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Pathogenic variants in RAF1 are a common cause of Noonan syndrome (NS), accounting for approximately 5% of cases. Nonetheless, RAF1-related NS is often associated with severe clinical features, particularly hypertrophic cardiomyopathy (HCM). Although initial studies highlighted the occurrence of genotype-phenotype correlations, a comprehensive analysis specifically focused on RAF1 variants is still lacking. We conducted a retrospective observational study combining newly collected cases of RAF1-related NS from a national multicenter retrospective cohort with systematically reviewed cases from a literature search. Variants were classified by protein domain, while the most recurrent variant, p.Ser257Leu, was analyzed separately to assess variant- and domain-specific phenotype correlations. A total of 203 cases were included. Variants in the CR2 domain accounted for 83% of cases, with p.Ser257Leu alone representing 53%. HCM was observed in 80.1% of affected individuals, confirming its role as the predominant cardiac manifestation in RAF1-related NS; neurodevelopmental features were reported in 44.5% of patients. The prevalence of clinical features varied significantly according to variant location. HCM was markedly more frequently associated with CR2 variants (89.4%) and in subjects heterozygous for the p.Ser257Leu change (94.2%) compared with non-CR2 variants (37.1%). Conversely, neurodevelopmental features were more common in patients with non-CR2 variants (69.2%) than in those with CR2 variants (38.2%) or p.Ser257Leu (29.4%). CR2 and p.Ser257Leu variants were associated with earlier age at diagnosis and increased mortality. Our findings confirm and document more comprehensively domain- and variant-specific phenotypes in RAF1-related NS, emphasizing the importance of variant-level interpretation in clinical management and genetic counseling.