Is DSP p.Arg243Cys (c.727C>T) pathogenic?

DSP p.Arg243Cys (c.727C>T) is classified Uncertain significance in DSP (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-02-18). AlphaMissense: likely pathogenic (0.7681); Very rare (popmax 0.00167%, amr); Associated with woolly hair-skin fragility syndrome.

What condition is associated with DSP p.Arg243Cys (c.727C>T)?

DSP p.Arg243Cys (c.727C>T) is associated with woolly hair-skin fragility syndrome, cardiomyopathy, arrhythmogenic cardiomyopathy with wooly hair and keratoderma (ClinVar).

How common is DSP p.Arg243Cys (c.727C>T) in the general population?

DSP p.Arg243Cys (c.727C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about DSP p.Arg243Cys (c.727C>T)?

AlphaMissense predicts likely pathogenic (score 0.7681) — an in-silico prediction, not a clinical call.

DSP p.Arg243Cys

c.727C>T · rs1191710190 · VCV1444113

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely pathogenic

0.7681 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Conditions

woolly hair-skin fragility syndrome

Computational evidence

Protein change
AlphaMissense	0.7681	likely pathogenic
REVEL	0.618	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 29 kb · p 0.14 · regional, not allelic
Overall
CADD	25.1	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 0.00167% Admixed American · 1/59,998 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000434% 7/1,612,998 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	59,998
African / African-American	0.00134%	74,880
European (non-Finnish)	0.000424%	235,820

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.Arg243Cys
Coding: c.727C>T
MANE Select: NM_004415
dbSNP: rs1191710190
Type: single nucleotide variant
Location: chr6:7563736 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 243: the 'globular 1' region; the 'interaction with mapre1' region; the 'interaction with jup and pkp2' region; the 'interaction with pkp1' region; a UniProt-annotated variant site (in arvd8; uncertain significance); a UniProt-annotated variant site (in dcwhkta; uncertain significance); a UniProt-annotated variant site (in arvd8; likely pathogenic; results in an unstable protein that forms perinuclear aggregates)

Full DSP gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

woolly hair-skin fragility syndrome — 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

Similar variants

DSP p.Arg243His Uncertain significance ★★ same residue
DSP p.Arg243Ser Uncertain significance ★★ same residue
DSP p.Arg243= 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

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-arg243cys (accessed [today's date]).

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