# SOD1 A4V Research Report **Protein:** SOD1 A4V **Variant:** A4V **UniProt ID:** P00441 **Disease Association:** ALS **Report Generated:** 2026-05-29 19:40 UTC **AlphaFold Confidence (pLDDT):** 97.8% **Structure Folded:** 2026-05-28 --- ## Structure Summary SOD1 (superoxide dismutase 1) is an enzyme that protects cells from oxidative damage, and mutations in this protein cause about 20% of familial ALS cases. The A4V mutation, located at position 4 near the protein's N-terminus, is one of the most common and aggressive SOD1 mutations in North American ALS patients. AlphaFold2 predicted the A4V structure with very high confidence (average 97.8), providing a reliable structural model to understand how this mutation may destabilize the protein and contribute to the toxic aggregation seen in ALS. --- SOD1 is a critical antioxidant enzyme that converts harmful superoxide radicals into less damaging molecules, protecting motor neurons from oxidative stress. Mutations in the SOD1 gene account for approximately 2% of all ALS cases and about 20% of familial cases [2]. The A4V mutation, where alanine at position 4 is replaced by valine, is particularly significant as one of the most common SOD1 mutations in North American ALS populations and is associated with rapid disease progression, with patients typically surviving only 1-2 years after symptom onset. The AlphaFold2 prediction for SOD1 A4V achieved an exceptionally high average confidence score of 97.8 pLDDT, indicating that the computational model is highly reliable across virtually all regions of the protein structure. This high confidence allows for meaningful structural interpretation of how the A4V mutation affects the protein. Position 4 is located near the N-terminus of SOD1, a region critical for protein folding and stability. The substitution of the small, non-branched alanine with the larger, branched valine at this early position likely disrupts normal protein folding pathways and destabilizes the native structure, even though the mutation does not directly involve the enzyme's active site. The mechanism by which SOD1 mutations cause ALS involves a toxic gain-of-function rather than simple loss of enzymatic activity. Mutant SOD1 proteins, including A4V, tend to misfold and form toxic aggregates that accumulate in motor neurons [4]. These aggregates can interact with other ALS-associated proteins, as recent studies have shown that glycated SOD1 modulates levels of phosphorylated TDP-43, another hallmark protein in ALS pathology [1]. The A4V mutation's location near the N-terminus may particularly favor early misfolding events that initiate aggregation cascades. Therapeutic strategies like tofersen, an antisense oligonucleotide designed to reduce mutant SOD1 protein synthesis through targeted mRNA degradation, have shown promise in treating SOD1-associated ALS [4]. While most SOD1 mutations present with predominant lower motor neuron symptoms, the phenotypic spectrum can vary considerably [3]. The high structural confidence of the A4V prediction provides a robust foundation for understanding mutation-specific effects and could inform development of targeted therapies. The mutation's consistent association with rapid progression and its high prevalence in certain populations make it a priority target for both mechanistic studies and therapeutic intervention [2]. Understanding the structural consequences of mutations like A4V at atomic resolution remains essential for developing effective treatments for this devastating disease. ## Works Cited [1] Ribeiro et al. (2026). Molecular Modulation of the Crosstalk Between TDP-43 and SOD1. International journal of molecular sciences. [PubMed](https://pubmed.ncbi.nlm.nih.gov/42074053/) [2] Richard et al. (2026). From Mutation to Manifestation: Penetrance in Amyotrophic Lateral Sclerosis. Genes. [PubMed](https://pubmed.ncbi.nlm.nih.gov/42195033/) [3] Tavaglione et al. (2026). Expanding the phenotypic spectrum of SOD1‑related ALS: upper motor neuron predominance in a p.D91A case. Neurodegenerative disease management. [PubMed](https://pubmed.ncbi.nlm.nih.gov/42183665/) [4] Braza et al. (2026). Tofersen in SOD1-associated amyotrophic lateral sclerosis: From molecular mechanisms to regulatory milestones. