Is DSP p.Arg1302Cys (c.3904C>T) pathogenic?

DSP p.Arg1302Cys (c.3904C>T) is classified Conflicting classifications of pathogenicity in DSP (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2025-12-10). AlphaMissense: likely benign (0.1327); Ultra-rare (popmax 0.0107%, afr); Associated with arrhythmogenic right ventricular dysplasia 8.

What condition is associated with DSP p.Arg1302Cys (c.3904C>T)?

DSP p.Arg1302Cys (c.3904C>T) is associated with arrhythmogenic right ventricular dysplasia 8, cardiomyopathy, arrhythmogenic cardiomyopathy with wooly hair and keratoderma (ClinVar).

How common is DSP p.Arg1302Cys (c.3904C>T) in the general population?

DSP p.Arg1302Cys (c.3904C>T) is ultra-rare (popmax 0.0107%, afr) (gnomAD).

What do computational predictors say about DSP p.Arg1302Cys (c.3904C>T)?

AlphaMissense predicts likely benign (score 0.1327) — an in-silico prediction, not a clinical call.

DSP p.Arg1302Cys

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.3904C>T · rs775594375 · VCV691716

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

AlphaMissense

likely benign

0.1327 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0107%, afr)

Conditions

arrhythmogenic right ventricular dysplasia 8

Computational evidence

Protein change
AlphaMissense	0.1327	likely benign
REVEL	0.621	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 1.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 12 kb · p 0.0024 · 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 0.0107% African / African-American · 8/74,870 alleles

Filtering AF 0.00528% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00381%

Overall 0.00143% 23/1,613,920 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0203%	4,934
African / African-Americangrpmax	0.0107%	9,359
Remaining individualsnot grpmax-eligible	0.0048%	20,828
South Asian	0.00439%	22,770
European (non-Finnish)	0.000169%	589,995

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg1302Cys
Coding: c.3904C>T
MANE Select: NM_004415
dbSNP: rs775594375
Type: single nucleotide variant
Location: chr6:7580094 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1302: a UniProt-annotated variant site (in arvd8; uncertain significance); a UniProt-annotated variant site (in dcwhkta; uncertain significance); the 'central fibrous rod domain' region; the 'binds to telomeres' 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: cardiomyopathy arrhythmogenic cardiomyopathy with wooly hair and keratoderma lethal acantholytic epidermolysis bullosa keratosis palmoplantaris striata 2 cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis woolly hair-skin fragility syndrome

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

DSP p.Arg1302His Conflicting classifications of pathogenicity ★ same residue
DSP p.Arg1302Leu 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-arg1302cys (accessed [today's date]).

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