys (c.8524C>T) is associated with Brugada syndrome 1, cardiomyopathy, arrhythmogenic cardiomyopathy with wooly hair and keratoderma (ClinVar).

How common is DSP p.Arg2842Cys (c.8524C>T) in the general population?

DSP p.Arg2842Cys (c.8524C>T) is very rare (popmax 0.00552%, nfe) (gnomAD).

How is Brugada syndrome inherited?

Typically Autosomal dominant, Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about DSP p.Arg2842Cys (c.8524C>T)?

AlphaMissense predicts ambiguous (score 0.4038) — an in-silico prediction, not a clinical call.

DSP p.Arg2842Cys

c.8524C>T · rs144850908 · VCV405238

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

ambiguous

0.4038 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00552%, nfe)

Conditions

Brugada syndrome 1

Computational evidence

Protein change
AlphaMissense	0.4038	ambiguous
REVEL	0.437	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.8, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 1,308 bp · p 0.26 · regional, not allelic
Overall
CADD	29.1	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 0.00552% European (non-Finnish) · 65/1,178,570 alleles

Filtering AF 0.00443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00404%

Overall 0.00441% 71/1,609,658 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00552%	18,132
Remaining individualsnot grpmax-eligible	0.00482%	20,752
East Asian	0.00223%	44,866
Finnishnot grpmax-eligible	0.00156%	63,898
South Asian	0.00111%	90,254

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.Arg2842Cys
Coding: c.8524C>T
MANE Select: NM_004415
dbSNP: rs144850908
Type: single nucleotide variant
Location: chr6:7585786 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2842: 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; uncertain significance); the 'binds to telomeres' region; the 'globular 2' region; the 'disordered' region; the '6 x 4 aa tandem repeats of g-s-r-[sr]' 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

Brugada syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiomyopathy arrhythmogenic cardiomyopathy with wooly hair and keratoderma arrhythmogenic right ventricular dysplasia 8

For Brugada syndrome (Orphanet):

Inheritance: Autosomal dominant, Not applicable
Onset: Adult, Childhood
Prevalence: 1-5 / 10 000 (Europe)

Similar variants

DSP p.Arg2842His Uncertain significance ★★ same residue
DSP p.Arg2842Gly Uncertain significance ★ same residue
DSP p.Arg2842Leu Uncertain significance ★ same residue
DSP p.Arg2842= Likely benign ★ 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

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-arg2842cys (accessed [today's date]).

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