Is DSP p.Glu422Asp (c.1266G>C) pathogenic?

DSP p.Glu422Asp (c.1266G>C) is classified Uncertain significance in DSP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-17). AlphaMissense: ambiguous (0.5483); Absent from gnomAD v4.1; Associated with arrhythmogenic cardiomyopathy with wooly hair and keratoderma.

How common is DSP p.Glu422Asp (c.1266G>C) in the general population?

DSP p.Glu422Asp (c.1266G>C) is absent from gnomAD v4.1 (gnomAD).

How is Carvajal syndrome inherited?

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

What do computational predictors say about DSP p.Glu422Asp (c.1266G>C)?

AlphaMissense predicts ambiguous (score 0.5483) — an in-silico prediction, not a clinical call.

DSP p.Glu422Asp

Q: What condition is associated with DSP p.Glu422Asp (c.1266G>C)?

DSP p.Glu422Asp (c.1266G>C) is associated with arrhythmogenic cardiomyopathy with wooly hair and keratoderma, arrhythmogenic right ventricular dysplasia 8 (ClinVar).

c.1266G>C · rs1758913797 · VCV955229

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5483 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

arrhythmogenic cardiomyopathy with wooly hair and keratoderma

Computational evidence

Protein change
AlphaMissense	0.5483	ambiguous
REVEL	0.127	moderately benign-leaning
Splicing
SpliceAI	Δ0.38	donor loss · deltas
Pangolin	Δ0.71	loss · gain 0.01 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 29 kb · p 0.14 · regional, not allelic
Overall
CADD	34.0	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.Glu422Asp
Coding: c.1266G>C
MANE Select: NM_004415
dbSNP: rs1758913797
Type: single nucleotide variant
Location: chr6:7567906 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 422: an α-helix; the 'globular 1' region; the 'interaction with mapre1' region; the 'interaction with jup and pkp2' 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)

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

Disease context

arrhythmogenic cardiomyopathy with wooly hair and keratoderma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: arrhythmogenic right ventricular dysplasia 8

For Carvajal syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive
Onset: Childhood, Infancy, Neonatal

Similar variants

DSP p.Glu422= Uncertain significance ★★ same residue
DSP p.Glu422Lys 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-glu422asp (accessed [today's date]).

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