️ Episode 140: Landscapes of missense variant impact for human superoxide dismutase 1

In this episode of PaperCast Base by Base, we explore a large-scale functional analysis of missense variants in SOD1, a key gene implicated in amyotrophic lateral sclerosis (ALS). The study addresses the challenge of classifying variants of uncertain significance by systematically testing their functional impact across nearly all possible amino acid substitutions.

Study Highlights:
Using saturation mutagenesis combined with multiplexed yeast and human cell-based assays, researchers generated variant-effect maps covering 86% of all possible SOD1 missense variants. These maps measure both enzymatic activity and protein abundance, capturing functional effects that align with known biochemical features of SOD1. The results show that many variants exhibit damaging effects, while others remain tolerated, and importantly, the abundance assay provided new evidence to reclassify 41% of variants previously listed as uncertain. Structural and computational analyses further revealed insights into sequence-structure-function relationships, including metal binding, dimerization, and stability. Together, these findings demonstrate that large-scale variant-effect maps can provide critical evidence for clinical interpretation of SOD1 variants.

Conclusion:
This study highlights how systematic functional assays can accelerate variant classification in ALS and support more precise genetic diagnoses and therapeutic decisions.

Reference:
Axakova A, Ding M, Cote AG, Subramaniam R, Senguttuvan V, Zhang H, Weile J, Douville SV, Gebbia M, Al-Chalabi A, Wahl A, Reuter J, Hurt J, Mitchell AA, Fradette S, Andersen PM, van Loggerenberg W, Roth FP. Landscapes of missense variant impact for human superoxide dismutase 1. *Am J Hum Genet*. 2025 Oct 2;112(10):1-21. doi:10.1016/j.ajhg.2025.08.019

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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