SNCA
Chr 4ADsynuclein alpha
Also known as: NACP, PARK1, PARK4, PD1
Alpha-synuclein regulates synaptic vesicle trafficking and neurotransmitter release, acts as a molecular chaperone for SNARE proteins, and modulates dopamine transporter activity. Mutations cause autosomal dominant Parkinson disease and Lewy body dementia, typically with adult onset affecting movement and cognition. The gene is highly constrained against loss-of-function variants (pLI 0.88, LOEUF 0.43), reflecting its essential role in neuronal function.
Definitive — sufficient evidence for diagnostic panels
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
More LoF-intolerant than ~75% of genes
Mild missense constraint
This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.
Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
0 submitted variants in ClinVar
Protein Context — Lollipop Plot
SNCA · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
Molecular and Functional Imaging in Monogenic PD.
RECRUITINGSafety, Tolerability and Exploratory Efficacy of EC5026 in Parkinson's Disease (STEP Study)
RECRUITINGChinese PD-SNCA Registry
RECRUITINGLongitudinal Investigation of I2BS in PD
RECRUITINGSerotonin Release in Premotor and Motor PD
RECRUITINGAquaporin-4 Single Nucleotide Polymorphisms in Patients With Idiopathic and Familial Parkinson's Disease
ACTIVE NOT RECRUITINGUnderstanding Alpha-Synuclein Spread in Parkinson's Disease Through Blood Biomarkers and Neuroimaging
NOT YET RECRUITINGObserve Change in Nasal Swab DRD2 Gene Expression in Restless Legs Syndrome (RLS) Patients on Prolonged Dopamine Agonist Treatment
RECRUITINGExternal Resources
Links to major genomics databases and tools