Is LRRK2 p.Pro499= (c.1497A>C) pathogenic?

LRRK2 p.Pro499= (c.1497A>C) is classified Likely benign in LRRK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-28). Absent from gnomAD v4.1; Associated with autosomal dominant Parkinson disease 8.

What condition is associated with LRRK2 p.Pro499= (c.1497A>C)?

LRRK2 p.Pro499= (c.1497A>C) is associated with autosomal dominant Parkinson disease 8 (ClinVar).

How common is LRRK2 p.Pro499= (c.1497A>C) in the general population?

LRRK2 p.Pro499= (c.1497A>C) is absent from gnomAD v4.1 (gnomAD).

How is Hereditary late-onset Parkinson disease inherited?

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

LRRK2 p.Pro499=

c.1497A>C · rs2499550693 · VCV3013475

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

autosomal dominant Parkinson disease 8

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.89	GERP -4.4
Overall
CADD	5.146	PHRED · no single calibrated threshold — expert panels disagree

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: LRRK2
Protein: p.Pro499=
Coding: c.1497A>C
MANE Select: NM_198578
dbSNP: rs2499550693
Type: single nucleotide variant
Location: chr12:40259558 (GRCh38)
Gene constraint: LOEUF 0.778 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 58 PDB
Residue 499: an α-helix; the 'required for rab29-mediated activation' region

Full LRRK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal dominant Parkinson disease 8 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary late-onset Parkinson disease (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

LRRK2 p.Pro499Leu Uncertain significance ★ ⚠ same residue
LRRK2 p.Arg1441Cys Pathogenic ★★ ⚠ same condition
LRRK2 p.Arg1441Gly Pathogenic ★★ ⚠ same condition
LRRK2 p.Arg1441His Pathogenic/Likely pathogenic ★★ ⚠ same condition
LRRK2 p.Ile2020Thr Pathogenic ★★ ⚠ same condition
LRRK2 c.1102-3C>T Uncertain significance ★★ same condition
LRRK2 c.2241+1G>A Uncertain significance ★★ same condition
LRRK2 c.7028+2T>C Uncertain significance ★★ 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/lrrk2-p-pro499 (accessed [today's date]).

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