Is DSP p.Glu1833Val (c.5498A>T) pathogenic?

DSP p.Glu1833Val (c.5498A>T) is classified Conflicting classifications of pathogenicity in DSP (ClinVar, Conflicting submitters, 26 submitters; last evaluated 2026-06-01). AlphaMissense: ambiguous (0.5403); Low-frequency (popmax 1.22%, nfe); Associated with arrhythmogenic cardiomyopathy with wooly hair and keratoderma.

How common is DSP p.Glu1833Val (c.5498A>T) in the general population?

DSP p.Glu1833Val (c.5498A>T) is low-frequency (popmax 1.22%, nfe) (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.Glu1833Val (c.5498A>T)?

AlphaMissense predicts ambiguous (score 0.5403) — an in-silico prediction, not a clinical call.

DSP p.Glu1833Val

Q: What condition is associated with DSP p.Glu1833Val (c.5498A>T)?

DSP p.Glu1833Val (c.5498A>T) is associated with arrhythmogenic cardiomyopathy with wooly hair and keratoderma, long QT syndrome, cardiomyopathy (ClinVar).

c.5498A>T · rs78652302 · VCV44929

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 26 submitters

AlphaMissense

ambiguous

0.5403 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.22%, nfe)

Conditions

arrhythmogenic cardiomyopathy with wooly hair and keratoderma

Computational evidence

Protein change
AlphaMissense	0.5403	ambiguous
REVEL	0.245	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 1.2, 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 1.22% European (non-Finnish) · 14,336/1,179,812 alleles

Filtering AF 1.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.19%

Overall 1.07% 17,229/1,613,852 alleles · low-frequency

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	2.46%	41
European (non-Finnish)grpmax	1.22%	82
Remaining individualsnot grpmax-eligible	0.984%	102
Ashkenazi Jewishnot grpmax-eligible	0.831%	120
Admixed American	0.422%	237
African / African-American	0.196%	510
Middle Eastern	0.0825%	1,212
South Asian	0.056%	1,786
East Asian	0.00223%	44,872

Finnish 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.Glu1833Val
Coding: c.5498A>T
MANE Select: NM_004415
dbSNP: rs78652302
Type: single nucleotide variant
Location: chr6:7582760 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1833: 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 cardiomyopathy with wooly hair and keratoderma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: long QT syndrome cardiomyopathy hypertrophic cardiomyopathy hypertrophic cardiomyopathy 2 arrhythmogenic right ventricular dysplasia 8 lethal acantholytic epidermolysis bullosa keratosis palmoplantaris striata 2 cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis arrhythmogenic right ventricular cardiomyopathy woolly hair-skin fragility syndrome

For Carvajal syndrome (Orphanet):

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

Similar variants

DSP p.Glu1833= Benign/Likely benign ★★ same residue
DSP p.Glu1833Ter Likely pathogenic ★ 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-glu1833val (accessed [today's date]).

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