Is PKP2 p.Ser102Phe (c.305C>T) pathogenic?

PKP2 p.Ser102Phe (c.305C>T) is classified Conflicting classifications of pathogenicity in PKP2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-12-16). AlphaMissense: likely benign (0.0907); Very rare (popmax 6.26e-05%); Associated with Cardiovascular phenotype.

What condition is associated with PKP2 p.Ser102Phe (c.305C>T)?

PKP2 p.Ser102Phe (c.305C>T) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic right ventricular dysplasia 9 (ClinVar).

How common is PKP2 p.Ser102Phe (c.305C>T) in the general population?

PKP2 p.Ser102Phe (c.305C>T) is very rare (popmax 6.26e-05%) (gnomAD).

What do computational predictors say about PKP2 p.Ser102Phe (c.305C>T)?

AlphaMissense predicts likely benign (score 0.0907) — an in-silico prediction, not a clinical call.

PKP2 p.Ser102Phe

c.305C>T · rs990377209 · VCV1405775

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0907 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 6.26e-05%)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.0907	likely benign
REVEL	0.16	moderately benign-leaning
SaProt	LLR -8.44	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	phastCons 0.96
Regional constraint	o/e 0.91	unconstrained · MANE · 104 kb · p 0.0023 · regional, not allelic
Overall
CADD	14.6	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 6.26e-05%

Overall 6.26e-05% 1/1,598,704 alleles · very rare exomes 1/1,446,430 · genomes 0/152,274 · joint denominator

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.Ser102Phe
Coding: c.305C>T
MANE Select: NM_001005242
dbSNP: rs990377209
Type: single nucleotide variant
Location: chr12:32878951 (GRCh38)
Gene constraint: LOEUF 1.105 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.32 · 1 PDB
Residue 102: 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

Similar variants

PKP2 p.Ser102= Likely benign ★ 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-ser102phe (accessed [today's date]).

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