Our findings offer new molecular insights into the modulation of GPRC5B signaling by MLC1 and GlialCAM, specifically in regulating the constitutive signaling activity of GPRC5B, and propose a mechanistic model explaining how this protein complex may contribute to the pathogenesis of GPRC5B and MLC1-associated leukodystrophy. Here, HEPACAM is linked to leukodystrophy.