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.

GeneReviews 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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Dementia, Lewy bodyMIM #127750

Parkinson disease 1MIM #168601

Parkinson disease 4MIM #605543

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Parkinson disease · AD · ClinGen 2022

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

372

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.43

LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — SNCA

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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

Background carrier burden — how many people carry a rare variant somewhere in SNCA?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 360

175 rare PASS variants

Rare truncating (LoF)

1 in 9,100

19 rare PASS variants

Rare synonymous (reference)

1 in 450

79 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for SNCA. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 8 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 390	1 in 9,400
South Asian	~43k	1 in 200	1 in 4,800
Remaining (unassigned)	~30k	1 in 340	1 in 1,000
European (Finnish)	~27k	1 in 420	none seen
Admixed American	~22k	1 in 380	none seen
African / African American	~21k	1 in 500	≈ 1 in 10,000
East Asian	~20k	1 in 270	≈ 1 in 9,900
Middle Eastern	~2,884	≈ 1 in 960	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 3 of 5 coding exons well covered in gnomAD exomes; exons 5, 6 marginal. Genomes: all 5.? see exons ↓