Is DSP p.Arg2834Cys (c.8500C>T) pathogenic?

DSP p.Arg2834Cys (c.8500C>T) is classified Conflicting classifications of pathogenicity in DSP (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2025-12-15). AlphaMissense: ambiguous (0.5326); Very rare (popmax 0.00637%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with DSP p.Arg2834Cys (c.8500C>T)?

DSP p.Arg2834Cys (c.8500C>T) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic cardiomyopathy with wooly hair and keratoderma (ClinVar).

How common is DSP p.Arg2834Cys (c.8500C>T) in the general population?

DSP p.Arg2834Cys (c.8500C>T) is very rare (popmax 0.00637%, nfe) (gnomAD).

What do computational predictors say about DSP p.Arg2834Cys (c.8500C>T)?

AlphaMissense predicts ambiguous (score 0.5326) — an in-silico prediction, not a clinical call.

DSP p.Arg2834Cys

c.8500C>T · rs753033333 · VCV218636

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 11 submitters

AlphaMissense

ambiguous

0.5326 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00637%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.5326	ambiguous
REVEL	0.475	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 1,308 bp · p 0.26 · regional, not allelic
Overall
CADD	24.5	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 0.00637% European (non-Finnish) · 75/1,176,502 alleles

Filtering AF 0.00521% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00475%

Overall 0.00498% 80/1,607,478 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00637%	15,687
Remaining individualsnot grpmax-eligible	0.00483%	20,719
African / African-American	0.00269%	37,192

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.Arg2834Cys
Coding: c.8500C>T
MANE Select: NM_004415
dbSNP: rs753033333
Type: single nucleotide variant
Location: chr6:7585762 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2834: 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); a UniProt-annotated variant site (in arvd8; uncertain significance; no effect on localization to the plasma membrane or cell-cell junctions. decreases interaction with gsk3b resulting in a significant decrease in gsk3b-mediated phosphorylation of multiple downstream sites within the c-terminus. reduced trafficking of dsp to desmosome cell junctions and retention with intermediate filaments in the cytoplasm resulting in a decrease in intercellular adhesion when under mechanical stress); 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 modified residue (asymmetric dimethylarginine; by prmt1); 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

Cardiovascular phenotype — 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 lethal acantholytic epidermolysis bullosa keratosis palmoplantaris striata 2 cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis arrhythmogenic right ventricular cardiomyopathy woolly hair-skin fragility syndrome

Similar variants

DSP p.Arg2834His Conflicting classifications of pathogenicity ★ same residue
DSP p.Arg2834fs Conflicting classifications of pathogenicity ★ 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

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-arg2834cys (accessed [today's date]).

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