Is DSP p.Arg2826Cys (c.8476C>T) pathogenic?

DSP p.Arg2826Cys (c.8476C>T) is classified Conflicting classifications of pathogenicity in DSP (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-03-26). AlphaMissense: ambiguous (0.4655); Very rare (popmax 0.00134%, afr); Associated with lethal acantholytic epidermolysis bullosa.

What condition is associated with DSP p.Arg2826Cys (c.8476C>T)?

DSP p.Arg2826Cys (c.8476C>T) is associated with lethal acantholytic epidermolysis bullosa, arrhythmogenic cardiomyopathy with wooly hair and keratoderma, arrhythmogenic right ventricular dysplasia 8 (ClinVar).

How common is DSP p.Arg2826Cys (c.8476C>T) in the general population?

DSP p.Arg2826Cys (c.8476C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

How is Lethal acantholytic erosive disorder inherited?

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

What do computational predictors say about DSP p.Arg2826Cys (c.8476C>T)?

AlphaMissense predicts ambiguous (score 0.4655) — an in-silico prediction, not a clinical call.

DSP p.Arg2826Cys

c.8476C>T · rs139969658 · VCV199911

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.4655 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

lethal acantholytic epidermolysis bullosa

Computational evidence

Protein change
AlphaMissense	0.4655	ambiguous
REVEL	0.468	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 0.75, phastCons 1
Regional constraint	o/e 1.05	unconstrained · MANE · 1,308 bp · p 0.26 · regional, not allelic
Overall
CADD	25.8	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 0.00134% African / African-American · 1/74,646 alleles

Filtering AF 0.000543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000429%

Overall 0.00087% 14/1,609,602 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	62,264
African / African-Americangrpmax	0.00134%	74,646
European (non-Finnish)	0.00102%	98,118

Remaining individuals 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.Arg2826Cys
Coding: c.8476C>T
MANE Select: NM_004415
dbSNP: rs139969658
Type: single nucleotide variant
Location: chr6:7585738 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 2826: 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); 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

lethal acantholytic epidermolysis bullosa — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: arrhythmogenic cardiomyopathy with wooly hair and keratoderma arrhythmogenic right ventricular dysplasia 8 keratosis palmoplantaris striata 2 cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis woolly hair-skin fragility syndrome

For Lethal acantholytic erosive disorder (Orphanet):

Inheritance: Autosomal recessive
Onset: Antenatal, Neonatal

Similar variants

DSP p.Arg2826Ser Uncertain significance ★★ same residue
DSP p.Arg2826His Conflicting classifications of pathogenicity ★ same residue
DSP p.Arg2826= Likely benign ★ same residue
DSP p.Arg2826Gly 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

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-arg2826cys (accessed [today's date]).

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