# SOD1 G93A Research Report **Protein:** SOD1 G93A **Variant:** G93A **UniProt ID:** P00441 **Disease Association:** ALS **Report Generated:** 2026-07-14 00:23 UTC **AlphaFold Confidence (pLDDT):** 97.7% **Structure Folded:** 2026-07-12 --- ## Structure Summary SOD1 G93A is one of the most studied genetic mutations causing familial ALS, a fatal disease where motor neurons progressively die. AlphaFold2 modeling of this variant shows extremely high structural confidence (97.7% average), indicating the mutation likely preserves the protein's overall fold while potentially affecting other properties like stability or aggregation tendency. This high-quality structural prediction provides a foundation for understanding how this specific mutation contributes to motor neuron death in ALS patients. --- Superoxide dismutase 1 (SOD1) is an enzyme that protects cells from oxidative damage by converting harmful superoxide radicals into less dangerous molecules. Mutations in the SOD1 gene are the second most common genetic cause of amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease where motor neurons controlling voluntary muscle movement gradually die [2][3][6]. The G93A mutation is among the most extensively studied SOD1 variants associated with ALS, though the disease phenotype can vary considerably even among patients carrying identical mutations [6][7]. The AlphaFold2 structural prediction for SOD1 G93A shows exceptionally high confidence across the entire protein, with an average pLDDT score of 97.7. This indicates that the computational model reliably captures the protein's three-dimensional structure and suggests that the G93A mutation does not dramatically disrupt the overall protein architecture. This finding is consistent with the prevailing scientific understanding that SOD1 mutations cause disease not by destroying the protein's basic structure, but through more subtle mechanisms such as promoting protein instability, misfolding, and toxic aggregation into amyloid-like fibrils [5][8]. The disease mechanism in SOD1-ALS involves the mutant protein forming abnormal aggregates that accumulate in motor neurons. Research has shown that various SOD1 mutations, including those affecting similar structural regions, can destabilize the protein's native fold and promote the formation of beta-sheet-rich amyloid structures that are toxic to neurons [5]. Additionally, emerging evidence points to altered microglial function and impaired cellular clearance mechanisms as contributing factors in disease progression in SOD1 mouse models [1]. The high structural confidence of this prediction makes it a valuable starting point for understanding these pathological processes at the atomic level. Clinically, SOD1 mutations account for approximately 2% of all ALS cases but show variable penetrance and age of onset across different mutations [6][8]. Some SOD1 variants can present with atypical features, such as predominant upper motor neuron involvement rather than the more common lower motor neuron phenotype [7], or even juvenile-onset rapid progression in certain cases [4]. The availability of mutation-specific therapies like tofersen, an antisense oligonucleotide designed to reduce SOD1 protein levels, has made genetic testing increasingly important for treatment planning [3][8]. However, complete understanding of how specific mutations like G93A lead to selective motor neuron death remains an active area of investigation, with hypotheses focusing on toxic gain-of-function mechanisms involving protein aggregation, oxidative stress, and neuroinflammation. ## Works Cited [1] He et al. (2026). SGK1-mediated deficits in microglial phagocytosis drive pathological progression in amyotrophic lateral sclerosis. Journal of neuroinflammation. [PubMed](https://pubmed.ncbi.nlm.nih.gov/42387584/) [2] 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/) [3] 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/) [4] 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/) [5] 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/) [6] Richard et al. (2026). From Mutation to Manifestation: Penetrance in Amyotrophic Lateral Sclerosis. Genes. [PubMed](https://pubmed.ncbi.nlm.nih.gov/42195033/) [7] 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/) [8] 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 | 0.882 | 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) - **2026-07-12:** These papers are highly relevant to SOD1 G93A-associated ALS as they cover critical aspects including disease mechanisms (protein aggregation, EV signaling, immune dysregulation), therapeutic interventions (tofersen gene therapy, aggregation inhibitors), and genetic interactions that accelerate disease progression. The studies provide both mechanistic insights into how SOD1 mutations drive pathology and evidence for emerging targeted treatments specifically designed for SOD1-ALS patients. ### Clinical (1) - **2026-07-12:** ### Structural (1) - **2026-07-13:** AlphaFold structure update: Baseline check: 1 structure(s) found ### Synthesis (1) - **2026-07-13:** Synthesis of 5 findings (clinical, literature, peptides, structural, supplements): Recent research on SOD1 G93A-associated ALS reveals a multifaceted therapeutic landscape dominated b... --- *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)