Is PKP2 p.Arg441= (c.1323G>T) pathogenic?

PKP2 p.Arg441= (c.1323G>T) is classified Conflicting classifications of pathogenicity in PKP2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2026-01-31). Rare (popmax 0.332%, eas); Associated with Cardiovascular phenotype.

What condition is associated with PKP2 p.Arg441= (c.1323G>T)?

PKP2 p.Arg441= (c.1323G>T) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic right ventricular dysplasia 9 (ClinVar).

How common is PKP2 p.Arg441= (c.1323G>T) in the general population?

PKP2 p.Arg441= (c.1323G>T) is rare (popmax 0.332%, eas) (gnomAD).

PKP2 p.Arg441=

c.1323G>T · rs3748278 · VCV308510

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.332%, eas)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.41	phastCons 0.076
Overall
CADD	6.926	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.332% East Asian · 149/44,882 alleles

Filtering AF 0.288% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.272%

Overall 0.00948% 153/1,613,456 alleles · rare exomes 151/1,461,404 · genomes 2/152,052 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.332%	301
Remaining individualsnot grpmax-eligible	0.0032%	31,219
South Asian	0.0011%	91,038
European (non-Finnish)	8.48e-05%	1,179,852

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.Arg441=
Coding: c.1323G>T
MANE Select: NM_001005242
dbSNP: rs3748278
Type: single nucleotide variant
Location: chr12:32850821 (GRCh38)
Gene constraint: LOEUF 1.105 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.32 · 1 PDB
Residue 441: 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.Arg441Pro Uncertain significance ★★ ⚠ same residue
PKP2 p.Arg441Trp Uncertain significance ★★ ⚠ same residue
PKP2 p.Arg441Gln Conflicting classifications of pathogenicity ★ ⚠ 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

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-arg441 (accessed [today's date]).

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