Is DSP p.Arg2759His (c.8276G>A) pathogenic?

DSP p.Arg2759His (c.8276G>A) is classified Uncertain significance in DSP (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-27). AlphaMissense: ambiguous (0.5028); Very rare (popmax 0.00203%, nfe); Associated with arrhythmogenic cardiomyopathy with wooly hair and keratoderma.

What condition is associated with DSP p.Arg2759His (c.8276G>A)?

DSP p.Arg2759His (c.8276G>A) is associated with arrhythmogenic cardiomyopathy with wooly hair and keratoderma, cardiomyopathy, arrhythmogenic right ventricular dysplasia 8 (ClinVar).

How common is DSP p.Arg2759His (c.8276G>A) in the general population?

DSP p.Arg2759His (c.8276G>A) is very rare (popmax 0.00203%, nfe) (gnomAD).

How is Carvajal syndrome inherited?

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

What do computational predictors say about DSP p.Arg2759His (c.8276G>A)?

AlphaMissense predicts ambiguous (score 0.5028) — an in-silico prediction, not a clinical call.

DSP p.Arg2759His

c.8276G>A · rs936541705 · VCV836478

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.5028 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00203%, nfe)

Conditions

arrhythmogenic cardiomyopathy with wooly hair and keratoderma

Computational evidence

Protein change
AlphaMissense	0.5028	ambiguous
REVEL	0.452	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.9, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 1,308 bp · p 0.26 · regional, not allelic
Overall
CADD	24.3	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 0.00203% European (non-Finnish) · 24/1,180,020 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00178% 26/1,461,848 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00203%	49,168
African / African-American	0.00133%	75,038
South Asian	0.0011%	91,074

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.Arg2759His
Coding: c.8276G>A
MANE Select: NM_004415
dbSNP: rs936541705
Type: single nucleotide variant
Location: chr6:7585538 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2759: 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); an α-helix; the 'binds to telomeres' region; the 'globular 2' region; the '4.5 x 38 aa tandem repeats (domain c)' 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 cardiomyopathy with wooly hair and keratoderma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: cardiomyopathy arrhythmogenic right ventricular dysplasia 8

For Carvajal syndrome (Orphanet):

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

Similar variants

DSP p.Arg2759Cys Uncertain significance ★★ same residue
DSP p.Arg2759= 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
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-arg2759his (accessed [today's date]).

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