Is PKP2 p.Pro33= (c.99C>T) pathogenic?

PKP2 p.Pro33= (c.99C>T) is classified Likely benign in PKP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-16). Very rare (popmax 0.00114%, sas); Associated with cardiomyopathy.

What condition is associated with PKP2 p.Pro33= (c.99C>T)?

PKP2 p.Pro33= (c.99C>T) is associated with cardiomyopathy (ClinVar).

How common is PKP2 p.Pro33= (c.99C>T) in the general population?

PKP2 p.Pro33= (c.99C>T) is very rare (popmax 0.00114%, sas) (gnomAD).

PKP2 p.Pro33=

c.99C>T · rs778749586 · VCV1331811

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00114%, sas)

Conditions

cardiomyopathy

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 0.32	phastCons 0.97
Overall
CADD	12.03	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00114% South Asian · 1/87,728 alleles

Overall 0.000127% 2/1,579,094 alleles · very rare exomes 2/1,426,748 · genomes 0/152,346 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00163%	61,484
South Asiangrpmax	0.00114%	87,728

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro33=
Coding: c.99C>T
MANE Select: NM_001005242
dbSNP: rs778749586
Type: single nucleotide variant
Location: chr12:32896633 (GRCh38)
Gene constraint: LOEUF 1.105 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.32 · 1 PDB
Residue 33: the 'required for interaction with influenza a virus rna polymerase subunit pb1' region; 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

cardiomyopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PKP2 p.Pro33Ser Uncertain significance ★ ⚠ same residue
PKP2 c.1034+1G>C Likely pathogenic ★★ same condition
PKP2 c.1034+1G>T Likely pathogenic ★★ same condition
PKP2 c.1170+1G>A Pathogenic/Likely pathogenic ★★ same condition
PKP2 c.1171-2A>G Pathogenic/Likely pathogenic ★★ same condition
PKP2 c.1378+1G>A Pathogenic/Likely pathogenic ★★ same condition
PKP2 c.1378+1G>C Pathogenic/Likely pathogenic ★★ same condition
PKP2 c.1556+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-pro33 (accessed [today's date]).

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