SNCA
protein-codingsynuclein alpha
Gene summary
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]
- PARK1
- PARK4
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~138.0 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0011562
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0011562
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0008200
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0007488
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0011562
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0005180
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0005180
Submitter: ClinGen
Mutations in the *SNCA* gene were first reported in relation to autosomal-dominant Parkinson´s disease in 1997 (Polymeropoulos et al., PMID: 9197268). Parkinson´s disease is a progressive degenerative disorder of the central nervous system characterized by loss of dopamine-producing neurons in the substantia nigra, and the presence of specific protein aggregates, termed Lewy bodies, in the substantia nigra and locus coeruleus. In these Lewy bodies, alpha-synuclein forms the major filamentous protein component (Spillantini et al. 1998, PMID: 9600990). Further, the mRNA expression of *SNCA* is increased in mid-brain tissue of sporadic patients with Parkinson´s disease (Chiba-Falek et al. 2006, PMID: 16795004). Signs and symptoms of Parkinson´s disease include tremor which is most pronounced during rest, muscle rigidity, slowing of the voluntary movements (bradykinesia), and a tendency to fall back (postural instability). Several clearly pathogenic, missense variants and *SNCA* gene multiplication have been reported in ~150 patients in ~50 publications (for review see Trinh et al. 2018, PMID: 30357936, www.mdsgene.org). Of these, 17 publications are included in this curation. The additional evidence from the literature was not included in this curation because the maximum score for genetic evidence of gene-disease relation for *SNCA* and Parkinson´s disease was reached (12 pts.). The *SNCA*-linked phenotype due to missense variants and gene triplications often includes cognitive decline in addition to Parkinson´s disease, has an earlier age at onset and a faster disease progression when compared to idiopathic Parkinson´s disease. In contrast, *SNCA* gene duplication carriers usually resemble idiopathic Parkinson´s disease. The disease follows a dominant mode of inheritance with age-dependent reduced penetrance. Penetrance seems to be the lowest for carriers of the *SNCA* gene duplication (Chartier-Harlin et al. 2004, PMID: 15451224, Farrer et al. 2004, PMID: 14755720). In addition to the pathogenic variants affecting the coding region of *SNCA*, many candidate and genome-wide association studies have identified non-coding variants within or near the *SNCA* locus as risk factors for Parkinson´s disease, likely through an over-expression paradigm (Nalls et al. 2019, PMID: 31701892; http://pdgene.org/view?gene=SNCA). One general mechanism of pathogenicity within Parkinson’s disease appears to be the toxic accumulation and aggregation of alpha-synuclein protein (Wong and Krainc 2017, PMID: 2817037). This gene-disease association is further supported by recurrent experimental evidence in animal models, cultured non-human cells, and patient-derived cells demonstrating a tendency for increased accumulation of mutant protein and linked mitochondrial dysfunction, which both are key findings in Parkinson´s disease (Giasson et al. 2002, PMID: 12062037; Kuo et al. 2010, PMID: 20106867; Zhou W 2000, PMID: 10825478; Li et al. 2013, PMID: 24392030; Dettmer et al. 2015, PMID: 26076669; Diao et al. 2021, PMID: 34572052). In summary, pathogenic variants in *SNCA* are definitively causing autosomal-dominant Parkinson´s disease. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Parkinson’s Disease Gene Curation Expert Panel on April 19th, 2022.
