Is LRRK2 p.Val641Ala (c.1922T>C) pathogenic?

LRRK2 p.Val641Ala (c.1922T>C) is classified Uncertain significance in LRRK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-05-19). AlphaMissense: likely benign (0.0989); Very rare (popmax 0.000593%, nfe); Associated with Inborn genetic diseases.

What condition is associated with LRRK2 p.Val641Ala (c.1922T>C)?

LRRK2 p.Val641Ala (c.1922T>C) is associated with Inborn genetic diseases (ClinVar).

How common is LRRK2 p.Val641Ala (c.1922T>C) in the general population?

LRRK2 p.Val641Ala (c.1922T>C) is very rare (popmax 0.000593%, nfe) (gnomAD).

What do computational predictors say about LRRK2 p.Val641Ala (c.1922T>C)?

AlphaMissense predicts likely benign (score 0.0989) — an in-silico prediction, not a clinical call.

LRRK2 p.Val641Ala

c.1922T>C · rs1329679047 · VCV1782712

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0989 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000593%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0989	likely benign
REVEL	0.007	strongly benign-leaning
SaProt	LLR -8.91	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 0.076	GERP -4.1, phastCons 0.011
Regional constraint	o/e 0.99	unconstrained · MANE · 98 kb · p 0.56 · regional, not allelic
Overall
CADD	13.64	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

Grpmax group 0.000593% European (non-Finnish) · 7/1,179,922 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000434% 7/1,613,876 alleles · very rare exomes 5/1,461,630 · genomes 2/152,246 · 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.Val641Ala
Coding: c.1922T>C
MANE Select: NM_198578
dbSNP: rs1329679047
Type: single nucleotide variant
Location: chr12:40274974 (GRCh38)
Gene constraint: LOEUF 0.778 · pLI <0.01 · ClinGen HI dosage-sensitivity unlikely (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 58 PDB
Residue 641: 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-val641ala (accessed [today's date]).

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