Objectives. To identify and functionally characterize variants in the trace amine associated receptor 1 (TAAR1) in a cohort of patients suffering from major mental disorders.Background and aims. The G protein-coupled receptor (GPCR) TAAR1 is widely expressed across brain areas involved in emotions, reward and cognition, and modulates monoaminergic and glutamatergic neurotransmission. The human gene for TAAR1 maps to locus 6q23, within a region associated to major mental disorders. Materials and methods. TAAR1 coding region and 5u2019- and 3u2019-UTRs were Sanger sequenced. A subset of the identified variants was introduced into TAAR1 using site-directed mutagenesis. HEK293 cells were transiently transfected with: i) wild-type TAAR1; ii) mutated TAAR1, either in homozygous or heterozygous state. The Nano-Glou00ae HiBiT extracellular detection system was used to quantify cell surface expression. Gs/adenylyl cyclase (Gu03b1s) activation was monitored using a real-time live-cell cAMP Assay (GloSensorTM Technology), upon stimulation with 3-iodothyronamine (T1AM 10-5 M), u03b2-phenylethylamine (PEA 10-5 M), or a high-affinity high-selectivity synthetic TAAR1 agonist, RO5166017 (10-5 M). Results. We detected 13 missense variants, with a significant enrichment in patients as compared to healthy controls. In cells co-trasfected with TAAR1-wild-type and TAAR1-variants - R23C, Y131C, C263R - we showed: i) a significant reduction of TAAR1 surface expression; ii) dampened Gu03b1s signaling in response to every tested ligand. R23C, Y131C, and C263R are rare in the general population and map in highly conserved positions.Conclusions. Our findings suggest that disruptions of TAAR1 activity may be relevant to the pathophysiology of mental disorders, thereby providing a promising target for novel psychopharmacological interventions.