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences. [PubMed](https://pubmed.ncbi.nlm.nih.gov/42173382/) ## Similar Research **Integrative genetic analysis illuminates ALS heritability and identifies risk genes.** Megat et al. (2023) *Relevant to ALS research* [Read on PubMed](https://pubmed.ncbi.nlm.nih.gov/36670122/) **Biomarker discovery in Alzheimer's and neurodegenerative diseases using Nucleic Acid Linked Immuno-Sandwich Assay.** Ashton et al. (2025) *Relevant to ALS research* [Read on PubMed](https://pubmed.ncbi.nlm.nih.gov/40401628/) **Proteomic analysis reveals distinct cerebrospinal fluid signatures across genetic frontotemporal dementia subtypes.** Sogorb-Esteve et al. (2025) *Relevant to ALS research* [Read on PubMed](https://pubmed.ncbi.nlm.nih.gov/39908349/) **MATR3 pathogenic variants differentially impair its cryptic splicing repression function.** Khan et al. (2024) *Relevant to ALS research* [Read on PubMed](https://pubmed.ncbi.nlm.nih.gov/38320753/) **Amyotrophic lateral sclerosis and frontotemporal dementia mutation reduces endothelial TDP-43 and causes blood-brain barrier defects.** Cheemala et al. (2025) *Relevant to ALS research* [Read on PubMed](https://pubmed.ncbi.nlm.nih.gov/40238886/) --- ## Clinical Data ### ClinVar - **Classification:** Pathogenic - **Review Status:** criteria provided, multiple submitters - **Last Evaluated:** 2026-01-01 ### gnomAD Not found in gnomAD. --- ## Open Targets Disease Associations | Disease | Score | Data Sources | |---------|-------|--------------| | amyotrophic lateral sclerosis | 0.870 | literature, genetic_association, genetic_literature, clinical | | familial amyotrophic lateral sclerosis | 0.735 | literature, animal_model, genetic_association, genetic_literature | | sporadic amyotrophic lateral sclerosis | 0.733 | literature, genetic_association, genetic_literature | | spastic tetraplegia and axial hypotonia, progressive | 0.607 | literature, genetic_association, genetic_literature | | motor neuron disease | 0.593 | literature, genetic_association | | neurodegenerative disease | 0.553 | literature, affected_pathway | | frontotemporal dementia with motor neuron disease | 0.349 | animal_model, genetic_association | | Limb muscle weakness | 0.340 | genetic_association | | Atrophy/Degeneration affecting the central nervous system | 0.321 | genetic_association | | Abnormal central motor function | 0.266 | genetic_association | *...and 1756 more associations* --- ## Agent Findings ### Literature (1) - **2026-05-29:** These papers provide crucial insights into SOD1-A4V ALS management, including the first targeted gene therapy (Tofersen), structural mechanisms of SOD1 protein aggregation, and presymptomatic biomarkers for early detection. The research establishes both therapeutic approaches and molecular understanding directly applicable to SOD1-A4V patients. ### Clinical (1) - **2026-05-28:** The first baseline data collection for SOD1 A4V represents the initial establishment of reference parameters for this highly aggressive ALS variant, which typically causes symptom onset within 1-2 years and rapid disease progression. This baseline is clinically critical because A4V patients have an extremely short survival time (often 6-18 months from symptom onset), making early and accurate biomarker establishment essential for monitoring disease trajectory and evaluating therapeutic interventions. These initial measurements will serve as the foundation for tracking the accelerated motor neuron degeneration characteristic of this variant and may inform urgent treatment decisions given the compressed clinical timeline. ### Structural (1) - **2026-05-29:** AlphaFold structure update: Baseline check: 1 structure(s) found ### Synthesis (1) - **2026-05-29:** Synthesis of 5 findings (clinical, literature, peptides, structural, supplements): The SOD1 A4V variant represents one of the most aggressive forms of familial ALS, with recent resear... --- *Generated by [Clarity Protocol](https://clarityprotocol.io)* **Data Sources:** - Structure predictions: AlphaFold via ColabFold - Clinical variant data: ClinVar, gnomAD - Disease associations: Open Targets Platform - Research findings: AI agents (PubMed, clinical databases)