Is DSP p.Arg2834fs (c.8496_8500dup) pathogenic?

DSP p.Arg2834fs (c.84968500dup) is classified Conflicting classifications of pathogenicity in DSP (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-01-22). Very rare (popmax 0.00337%, amr); Associated with arrhythmogenic cardiomyopathy with wooly hair and keratoderma.

How common is DSP p.Arg2834fs (c.8496_8500dup) in the general population?

DSP p.Arg2834fs (c.8496_8500dup) is very rare (popmax 0.00337%, amr) (gnomAD).

How is Carvajal syndrome inherited?

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

DSP p.Arg2834fs

Q: What condition is associated with DSP p.Arg2834fs (c.8496_8500dup)?

DSP p.Arg2834fs (c.8496_8500dup) is associated with arrhythmogenic cardiomyopathy with wooly hair and keratoderma, arrhythmogenic right ventricular dysplasia 8 (ClinVar).

c.8496_8500dup · rs1561706117 · VCV2098315

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00337%, amr)

Conditions

arrhythmogenic cardiomyopathy with wooly hair and keratoderma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	escapes	premature termination codon in the last exon (24 of 24) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 8.2	GERP 0.83, phastCons 1
Region caveats
Repeat context	tandem	TCCCGCTCCGGA simple repeat · ambiguous alignment · confidence, not pathogenicity

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00337% Admixed American · 2/59,286 alleles

Filtering AF 0.00056% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000209%

Overall 0.000124% 2/1,608,130 alleles · very rare exomes 2/1,456,024 · genomes 0/152,106 · joint denominator

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.Arg2834fs
Coding: c.8496_8500dup
MANE Select: NM_004415
dbSNP: rs1561706117
Type: Duplication
Location: chr6:7585757 (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

arrhythmogenic cardiomyopathy with wooly hair and keratoderma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: arrhythmogenic right ventricular dysplasia 8

For Carvajal syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Childhood, Infancy, Neonatal

Similar variants

DSP p.Arg2834Cys Conflicting classifications of pathogenicity ★ same residue
DSP p.Arg2834His Conflicting classifications of pathogenicity ★ same residue
DSP p.Arg2151fs Pathogenic/Likely pathogenic ★★ same condition
DSP p.Arg2156fs Pathogenic/Likely pathogenic ★★ same condition
DSP p.Asn1865fs Pathogenic ★★ same condition
DSP p.Asn274fs Pathogenic ★★ same condition
DSP p.Asp1248fs Pathogenic ★★ same condition
DSP p.Gln216fs 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-arg2834fs (accessed [today's date]).

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