The Potassium Channel Tetramerization Domain-containing 1 (KCTD1) protein has been associated with cancer whereas pathogenic variants give rise to dental anomalies and aplasia cutis. KCTD1 has been implicated in signaling pathways connected to growth and development. Yet the spectrum of pathology tied to KCTD1 underscores our nascent appreciation of its multifaceted roles. The objective of this study was to comprehensively examine the role of KCTD1 and its pathogenic variants across multiple signaling pathways in parallel. Here, we uncovered that KCTD1 human polymorphisms are more stable than previously suggested. Luminescence assays in cultured cells found that KCTD1 and its stable variants strongly inhibit Wnt, Hedgehog (Hh), and Notch pathways. We further identified that KCTD1 interacts with the Notch transcriptional repressor RBPJ. KCTD1 variants also shape G protein-coupled receptor (GPCR) signaling by increasing the abundance of Adenylyl Cyclase Type 5 (AC5), which increases neuronal cAMP signaling in response to evoked dopamine in acute brain slices. Additionally, BRET-based biosensors revealed AC5 can compete with other effectors for Gβγ. Through this mechanism, KCTD1 is able to bias GPCR signals toward the cAMP pathway. Altogether, data demonstrate that KCTD1 is a general regulator of developmental (Wnt, Hh, Notch) and GPCR (AC5→cAMP) signaling. Our study further establishes roles for KCTD1 variants across common signaling pathways.