SPAG16 encodes two protein isoforms with distinct functions in ciliary and flagellar biology. The 71-kDa SPAG16L localizes to the axonemal central apparatus of motile cilia and flagella 1, functioning as the mammalian ortholog of Chlamydomonas PF20 2. SPAG16L is essential for central pair assembly; loss of function causes male infertility with severe sperm motility defects 1. The 35-kDa SPAG16S isoform, expressed exclusively in male germ cells, localizes to nuclear speckles and regulates SPAG16L mRNA expression by modulating promoter activity 1. S-SOX5 transcription factor directly activates the SPAG16L promoter through multiple binding sites 3, suggesting coordinated regulation of axonemal protein genes. Beyond reproductive function, SPAG16 has emerged as a disease-relevant autoantigen. Anti-SPAG16 antibodies are detected in 21-22% of multiple sclerosis (MS) patients with 95% specificity 4, with SPAG16 upregulated in reactive astrocytes within MS lesions 4. In primary progressive MS, anti-SPAG16 seropositivity associates with increased disability severity and progression index 5. Additionally, SPAG16 genetic variants (rs7607479) correlate with radiographic progression in ACPA-positive rheumatoid arthritis, potentially through regulation of MMP-3 expression 6.