Is PKP2 p.Pro103Ser (c.307C>T) pathogenic?

PKP2 p.Pro103Ser (c.307C>T) is classified Uncertain significance in PKP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-25). AlphaMissense: likely benign (0.0789); Absent from gnomAD v4.1; Associated with arrhythmogenic right ventricular dysplasia 9.

What condition is associated with PKP2 p.Pro103Ser (c.307C>T)?

PKP2 p.Pro103Ser (c.307C>T) is associated with arrhythmogenic right ventricular dysplasia 9 (ClinVar).

How common is PKP2 p.Pro103Ser (c.307C>T) in the general population?

PKP2 p.Pro103Ser (c.307C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PKP2 p.Pro103Ser (c.307C>T)?

AlphaMissense predicts likely benign (score 0.0789) — an in-silico prediction, not a clinical call.

PKP2 p.Pro103Ser

Q: How is Inherited isolated arrhythmogenic cardiomyopathy inherited?

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

c.307C>T · rs139215336 · VCV1485413

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0789 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

arrhythmogenic right ventricular dysplasia 9

Computational evidence

Protein change
AlphaMissense	0.0789	likely benign
REVEL	0.048	moderately benign-leaning
SaProt	LLR -6.01	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 3.2	phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 104 kb · p 0.0023 · regional, not allelic
Overall
CADD	16.95	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PKP2
Protein: p.Pro103Ser
Coding: c.307C>T
MANE Select: NM_001005242
dbSNP: rs139215336
Type: single nucleotide variant
Location: chr12:32878949 (GRCh38)
Gene constraint: LOEUF 1.105 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 64.32 · 1 PDB
Residue 103: 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.Pro103Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
PKP2 p.Pro103Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
PKP2 p.Pro103= Likely benign ★ same residue
PKP2 p.Pro103fs Pathogenic ★ 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

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-pro103ser (accessed [today's date]).

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