Is PKP2 p.Phe339= (c.1017C>T) pathogenic?

PKP2 p.Phe339= (c.1017C>T) is classified Conflicting classifications of pathogenicity in PKP2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-11-20). Very rare (popmax 0.00267%, afr); Associated with Cardiovascular phenotype.

What condition is associated with PKP2 p.Phe339= (c.1017C>T)?

PKP2 p.Phe339= (c.1017C>T) is associated with Cardiovascular phenotype, arrhythmogenic right ventricular dysplasia 9, arrhythmogenic right ventricular cardiomyopathy (ClinVar).

How common is PKP2 p.Phe339= (c.1017C>T) in the general population?

PKP2 p.Phe339= (c.1017C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

PKP2 p.Phe339=

c.1017C>T · rs751068912 · VCV1747471

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

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 3.4	phastCons 0.99
Overall
CADD	5.522	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,922 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00197% 3/152,254 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,461
Admixed American	0.00167%	60,006

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.Phe339=
Coding: c.1017C>T
MANE Select: NM_001005242
dbSNP: rs751068912
Type: single nucleotide variant
Location: chr12:32877863 (GRCh38)
Gene constraint: LOEUF 1.105 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.32 · 1 PDB
Residue 339: the 'required for interaction with influenza a virus rna polymerase subunit pb1' region; a UniProt-annotated variant site (in arvd9; uncertain significance); the 'required for binding to single-stranded dna' region

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: arrhythmogenic right ventricular dysplasia 9 arrhythmogenic right ventricular cardiomyopathy

Similar variants

PKP2 p.Phe339Cys Uncertain significance ★ ⚠ 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
PKP2 c.1170+2T>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-phe339 (accessed [today's date]).

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