Is DSP p.Ser1562Pro (c.4684T>C) pathogenic?

DSP p.Ser1562Pro (c.4684T>C) is classified Uncertain significance in DSP (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-09-19). AlphaMissense: likely pathogenic (0.8584); Very rare (popmax 0.00401%, afr); Associated with cardiomyopathy.

How common is DSP p.Ser1562Pro (c.4684T>C) in the general population?

DSP p.Ser1562Pro (c.4684T>C) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about DSP p.Ser1562Pro (c.4684T>C)?

AlphaMissense predicts likely pathogenic (score 0.8584) — an in-silico prediction, not a clinical call.

DSP p.Ser1562Pro

Q: What condition is associated with DSP p.Ser1562Pro (c.4684T>C)?

DSP p.Ser1562Pro (c.4684T>C) is associated with cardiomyopathy, arrhythmogenic cardiomyopathy with wooly hair and keratoderma, arrhythmogenic right ventricular dysplasia 8 (ClinVar).

c.4684T>C · rs1394590334 · VCV568035

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.8584 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

1/2 damaging

AlphaMissense, REVEL

Conditions

cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.8584	likely pathogenic
REVEL	0.277	benign-leaning
⇒ AlphaMissense calls this damaging; REVEL does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.1	GERP 1.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 12 kb · p 0.0024 · regional, not allelic
Overall
CADD	22.2	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 0.00401% African / African-American · 3/74,856 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000495%

Overall 0.000434% 7/1,613,924 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00401%	24,952
European (non-Finnish)	0.000339%	295,009

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.Ser1562Pro
Coding: c.4684T>C
MANE Select: NM_004415
dbSNP: rs1394590334
Type: single nucleotide variant
Location: chr6:7580874 (GRCh38)
Gene constraint: LOEUF 0.443 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Residue 1562: 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); 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

cardiomyopathy — 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

Similar variants

DSP p.Ser1562Cys Uncertain significance ★ ⚠ same residue
DSP p.Ser1562= Likely benign ★ same residue
DSP p.Ser1562Tyr 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

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-ser1562pro (accessed [today's date]).

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