There is accumulating evidence in the literature indicating a strong correlation between Fabry disease (FD) phenotypes and specific sequence variations in the Galactosidase Alpha ( ) gene. Among them, the potential pathogenicity and clinical relevance of variation in patients with FD remain debated. We performed a systematic review and meta-analysis of studies reporting as single occurring variant in the gene and sought to evaluate (1) the prevalence of variation in different populations with or without clinical manifestations of FD, (2) the clinical FD phenotype in -positive patients, and (3) the proportion of -positive patients presenting abnormal laboratory findings (alpha-galactosidase-A deficiency or globotriaosylceramide accumulation). Forty cohorts comprising 211 individuals with variation among 42,723 participants with available gene-sequencing data were included. Patients highly suspected for FD had a higher prevalence of variation (4.9%, 95% CI 1.6%-9.9%; I = 95.5%) compared with the general population (0%, 95% CI 0%-0.1%; I = 1.9%; = 0.004). The prevalence of variation was 0.6% (95% CI 0.3%-1%; I = 74.1%), 0.4% (95% CI 0.2%-0.7%; I = 0%), and 0.3% (95% CI 0.2%-0.4%; I = 0%) in patients presenting with neurologic, cardiac, or renal manifestations, respectively. was associated with a milder, late-onset FD phenotype, as indicated by the mean patient age of 51 years (95% CI 44-59; I = 94%) and the evidence of alpha-galactosidase A deficiency and globotriaosylceramide accumulation in 26.7% (95% CI 15.3%-40%; I = 34%) and 16.2% (95% CI 8%-26.4%; I = 35%) of cases, respectively. -positive patients displayed predominantly neurologic FD manifestations (58.1%, 95% CI 37.7%-77.1%; I = 78%), with central and peripheral nervous system (CNS/PNS) involvement noted in 28.2% (95% CI 15.4%-43.2%; I = 51%) and 28.5% (95% CI 17.8%-40.5%; I = 61%) of cases, respectively. variation seems to correlate with an atypical, mild late-onset phenotype with predominantly neurologic FD manifestations. Monitoring for CNS/PNS involvement is thus paramount to identify -positive patients with latent or early-FD pathology, which may qualify for enzyme-replacement therapy or chaperone treatment.