STX16 (syntaxin 16) is a SNARE protein involved in vesicular trafficking, specifically mediating membrane fusion during retrograde transport from late endosomes to the trans-Golgi network 1. As a SNARE complex component, STX16 functions in vesicle docking and fusion processes essential for intracellular protein transport 1. The primary clinical significance of STX16 relates to its role as an imprinting control region (STX16-ICR) regulating the GNAS locus on chromosome 20.3. Maternal microdeletions or deletions of STX16 cause autosomal dominant pseudohypoparathyroidism type 1B (PHP1B) 234. These STX16 deletions disrupt the imprinting control region, leading to loss of methylation at the GNAS exon A/B differentially methylated region, resulting in biallelic expression of A/B transcripts and reduced Gsα (stimulatory G protein alpha-subunit) expression 25. The STX16-ICR functions as a biallelically active embryonic enhancer that controls allele-specific chr20 conformations and GNAS promoter activity, with pathogenicity dependent on maternal inheritance 6. This epigenetic dysregulation causes multihormone resistance, particularly to parathyroid hormone and thyroid-stimulating hormone, manifesting as PHP1B with hypocalcemia and hyperphosphatemia 34. Beyond imprinting disorders, STX16 is upregulated in clear cell renal cell carcinoma, where it promotes tumor progression and immune modulation 7.