Is PKP2 p.Cys603fs (c.1807_1829del) pathogenic?

PKP2 p.Cys603fs (c.18071829del) is classified Pathogenic/Likely pathogenic in PKP2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-12-28). Very rare (popmax 8.47e-05%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with PKP2 p.Cys603fs (c.1807_1829del)?

PKP2 p.Cys603fs (c.1807_1829del) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic right ventricular dysplasia 9 (ClinVar).

How common is PKP2 p.Cys603fs (c.1807_1829del) in the general population?

PKP2 p.Cys603fs (c.1807_1829del) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

PKP2 p.Cys603fs

c.1807_1829del · rs1555142963 · VCV423349

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 8 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 3.3	phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,996 alleles

Overall 6.2e-05% 1/1,614,004 alleles · very rare exomes 1/1,461,630 · genomes 0/152,374 · joint denominator

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: PKP2
Protein: p.Cys603fs
Coding: c.1807_1829del
MANE Select: NM_001005242
dbSNP: rs1555142963
Type: Deletion
Location: chr12:32822477 (GRCh38)
Gene constraint: LOEUF 1.105 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.32 · 1 PDB
Residue 603: a UniProt-annotated variant site (in arvd9; uncertain significance); an α-helix

Full PKP2 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 right ventricular dysplasia 9

Similar variants

PKP2 p.Cys603Trp Uncertain significance ★★ ⚠ same residue
PKP2 p.Cys603= Likely benign ★★ same residue
PKP2 c.224-1639_274del Pathogenic/Likely pathogenic ★★ same condition
PKP2 c.2437_2445+41del Pathogenic/Likely pathogenic ★★ same condition
PKP2 p.Ala418fs Pathogenic/Likely pathogenic ★★ same condition
PKP2 p.Ala657fs Pathogenic/Likely pathogenic ★★ same condition
PKP2 p.Ala796fs Pathogenic/Likely pathogenic ★★ same condition
PKP2 p.Arg591fs 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/pkp2-p-cys603fs (accessed [today's date]).

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