SPTBN2 encodes a non-erythrocytic spectrin beta subunit that functions as a critical component of the neuronal membrane skeleton 1. As part of the spectrin heterotetrameric complex, SPTBN2 binds cytoskeletal elements and the plasma membrane to facilitate proper localization of essential membrane proteins, signal transduction, and cellular scaffolding 1. Beyond its structural role, SPTBN2 facilitates vesicle-mediated transport and membrane protein trafficking through its CH domain interactions, as demonstrated by its role in positioning SLC7A11 on the cell membrane in lung cancer cells 2. Disease relevance centers on neurological spectrinopathies. Pathogenic SPTBN2 variants cause spinocerebellar ataxia type 5 (SCA5) and autosomal recessive spinocerebellar ataxia 14, with heterozygous variants producing early-onset disease featuring severe cerebellar atrophy and developmental delay 34. SPTBN2 mutations rank among the six most commonly identified genes in ataxia patients, accounting for >40% of molecular diagnoses in targeted exome studies 5. Recent evidence suggests SPTBN2 also suppresses ferroptosis in non-small cell lung cancer by maintaining SLC7A11-mediated cystine uptake, positioning it as a potential oncology therapeutic target 26. Clinically, SPTBN2 variants demonstrate extreme phenotypic heterogeneity, with both infantile-onset and adult-onset presentations depending on variant type and protein charge changes, complicating genotype-phenotype prediction 4.