Is DSP p.Ser1049= (c.3147G>A) pathogenic?

DSP p.Ser1049= (c.3147G>A) is classified Conflicting classifications of pathogenicity in DSP (ClinVar, Conflicting submitters, 10 submitters; last evaluated 2025-10-29). Very rare (popmax 0.004%, afr); Associated with Cardiovascular phenotype.

What condition is associated with DSP p.Ser1049= (c.3147G>A)?

DSP p.Ser1049= (c.3147G>A) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic cardiomyopathy with wooly hair and keratoderma (ClinVar).

How common is DSP p.Ser1049= (c.3147G>A) in the general population?

DSP p.Ser1049= (c.3147G>A) is very rare (popmax 0.004%, afr) (gnomAD).

DSP p.Ser1049=

c.3147G>A · rs756341143 · VCV357948

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 10 submitters

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -5.7	GERP -3.1
Overall
CADD	1.834	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,922 alleles

Filtering AF 0.00188% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00164%

Overall 0.00229% 37/1,614,026 alleles · very rare exomes 34/1,461,860 · genomes 3/152,166 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,974
European (non-Finnish)	0.00263%	38,066
East Asian	0.00223%	44,884
Remaining individualsnot grpmax-eligible	0.0016%	62,486
South Asian	0.0011%	91,080

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.Ser1049=
Coding: c.3147G>A
MANE Select: NM_004415
dbSNP: rs756341143
Type: single nucleotide variant
Location: chr6:7579337 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1049: a UniProt-annotated variant site (in arvd8; uncertain significance); a UniProt-annotated variant site (in dcwhkta; uncertain significance); the 'globular 1' 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

Cardiovascular phenotype — 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 woolly hair-skin fragility syndrome

Similar variants

DSP p.Ser1049Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
DSP p.Ser1049Trp 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-ser1049 (accessed [today's date]).

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