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Objectives To characterize real-world data describing the genetic landscape, clinical phenotype, and outcomes of a monogenic lupus cohort.Methods In this nationwide study, we evaluated all genetically confirmed monogenic lupus patients across Türkiye. Clinical, laboratory, treatment, and outcome data were compared between groups defined by pathogenic variants in distinct pathways.Results A total of 88 patients were included. Genetic analysis revealed complement pathway deficiencies in 28 patients (31.8%). Defects in nucleic acid metabolism and clearance constituted the largest subgroup, observed in 36 patients (40.9%), predominantly involving DNASE1L3 and TREX1. Type I interferon signaling and regulation defects were detected in 6 patients (6.8%), including DDX58, IFIH1, ADAR, IRF5, and IRAK1. Defects in immune regulation and lymphocyte signaling were identified in 17 patients (19.3%), involving genes associated with immune tolerance and JAK–STAT dysregulation such as ACP5, PRKCD/PRKCQ, STAT3 gain-of-function, SOCS1, SHOC2, ZAP70, RAG1, HDAC7, FOXP3, and RELA. Consanguinity was reported in 56 patients (63.6%), and a positive family history in 34 (38.6%). Antinuclear antibodies were positive in 66 patients (75%) and anti-dsDNA in 33 (37.5%). Hypocomplementemia was present in 56 patients (63.6%). Clinically, mucocutaneous involvement predominated, particularly acute cutaneous manifestations (61.3%), followed by hematologic involvement (44.3%), arthritis (37.5%), and renal disease (35.2%). Lupus nephritis occurred in 31 patients (35.2%), with class IV nephritis being the most frequent histopathological subtype (32%). Neurological manifestations not captured by current classification criteria were observed in 18 patients (20.4%), including spasticity, Babinski sign, hyperreflexia, developmental delay, and encephalitis. Pulmonary involvement occurred in 21.6%, and intracranial calcifications were detected in 13.6%. Vasculopathic features were common, including Raynaud phenomenon (n=22, 25%), chilblain lesions (n=18, 20.4%), livedo (n=18, 20.4%), and palmar–plantar erythema (n=19, 21.5%). Most patients (n= 77, 87.5%) required corticosteroid therapy. JAK inhibitors were used in 29 patients (33%); response was complete in 3, partial in 21, and absent in 5, while 2 patients developed severe infections. At the last follow-up, 47 patients (53.4%) had a PedSDI score of at least 1, indicating substantial cumulative organ damage. Seven patients died during follow-up.Conclusions This largest monogenic lupus cohort demonstrates atypical neurological, vasculopathic, and immunodeficiency-related features and a high burden of cumulative organ damage.