Is PKP2 p.Pro103Ala (c.307C>G) pathogenic?

PKP2 p.Pro103Ala (c.307C>G) is classified Conflicting classifications of pathogenicity in PKP2 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-04-16). AlphaMissense: likely benign (0.067); Very rare (popmax 0.000429%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with PKP2 p.Pro103Ala (c.307C>G)?

PKP2 p.Pro103Ala (c.307C>G) is associated with Cardiovascular phenotype, cardiomyopathy, arrhythmogenic right ventricular dysplasia 9 (ClinVar).

How common is PKP2 p.Pro103Ala (c.307C>G) in the general population?

PKP2 p.Pro103Ala (c.307C>G) is very rare (popmax 0.000429%, nfe) (gnomAD).

What do computational predictors say about PKP2 p.Pro103Ala (c.307C>G)?

AlphaMissense predicts likely benign (score 0.067) — an in-silico prediction, not a clinical call.

PKP2 p.Pro103Ala

c.307C>G · rs139215336 · VCV628363

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.067 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000429%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.067	likely benign
REVEL	0.179	moderately benign-leaning
SaProt	LLR -6.42	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	16.61	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 0.000429% European (non-Finnish) · 5/1,166,566 alleles

Filtering AF 0.000126% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.1e-05%

Overall 0.000376% 6/1,597,354 alleles · very rare exomes 6/1,445,088 · genomes 0/152,266 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00162%	61,806
European (non-Finnish)grpmax	0.000429%	233,313

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.Pro103Ala
Coding: c.307C>G
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

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.Pro103Ser Uncertain significance ★★ ⚠ 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>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

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-pro103ala (accessed [today's date]).

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