SV2C – Parkinson Disease

The gene SV2C (HGNC:30670) has been implicated as a risk locus for Parkinson disease (MONDO_0005180) through multiple large-scale association studies. The evidence spans diverse ancestries with substantial case‑control cohorts, including European and East Asian populations. In one study, an analysis of 9673 PD patients and 8465 controls demonstrated a significant association with the SV2C locus (PMID:33760272). In another extensive study, over 31,575 individuals in the discovery phase and replication in cohorts totaling nearly 1.9 million individuals further corroborated these findings (PMID:32310270).

Genetic evidence supporting the role of SV2C in Parkinson disease is strong. A recurrent missense variant, c.1627G>A (p.Asp543Asn), was identified as significantly associated with PD risk in a study involving 9810 East Asian individuals (PMID:39973496). This variant, observed in multiple independent cohorts, highlights the importance of SV2C in the disease’s genetic architecture even though additional rare coding changes were not found to contribute significantly.

Functional studies, although not directly in a Parkinson disease context, have provided important insights into the role of SV2C in synaptic vesicle dynamics. Assays examining the glycosylation state of SV2C have revealed that modifications such as the N559‑glycan critically influence protein–protein interactions, which are fundamental to synaptic function (PMID:27313224). Additional experiments comparing SV2 isoform binding dynamics further support the biological plausibility of SV2C’s contribution to neuronal processes that, when dysregulated, may predispose to Parkinson disease (PMID:27196927).

No significant conflicting evidence has been reported; however, it is noted that while multiple studies reaffirm the association of the p.Asp543Asn variant with PD risk, other rare variants in SV2C do not appear to play a major role. Overall, the reproducibility across genetic studies and the supportive functional data combine to yield a robust association between SV2C and Parkinson disease.

This comprehensive synthesis of genetic and functional evidence underscores the clinical utility of SV2C in risk stratification. The established association not only informs diagnostic decision‑making but also serves as a basis for future targeted research and the potential commercial development of genetic assays.

Key Take‑home: SV2C is a strongly validated risk locus for Parkinson disease, meriting integration into diagnostic pipelines and further investigation in precision medicine applications.

References

• Movement Disorders • 2021 • Replication of a Novel Parkinson's Locus in a European Ancestry Population PMID:33760272
• JAMA Neurology • 2020 • Identification of Risk Loci for Parkinson Disease in Asians and Comparison of Risk Between Asians and Europeans: A Genome‑Wide Association Study PMID:32310270
• Journal of Parkinson's disease • 2025 • Rare SV2C coding variants in Parkinson's disease risk PMID:39973496
• The Biochemical Journal • 2016 • Only the complex N559‑glycan in the synaptic vesicle glycoprotein 2C mediates high affinity binding to botulinum neurotoxin serotype A1 PMID:27313224
• Toxins • 2016 • Botulinum Neurotoxin Serotype A Recognizes Its Protein Receptor SV2 by a Different Mechanism than Botulinum Neurotoxin B Synaptotagmin PMID:27196927

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