ARHGAP36 is an atypical Rho GTPase-activating protein that plays multifaceted roles in cellular signaling and disease pathogenesis. The protein functions as a positive regulator of the Hedgehog signaling pathway by inhibiting Gli repressor formation and promoting Gli transcription factor activation through a Smoothened-independent mechanism 1. ARHGAP36 operates via a Patched1-ArhGAP36-PKA-Inversin axis that controls the ciliary translocation of Smoothened, essential for Sonic Hedgehog pathway activation 2. The protein contains distinct functional domains including a GAP homology domain essential for Gli activation and a C-terminal domain that counteracts N-terminal autoinhibitory motifs 3. ARHGAP36 dysregulation is implicated in multiple diseases: germline intergenic duplications at the ARHGAP36 locus cause Bazex-Dupré-ChrX syndrome, a rare X-linked basal cell carcinoma susceptibility disorder 4. The gene is overexpressed in medulloblastomas resistant to Smoothened inhibitors and in papillary thyroid carcinoma, where it regulates proliferation and migration 15. Additionally, ARHGAP36 overexpression can drive heterotopic ossification through enhancer hijacking mechanisms 6. In breast cancer, ARHGAP36 promotes cell invasion and migration and is negatively regulated by miR-4719 7.