Is PKP2 p.Ile778Phe (c.2332A>T) pathogenic?

PKP2 p.Ile778Phe (c.2332A>T) is classified Uncertain significance in PKP2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-08-08). AlphaMissense: ambiguous (0.464); Very rare (popmax 8.47e-05%, nfe); Associated with arrhythmogenic right ventricular cardiomyopathy.

What condition is associated with PKP2 p.Ile778Phe (c.2332A>T)?

PKP2 p.Ile778Phe (c.2332A>T) is associated with arrhythmogenic right ventricular cardiomyopathy, cardiomyopathy (ClinVar).

How common is PKP2 p.Ile778Phe (c.2332A>T) in the general population?

PKP2 p.Ile778Phe (c.2332A>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about PKP2 p.Ile778Phe (c.2332A>T)?

AlphaMissense predicts ambiguous (score 0.464) — an in-silico prediction, not a clinical call.

PKP2 p.Ile778Phe

c.2332A>T · rs145324631 · VCV191763

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.464 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

arrhythmogenic right ventricular cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.464	ambiguous
REVEL	0.345	indeterminate
SaProt	LLR -9.10	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 104 kb · p 0.0023 · regional, not allelic
Overall
CADD	21.1	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM I822F vs ClinVar I778F) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,010 alleles

Overall 0.000205% 3/1,461,882 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,802
European (non-Finnish)grpmax	8.47e-05%	1,180,011

Ashkenazi Jewish 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.Ile778Phe
Coding: c.2332A>T
MANE Select: NM_001005242
dbSNP: rs145324631
Type: single nucleotide variant
Location: chr12:32796134 (GRCh38)
Gene constraint: LOEUF 1.105 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.32 · 1 PDB
Residue 778: a UniProt-annotated variant site (in arvd9; uncertain significance)

Full PKP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: cardiomyopathy

Similar variants

PKP2 p.Ile778Val 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.1170+2T>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

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-ile778phe (accessed [today's date]).

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