Is DSP p.Arg1537Cys (c.4609C>T) pathogenic?

DSP p.Arg1537Cys (c.4609C>T) is classified Benign/Likely benign in DSP (ClinVar, Multiple submitters, 23 submitters; last evaluated 2026-07-01). AlphaMissense: likely benign (0.1765); Low-frequency (popmax 1.66%, nfe); Associated with arrhythmogenic right ventricular cardiomyopathy.

What condition is associated with DSP p.Arg1537Cys (c.4609C>T)?

DSP p.Arg1537Cys (c.4609C>T) is associated with arrhythmogenic right ventricular cardiomyopathy, cardiomyopathy, arrhythmogenic cardiomyopathy with wooly hair and keratoderma (ClinVar).

How common is DSP p.Arg1537Cys (c.4609C>T) in the general population?

DSP p.Arg1537Cys (c.4609C>T) is low-frequency (popmax 1.66%, nfe) (gnomAD).

What do computational predictors say about DSP p.Arg1537Cys (c.4609C>T)?

AlphaMissense predicts likely benign (score 0.1765) — an in-silico prediction, not a clinical call.

DSP p.Arg1537Cys

c.4609C>T · rs28763967 · VCV44917

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 23 submitters

AlphaMissense

likely benign

0.1765 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.66%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, REVEL

Conditions

arrhythmogenic right ventricular cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.1765	likely benign
REVEL	0.277	benign-leaning
⇒ AlphaMissense and REVEL both call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 12 kb · p 0.0024 · regional, not allelic
Overall
CADD	24.9	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 1.66% European (non-Finnish) · 19,593/1,180,034 alleles

Filtering AF 1.64% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.63%

Overall 1.32% 21,306/1,614,112 alleles · low-frequency

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	1.66%	60
Remaining individualsnot grpmax-eligible	1.15%	87
Admixed American	0.702%	143
Amishnot grpmax-eligible	0.548%	182
Finnishnot grpmax-eligible	0.392%	255
African / African-American	0.291%	344
Middle Eastern	0.115%	866
Ashkenazi Jewishnot grpmax-eligible	0.0946%	1,057
South Asian	0.067%	1,493
East Asian	0.00446%	22,444

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.Arg1537Cys
Coding: c.4609C>T
MANE Select: NM_004415
dbSNP: rs28763967
Type: single nucleotide variant
Location: chr6:7580799 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1537: 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); 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 cardiomyopathy — 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 Brugada syndrome woolly hair-skin fragility syndrome

Similar variants

DSP p.Arg1537His Conflicting classifications of pathogenicity ★ ⚠ same residue
DSP p.Arg1537Ser Uncertain significance ★ ⚠ 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-arg1537cys (accessed [today's date]).

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