NM_198578.4:c.6055G>A (p.Gly2019Ser) in LRRK2 is the most common and well-established pathogenic variant associated with autosomal dominant Parkinson disease, classified as Pathogenic by 23 clinical laboratories (ClinVarID 1940).

PS4_VeryStrong: Overwhelming case-control evidence shows significant enrichment in Parkinson disease patients across multiple populations, with an odds ratio of 17.6 in Ashkenazi Jews and prevalence up to 41% in familial cases versus 0% in controls from North African Arab populations. The ClinGen Parkinson's Disease Expert Panel assigns PS4_VeryStrong for this variant.

PS3_Strong: Well-established functional studies consistently demonstrate G2019S increases LRRK2 kinase activity 2-3 fold relative to wild-type, and this increased kinase activity mediates neuronal toxicity, confirming a pathogenic gain-of-function mechanism.

PP1_Strong: Strong co-segregation with disease demonstrated across multiple large families in diverse populations, with shared founder haplotypes dating to the 13th century in European and North African populations and independent founder events in Japanese populations.

PM1_Moderate: The variant is located in the kinase activation loop, a critical functional domain. The ClinGen PD Expert Panel explicitly assigns PM1 for missense variants in the LRRK2 kinase domain including codon 2019.

PM2_Supporting: The variant is present at very low frequency in population databases (gnomAD v2.1 AF=0.0488%, 138/282,542 alleles; absent from gnomAD v4.1).

PP3_Supporting: Multiple in silico tools predict a damaging effect (REVEL=0.97, BayesDel=0.57).

PP5_Supporting: Reported as Pathogenic by 23 clinical diagnostic laboratories in ClinVar.

Using the generic ACMG/AMP 2015 classification framework (the ClinGen LRRK2 VCEP v1.0.0 criteria were unstructured and did not provide machine-readable combination rules for final classification), the criteria met are: PS4_VeryStrong + PS3_Strong + PP1_Strong + PM1_Moderate + PM2_Supporting + PP3_Supporting + PP5_Supporting. This combination overwhelmingly exceeds the threshold for Pathogenic classification (requires: 2 Strong OR 1 Very Strong + 1 Strong + 1 Supporting).

Final classification: PATHOGENIC.