SPTLC1 encodes serine palmitoyltransferase long chain base subunit 1, a critical component of the serine palmitoyltransferase (SPT) complex that catalyzes the initial and rate-limiting step of sphingolipid biosynthesis by condensing L-serine with activated acyl-CoA (primarily palmitoyl-CoA) to form long-chain bases 1. SPTLC1 forms the catalytic core when paired with SPTLC2 or SPTLC3, with complex composition determining substrate specificity; the SPTLC1-SPTLC2-SPTSSA complex preferentially uses C16-CoA substrate, while SPTLC1-SPTLC2-SPTSSB shows strong C18-CoA preference 1. Under low serine availability, SPT can metabolize L-alanine instead, producing pathogenic 1-deoxysphingolipids 2. De novo SPTLC1 variants cause juvenile amyotrophic lateral sclerosis (ALS) with failure to thrive, presenting with elevated sphinganine and ceramide levels 34. C-terminal SPTLC1 variants cause hereditary sensory and autonomic neuropathy type 1A (HSAN1) through 1-deoxysphingolipid accumulation 2. Clinical phenotype depends on variant location and serine availability—ALS-associated variants impair ORMDL protein binding, increasing canonical sphingolipid synthesis, while substrate-level modulation can shift phenotypes 2. Reduced SPTLC1 expression variants associate with improved fitness in aging, suggesting therapeutic potential for age-related sarcopenia 5.