# SOD1 A4V Research Report **Protein:** SOD1 A4V **Variant:** A4V **UniProt ID:** P00441 **Disease Association:** ALS **Report Generated:** 2026-07-14 01:49 UTC **AlphaFold Confidence (pLDDT):** 97.7% **Structure Folded:** 2026-07-03 --- ## Structure Summary SOD1 A4V is one of the most aggressive genetic mutations linked to amyotrophic lateral sclerosis (ALS), a fatal disease where motor neurons progressively degenerate. Analysis of the A4V variant using AlphaFold2 structure prediction revealed a highly confident three-dimensional model (average confidence 97.7%) that can guide understanding of how this specific mutation disrupts the protein's normal protective function against cellular damage. This structural information provides a foundation for developing targeted therapies like tofersen, an antisense drug already approved for SOD1-related ALS. --- Superoxide dismutase 1 (SOD1) is an enzyme that protects cells from oxidative damage by converting harmful superoxide radicals into less reactive molecules. Mutations in the SOD1 gene account for approximately 2% of all ALS cases and roughly 20% of familial (inherited) ALS [5]. The A4V mutation, where alanine at position 4 is replaced by valine, is particularly significant as it represents one of the most common and aggressive SOD1 mutations found in North American ALS patients. Unlike some SOD1 variants that show incomplete penetrance (meaning not everyone with the mutation develops disease), A4V typically causes rapid disease progression [3]. The AlphaFold2 structure prediction for SOD1 A4V achieved an exceptionally high average confidence score of 97.7% pLDDT (predicted Local Distance Difference Test), indicating that the computational model is highly reliable across nearly all regions of the protein. This high confidence level allows for detailed analysis of how the mutation might affect protein structure and stability. The mutation occurs at position 4, very near the N-terminus (beginning) of the protein, which could influence how the protein folds initially and maintains its structural integrity over time. SOD1 mutations are thought to cause ALS not by eliminating the protein's normal antioxidant function, but rather by causing the mutant protein to misfold and form toxic aggregates that accumulate in motor neurons. Research has demonstrated that various SOD1 mutations, including those affecting different residues, can destabilize the protein's local structure and promote aggregation into beta-sheet-rich amyloid fibrils that are toxic to cells [2]. The position of the A4V mutation near the N-terminus may particularly affect protein stability during the early stages of folding, potentially explaining its aggressive clinical phenotype. Studies of other SOD1 mutations have shown that even single amino acid changes can dramatically alter disease progression rates and clinical presentations [1][6]. The structural insights from this analysis are clinically relevant given recent therapeutic advances. Tofersen, an antisense oligonucleotide drug that reduces production of mutant SOD1 protein by degrading its messenger RNA, has been approved for treating SOD1-related ALS [5]. Understanding the precise structural consequences of different SOD1 mutations like A4V can help predict which patients might benefit most from such targeted therapies and inform the development of additional structure-based therapeutic approaches. The high-confidence structural model generated here provides a valuable resource for designing experiments to test how the A4V mutation affects protein stability, aggregation propensity, and interactions with other cellular components. Clinically, SOD1-related ALS shows considerable phenotypic variability, with some mutations predominantly affecting lower motor neurons while others show more mixed or even upper motor neuron predominance [4]. Understanding the structural basis for these differences remains an important research goal. The comprehensive genetic testing now available has revealed that disease-causing variants occur in 10-15% of apparently sporadic ALS cases, underscoring the importance of genetic screening and mutation-specific structural analysis for all ALS patients [7][8]. ## Works Cited [1] Ozlu et al. (2026). Two Patients With Juvenile-Onset, Rapidly Progressive Amyotrophic Lateral Sclerosis Associated With an SOD1 Variant (p.Asp125Gly) With Incomplete Penetrance. Muscle & nerve. [PubMed](https://pubmed.ncbi.nlm.nih.gov/42265995/) [2] Hosseinpoor et al. (2026). Inhibitory effect of silymarin on amyloid formation in ALS-associated hSOD1 P66R mutant. International journal of biological macromolecules. [PubMed](https://pubmed.ncbi.nlm.nih.gov/42250707/) [3] Richard et al. (2026). From Mutation to Manifestation: Penetrance in Amyotrophic Lateral Sclerosis. Genes. [PubMed](https://pubmed.ncbi.nlm.nih.gov/42195033/) [4] 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/) [5] 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/) [6] Pi et al. (2026). Mechanism of the N87D mutation in SOD1-atypical amyotrophic lateral sclerosis case report and literature review molecular mechanism of N87D mutation in SOD1. Neurogenetics. [PubMed](https://pubmed.ncbi.nlm.nih.gov/42118400/) [7] Kotambail et al. (2026). Genome-wide spectrum of coding DNA variations in Indian patients with amyotrophic lateral sclerosis. Journal of neurology. [PubMed](https://pubmed.ncbi.nlm.nih.gov/42384233/) [8] Felice et al. (2026). The Impact of Sponsored Genetic Testing in 170 Consecutive Consenting Patients With Amyotrophic Lateral Sclerosis: A Single-Site Retrospective Review. Muscle & nerve. [PubMed](https://pubmed.ncbi.nlm.nih.gov/42324839/) ## 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 | 0.882 | genetic_literature, clinical, literature, genetic_association, animal_model | | spastic tetraplegia and axial hypotonia, progressive | 0.689 | literature, animal_model, genetic_association, genetic_literature | | motor neuron disorder | 0.594 | literature, genetic_association | | neurodegenerative disease | 0.554 | literature, affected_pathway | | familial amyotrophic lateral sclerosis | 0.502 | literature, animal_model, genetic_literature | | sporadic amyotrophic lateral sclerosis | 0.497 | literature, animal_model, genetic_literature | | frontotemporal dementia with motor neuron disease | 0.356 | animal_model, genetic_association | | Limb muscle weakness | 0.340 | genetic_association | | Atrophy/Degeneration affecting the central nervous system | 0.309 | genetic_association | | skull disorder | 0.267 | genetic_association | *...and 4183 more associations* --- ## Agent Findings ### Literature (1) - **2026-07-04:** These papers are highly relevant for understanding SOD1 A4V and ALS treatment strategies. They document the approval and mechanism of SOD1-targeted gene therapy (tofersen), elucidate the molecular pathways through which SOD1 mutations cause disease, and reveal how SOD1-ALS differs from other genetic subtypes in terms of disease mechanisms and biomarker profiles, which has direct implications for diagnosis, prognosis, and personalized treatment of patients with SOD1 variants like A4V. ### Clinical (1) - **2026-07-04:** ### Structural (1) - **2026-07-04:** AlphaFold structure update: Baseline check: 1 structure(s) found ### Synthesis (1) - **2026-07-04:** Synthesis of 2 findings (peptides, supplements): The SOD1 A4V variant research landscape reveals a significant therapeutic gap between advanced gene-... --- *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)