Is PKP2 p.Arg196Pro (c.587G>C) pathogenic?

PKP2 p.Arg196Pro (c.587G>C) is classified Uncertain significance in PKP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-21). AlphaMissense: likely pathogenic (0.836); Very rare (popmax 0.00267%, afr); Associated with arrhythmogenic right ventricular dysplasia 9.

What condition is associated with PKP2 p.Arg196Pro (c.587G>C)?

PKP2 p.Arg196Pro (c.587G>C) is associated with arrhythmogenic right ventricular dysplasia 9 (ClinVar).

How common is PKP2 p.Arg196Pro (c.587G>C) in the general population?

PKP2 p.Arg196Pro (c.587G>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about PKP2 p.Arg196Pro (c.587G>C)?

AlphaMissense predicts likely pathogenic (score 0.836) — an in-silico prediction, not a clinical call.

PKP2 p.Arg196Pro

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.587G>C · VCV4719937

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.836 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

arrhythmogenic right ventricular dysplasia 9

Computational evidence

Protein change
AlphaMissense	0.836	likely pathogenic
REVEL	0.501	indeterminate
SaProt	LLR -6.79	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	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

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/75,038 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000205% 3/1,461,470 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,519
South Asian	0.0011%	91,084

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.Arg196Pro
Coding: c.587G>C
MANE Select: NM_001005242
Type: single nucleotide variant
Location: chr12:32878293 (GRCh38)
Gene constraint: LOEUF 1.105 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.32 · 1 PDB
Residue 196: 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

arrhythmogenic right ventricular dysplasia 9 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Inherited isolated arrhythmogenic cardiomyopathy (Orphanet):

Inheritance: Autosomal dominant
Onset: No data available

Similar variants

PKP2 p.Arg196Cys Uncertain significance ★★ ⚠ same residue
PKP2 p.Arg196His Uncertain significance ★★ same residue
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-arg196pro (accessed [today's date]).

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