SNCA

Chr 4AD

synuclein alpha

Also known as: NACP, PARK1, PARK4, PD1

NCBI Gene: 6622 ENSG00000145335 UniProt: P37840 OMIM: 163890

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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Alpha-synuclein is a member of the synuclein family, which also includes beta- and gamma-synuclein. Synucleins are abundantly expressed in the brain and alpha- and beta-synuclein inhibit phospholipase D2 selectively. SNCA may serve to integrate presynaptic signaling and membrane trafficking. Defects in SNCA have been implicated in the pathogenesis of Parkinson disease. SNCA peptides are a major component of amyloid plaques in the brains of patients with Alzheimer's disease. Alternatively spliced transcripts encoding different isoforms have been identified for this gene. [provided by RefSeq, Feb 2016]

OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.433 OMIM phenotypes

Clinical Summary— SNCA

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Gene-Disease Validity (ClinGen)

Parkinson disease · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.88) — some intolerance to loss-of-function variants.

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Clinical Trials

7 active or recruiting trials — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.43LOEUF

pLI 0.883

Z-score 2.45

OE 0.00 (0.00–0.43)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.46Z-score

OE missense 0.85 (0.69–1.05)

61 obs / 72.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–0.43)

0≤0.351.4

Missense OE?0.85 (0.69–1.05)

0≤0.61.4

Synonymous OE?1.30

0≤1.21.6

LoF obs/exp: 0 / 7.0Missense obs/exp: 61 / 72.0Syn Z: -1.14

This gene — mechanism propensity

0.6937th %ile

GOF

0.82top 10%

LOF

0.4529th %ile

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.

GOFprediction above median · 1 literature citation

DNprediction above median

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

GOFThe pathogenic A53T and A30P alpha-synuclein mutants bound to the receptor for this pathway on the lysosomal membrane, but appeared to act as uptake blockers, inhibiting both their own degradation and that of other substrates. These findings may underlie the toxic gain-of-function by the mutants.1

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References