SNCA

Chr 4AD

synuclein alpha

Also known as: NACP, PARK1, PARK4, PD1

NCBI Gene: 6622ENSG00000145335UniProt: P37840

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]

Primary Disease Associations & Inheritance

Dementia, Lewy bodyMIM #127750
AD
Parkinson disease 1MIM #168601
AD
Parkinson disease 4MIM #605543
AD
196
ClinVar variants
33
Pathogenic / LP
0.88
pLI score
8
Active trials
Clinical Summary— SNCA
🧬
Gene-Disease Validity (ClinGen)
Parkinson disease · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.88) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
33 Pathogenic / Likely Pathogenic· 79 VUS of 196 total submissions
💊
Clinical Trials
8 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
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?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.46Z-score
OE missense 0.85 (0.69–1.05)
61 obs / 72.0 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.43)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.85 (0.69–1.05)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.30
0≤1.21.6
LoF obs/exp: 0 / 7.0Missense obs/exp: 61 / 72.0Syn Z: -1.14

ClinVar Variant Classifications

196 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic30
Likely Pathogenic3
VUS79
Likely Benign49
Benign27
Conflicting8
30
Pathogenic
3
Likely Pathogenic
79
VUS
49
Likely Benign
27
Benign
8
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
2
28
0
30
Likely Pathogenic
0
0
3
0
3
VUS
1
29
49
0
79
Likely Benign
0
3
30
16
49
Benign
0
0
27
0
27
Conflicting
—8
Total13413716196

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View 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.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
SYNUCLEIN, ALPHA; SNCA
MIM #163890 · *

Dementia, Lewy body

MIM #127750

Molecular basis of disorder known

Autosomal dominant

Parkinson disease 1

MIM #168601

Molecular basis of disorder known

Autosomal dominant

Parkinson disease 4

MIM #605543

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — SNCA
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Monogenic Parkinson's Disease: Genotype, Phenotype, Pathophysiology, and Genetic Testing.
Jia F et al.·Genes (Basel)
2022Review
Mitochondria and Parkinson's Disease: Clinical, Molecular, and Translational Aspects.
Borsche M et al.·J Parkinsons Dis
2021Review
A biological definition of neuronal α-synuclein disease: towards an integrated staging system for research.
Simuni T et al.·Lancet Neurol
2024Review
Clinical and imaging evidence of brain-first and body-first Parkinson's disease.
Horsager J et al.·Neurobiol Dis
2022Review
The mutation spectrum of Parkinson-disease-related genes in early-onset Parkinson's disease in ethnic Chinese.
Chen YP et al.·Eur J Neurol
2022
Parkinson's Disease: Biomarkers for Diagnosis and Disease Progression.
Arya R et al.·Int J Mol Sci
2024Review
Large-scale meta-analysis of genome-wide association data identifies six new risk loci for Parkinson's disease.
Nalls MA et al.·Nat Genet
2014Meta-analysis
Brain high-throughput multi-omics data reveal molecular heterogeneity in Alzheimer's disease.
Eteleeb AM et al.·PLoS Biol
2024
The role of genetics in Parkinson's disease: a large cohort study in Chinese mainland population.
Zhao Y et al.·Brain
2020Cohort
Gene replacement-Alzheimer's disease (GR-AD): Modeling the genetics of human dementias in mice.
Benzow K et al.·Alzheimers Dement
2024Functional
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Familial young-onset Parkinson's disease associated with SNCA gene duplication: a case series of three sisters from Turkey.
Işeri P et al.·Neurocase
2026Cohort
Degradation of alpha-synuclein/SNCA mRNA by RNautophagy.
Kabuta C et al.·Neurochem Int
2026
SNCA (α-synuclein) H50Q mutation reveals distinct neurodegenerative patterns and adaptive responses in Parkinson's disease Drosophila model.
Samson JS et al.·Biochem Biophys Res Commun
2026Functional
Increased Serum Neurofilament Light Chain Levels in Parkinson's Disease Patients Carrying the p.A53T SNCA Mutation: Data from the Parkinson's Progression Markers Initiative Study.
Papagiannakis N et al.·Mov Disord
2026Cohort
SNCA triplication disrupts proteostasis and extracellular architecture prior to neurodegeneration in human midbrain organoids.
Statoulla E et al.·NPJ Parkinsons Dis
2026
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Parkinson Disease

Chinese PD-SNCA Registry

RECRUITING
NCT03523052Xiangya Hospital of Central South UniversityStarted 2017-02-01
Restless Leg Syndrome (RLS)

Observe Change in Nasal Swab DRD2 Gene Expression in Restless Legs Syndrome (RLS) Patients on Prolonged Dopamine Agonist Treatment

RECRUITING
NCT06726785HBC Immunology IncStarted 2025-07-01
Parkinson Disease

Microbiome Composition and Function Contributes to Cognitive Impairment and Neuroinflammation in Parkinson's Disease

RECRUITING
NCT05419453California State University, San BernardinoStarted 2021-04-30
Parkinson DiseaseParkinson'sParkinson's Disease

Serotonin Release in Premotor and Motor PD

RECRUITING
NCT05516732University of ExeterStarted 2022-07-01
Positron Emission Tomography (PET) scan using CIMBI-36 tracerMagnetic Resonance Imaging (MRI) ScanPositron Emission Tomography (PET) scan using DASB tracer
Parkinson&#39;s Disease (PD)

Safety, Tolerability and Exploratory Efficacy of EC5026 in Parkinson's Disease (STEP Study)

RECRUITING
NCT07142044Phase PHASE1, PHASE2EicOsis Human Health Inc.Started 2025-10
EC5026 oral tabletPlacebo
Parkinson DiseaseNervous System DisorderNeurodegenerative Diseases

Molecular and Functional Imaging in Monogenic PD.

RECRUITING
NCT05518617University of ExeterStarted 2022-07-01
Positron Emission Tomography (PET) scan using DASB tracer
Parkinson Disease

Aquaporin-4 Single Nucleotide Polymorphisms in Patients With Idiopathic and Familial Parkinson's Disease

ACTIVE NOT RECRUITING
NCT04553185University of ExeterStarted 2018-11-28
Study procedure
Parkinson'sParkinson DiseaseParkinson's Disease

Longitudinal Investigation of I2BS in PD

RECRUITING
NCT05516719University of ExeterStarted 2021-11-01
Positron Emission Tomography (PET) scan using BU99008 tracerFP-CIT Single-photon Emission Computed Tomography (SPECT) scanMagnetic Resonance Imaging (MRI) Scan

External Resources

Links to major genomics databases and tools