Is PKP2 p.Pro84Ser (c.250C>T) pathogenic?

PKP2 p.Pro84Ser (c.250C>T) is classified Uncertain significance in PKP2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-04-01). AlphaMissense: likely pathogenic (0.7692); Very rare (popmax 0.00394%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with PKP2 p.Pro84Ser (c.250C>T)?

PKP2 p.Pro84Ser (c.250C>T) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic right ventricular dysplasia 9 (ClinVar).

How common is PKP2 p.Pro84Ser (c.250C>T) in the general population?

PKP2 p.Pro84Ser (c.250C>T) is very rare (popmax 0.00394%, nfe) (gnomAD).

What do computational predictors say about PKP2 p.Pro84Ser (c.250C>T)?

AlphaMissense predicts likely pathogenic (score 0.7692) — an in-silico prediction, not a clinical call.

PKP2 p.Pro84Ser

c.250C>T · rs756468173 · VCV378367

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.7692 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00394%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.7692	likely pathogenic
REVEL	0.561	indeterminate
SaProt	LLR -6.66	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 12	phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 104 kb · p 0.0023 · regional, not allelic
Overall
CADD	24.6	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 0.00394% European (non-Finnish) · 46/1,166,830 alleles

Filtering AF 0.00302% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0027%

Overall 0.003% 48/1,597,646 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00394%	25,366
Remaining individualsnot grpmax-eligible	0.00323%	30,913

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.Pro84Ser
Coding: c.250C>T
MANE Select: NM_001005242
dbSNP: rs756468173
Type: single nucleotide variant
Location: chr12:32879006 (GRCh38)
Gene constraint: LOEUF 1.105 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.32 · 1 PDB
Residue 84: 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: cardiomyopathy arrhythmogenic right ventricular dysplasia 9 arrhythmogenic right ventricular cardiomyopathy

Similar variants

PKP2 p.Pro84= Likely benign ★★ same residue
PKP2 p.Pro84fs 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-pro84ser (accessed [today's date]).

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