Is PKP2 p.Cys603Trp (c.1809T>G) pathogenic?

PKP2 p.Cys603Trp (c.1809T>G) is classified Uncertain significance in PKP2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-10-25). AlphaMissense: likely pathogenic (0.9695); Ultra-rare (popmax 0.0109%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with PKP2 p.Cys603Trp (c.1809T>G)?

PKP2 p.Cys603Trp (c.1809T>G) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic right ventricular dysplasia 9 (ClinVar).

How common is PKP2 p.Cys603Trp (c.1809T>G) in the general population?

PKP2 p.Cys603Trp (c.1809T>G) is ultra-rare (popmax 0.0109%, nfe) (gnomAD).

What do computational predictors say about PKP2 p.Cys603Trp (c.1809T>G)?

AlphaMissense predicts likely pathogenic (score 0.9695) — an in-silico prediction, not a clinical call.

PKP2 p.Cys603Trp

c.1809T>G · rs767935208 · VCV567604

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

likely pathogenic

0.9695 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0109%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.9695	likely pathogenic · top 6% in PKP2
REVEL	0.766	pathogenic-leaning
SaProt	LLR -12.55	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.1	phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 104 kb · p 0.0023 · regional, not allelic
Overall
CADD	23.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM C647W vs ClinVar C603W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0109% European (non-Finnish) · 129/1,180,048 alleles

Filtering AF 0.00936% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00879%

Overall 0.00824% 133/1,614,022 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0109%	9,148
Remaining individualsnot grpmax-eligible	0.0032%	31,243
African / African-American	0.00267%	37,463

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.Cys603Trp
Coding: c.1809T>G
MANE Select: NM_001005242
dbSNP: rs767935208
Type: single nucleotide variant
Location: chr12:32822497 (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 arrhythmogenic right ventricular cardiomyopathy

Similar variants

PKP2 p.Cys603= Likely benign ★★ same residue
PKP2 p.Cys603fs Pathogenic/Likely pathogenic ★★ same residue
PKP2 c.1034+1G>A Likely pathogenic ★★ same condition
PKP2 c.1034+1G>C Likely pathogenic ★★ same condition
PKP2 c.1034+1G>T Likely pathogenic ★★ same condition
PKP2 c.1035-2A>G Likely pathogenic ★★ same condition
PKP2 c.1170+1G>A Pathogenic/Likely pathogenic ★★ same condition
PKP2 c.1170+1G>C 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-cys603trp (accessed [today's date]).

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