Is LRRK2 p.Phe511Ser (c.1532T>C) pathogenic?

LRRK2 p.Phe511Ser (c.1532T>C) is classified Uncertain significance in LRRK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-09). AlphaMissense: ambiguous (0.5532); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with LRRK2 p.Phe511Ser (c.1532T>C)?

LRRK2 p.Phe511Ser (c.1532T>C) is associated with Inborn genetic diseases (ClinVar).

How common is LRRK2 p.Phe511Ser (c.1532T>C) in the general population?

LRRK2 p.Phe511Ser (c.1532T>C) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about LRRK2 p.Phe511Ser (c.1532T>C)?

AlphaMissense predicts ambiguous (score 0.5532) — an in-silico prediction, not a clinical call.

LRRK2 p.Phe511Ser

c.1532T>C · rs1327063867 · VCV3229518

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5532 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5532	ambiguous
REVEL	0.282	benign-leaning
SaProt	LLR -8.40	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.2, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 98 kb · p 0.56 · regional, not allelic
Overall
CADD	24.8	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 0.00134% African / African-American · 1/74,900 alleles

Overall 6.2e-05% 1/1,612,734 alleles · very rare exomes 1/1,460,634 · genomes 0/152,100 · 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: LRRK2
Protein: p.Phe511Ser
Coding: c.1532T>C
MANE Select: NM_198578
dbSNP: rs1327063867
Type: single nucleotide variant
Location: chr12:40259593 (GRCh38)
Gene constraint: LOEUF 0.778 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 58 PDB
Residue 511: 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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

LRRK2 p.Ala1396Ser Uncertain significance ★★ ⚠ same condition
LRRK2 p.Ala1413Glu Uncertain significance ★★ ⚠ same condition
LRRK2 p.Ala1430Val Uncertain significance ★★ ⚠ same condition
LRRK2 p.Ala1440Val Uncertain significance ★★ same condition
LRRK2 p.Ala1572Thr Uncertain significance ★★ ⚠ same condition
LRRK2 p.Ala1659Gly Uncertain significance ★★ same condition
LRRK2 p.Ala233Val Uncertain significance ★★ ⚠ same condition
LRRK2 p.Ala417Val 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-phe511ser (accessed [today's date]).

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