Inheritance Pattern: AD
Disease ID:MONDO:0007488
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009830
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0018466
Submitter: Orphanet
Clinical Genomic Database (CGD)
Manifestation: Neurologic
Intervention: Neurologic
Rationale: Levodopa can be beneficial in individuals with Parkinson disease
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SNCA variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000345.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 18 | 18 | ||||
| missense | 4 | 5 | 29 | 3 | 41 | |
| nonsense | 0 | |||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | ||||
| Total | 4 | 5 | 30 | 21 | 0 | 60 |
Highest pathogenic variant AF is 0.0000065799863
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000336.1 | 5 | MANE Select | |
| Ensembl | ENSP00000378442.4 | 5 | MANE Select | |
| RefSeq | NP_001139526.1 | 5 | Standard | |
| RefSeq | NP_001139527.1 | 5 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Alzheimer,s disease - Homo sapiens (human)
- Parkinson,s disease - Homo sapiens (human)
- Alzheimers Disease
- Parkin-Ubiquitin Proteasomal System pathway
- Parkinsons Disease Pathway
Biological Process
- negative regulation of transcription by RNA polymerase II
- microglial cell activation
- positive regulation of receptor recycling
- negative regulation of protein phosphorylation
- positive regulation of neurotransmitter secretion
Molecular Function
- magnesium ion binding
- actin binding
- fatty acid binding
- copper ion binding
- calcium ion binding
Cellular Component
- extracellular region
- extracellular space
- nucleus
- nuclear outer membrane
- cytoplasm
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000394986
- Coding exons
- 5
- Length
- 114217
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.460 | 61 | 72.0 | 0.847 | 0.00000331 | 896 |
| Missense (PolyPhen) | 16 | 31.898 | 0.50159 | 380 | ||
| Synonymous | -1.14 | 31 | 23.9 | 1.30 | 0.00000114 | 276 |
| Loss of Function | 2.45 | 0 | 6.98 | 0.00 | 2.99e-7 | 94 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: May be involved in the regulation of dopamine release and transport. Induces fibrillization of microtubule-associated protein tau. Reduces neuronal responsiveness to various apoptotic stimuli, leading to a decreased caspase-3 activation.;
- Disease
- DISEASE: Note=Genetic alterations of SNCA resulting in aberrant polymerization into fibrils, are associated with several neurodegenerative diseases (synucleinopathies). SNCA fibrillar aggregates represent the major non A-beta component of Alzheimer disease amyloid plaque, and a major component of Lewy body inclusions. They are also found within Lewy body (LB)-like intraneuronal inclusions, glial inclusions and axonal spheroids in neurodegeneration with brain iron accumulation type 1.; DISEASE: Parkinson disease 1, autosomal dominant (PARK1) [MIM:168601]: A complex neurodegenerative disorder characterized by bradykinesia, resting tremor, muscular rigidity and postural instability. Additional features are characteristic postural abnormalities, dysautonomia, dystonic cramps, and dementia. The pathology of Parkinson disease involves the loss of dopaminergic neurons in the substantia nigra and the presence of Lewy bodies (intraneuronal accumulations of aggregated proteins), in surviving neurons in various areas of the brain. The disease is progressive and usually manifests after the age of 50 years, although early- onset cases (before 50 years) are known. The majority of the cases are sporadic suggesting a multifactorial etiology based on environmental and genetic factors. However, some patients present with a positive family history for the disease. Familial forms of the disease usually begin at earlier ages and are associated with atypical clinical features. {ECO:0000269|PubMed:14755719, ECO:0000269|PubMed:23427326, ECO:0000269|PubMed:23457019, ECO:0000269|PubMed:24936070, ECO:0000269|PubMed:25561023, ECO:0000269|PubMed:9197268, ECO:0000269|PubMed:9462735}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Parkinson disease 4, autosomal dominant (PARK4) [MIM:605543]: A complex neurodegenerative disorder with manifestations ranging from typical Parkinson disease to dementia with Lewy bodies. Clinical features include parkinsonian symptoms (resting tremor, rigidity, postural instability and bradykinesia), dementia, diffuse Lewy body pathology, autonomic dysfunction, hallucinations and paranoia. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Dementia Lewy body (DLB) [MIM:127750]: A neurodegenerative disorder characterized by mental impairment leading to dementia, parkinsonism, fluctuating cognitive function, visual hallucinations, falls, syncopal episodes, and sensitivity to neuroleptic medication. Brainstem or cortical intraneuronal accumulations of aggregated proteins (Lewy bodies) are the only essential pathologic features. Patients may also have hippocampal and neocortical senile plaques, sometimes in sufficient number to fulfill the diagnostic criteria for Alzheimer disease. {ECO:0000269|PubMed:14755719}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.416
Intolerance Scores
- LoFtool
- 0.105
- RVIS EVS
- -0.14
- RVIS percentile EVS
- 42.88
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.961
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |