Is DSP p.Ser594Arg (c.1782C>A) pathogenic?

DSP p.Ser594Arg (c.1782C>A) is classified Likely pathogenic in DSP (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-07-01). AlphaMissense: likely pathogenic (0.9848); Absent from gnomAD v4.1; Associated with keratosis palmoplantaris striata 2.

What condition is associated with DSP p.Ser594Arg (c.1782C>A)?

DSP p.Ser594Arg (c.1782C>A) is associated with keratosis palmoplantaris striata 2 (ClinVar).

How common is DSP p.Ser594Arg (c.1782C>A) in the general population?

DSP p.Ser594Arg (c.1782C>A) is absent from gnomAD v4.1 (gnomAD).

How is Striate palmoplantar keratoderma inherited?

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

What do computational predictors say about DSP p.Ser594Arg (c.1782C>A)?

AlphaMissense predicts likely pathogenic (score 0.9848) — an in-silico prediction, not a clinical call.

DSP p.Ser594Arg

c.1782C>A · rs2533894081 · VCV1710286

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9848 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

keratosis palmoplantaris striata 2

Computational evidence

Protein change
AlphaMissense	0.9848	likely pathogenic ✓ concordant with ClinVar · top 6% in DSP
REVEL	0.523	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 0.015, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 1,387 bp · p 1.5e-05 · regional, not allelic
Overall
CADD	24.5	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DSP
Protein: p.Ser594Arg
Coding: c.1782C>A
MANE Select: NM_004415
dbSNP: rs2533894081
Type: single nucleotide variant
Location: chr6:7571463 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 594: an α-helix; the 'globular 1' region; the 'interaction with mapre1' 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); 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

keratosis palmoplantaris striata 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Striate palmoplantar keratoderma (Orphanet):

Inheritance: Autosomal dominant
Onset: Infancy, Neonatal

Similar variants

DSP c.939+1G>A Pathogenic/Likely pathogenic ★★ same condition
DSP p.Arg1400Ter Pathogenic/Likely pathogenic ★★ same condition
DSP p.Gln331Ter Pathogenic ★★ same condition
DSP p.Glu1081Ter Pathogenic/Likely pathogenic ★★ same condition
DSP p.Lys2356Ter Pathogenic/Likely pathogenic ★★ same condition
DSP p.Tyr1169Ter Likely pathogenic ★★ same condition
DSP p.Tyr2547Ter Pathogenic/Likely pathogenic ★★ same condition
DSP c.1044+3A>C Uncertain significance ★★ 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-ser594arg (accessed [today's date]).

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