The p.Pro384Leu variant in MECP2 (NM_004992.3) has been reported as a de novo occurrence (biological parentage unconfirmed) in an individual with a neurological condition (PMID 22277191) (PM6). The p.Pro384Leu variant has been observed in 1 additional individual with intellectual disability (PMID 22277191) (not sufficient to meet PS4_supporting criteria). The p.Pro384Leu variant is observed in at least 8 unaffected individuals, most of whom are male (internal database - GeneDx; internal database - Invitae) (BS2). The p.Pro384Leu variant is found in a patient with an alternate molecular basis of disease (internal database - Invitae) (BP5). The p.Pro384Leu variant in MECP2 is present in 2 female individual(s) in gnomAD (0.0012%) (not sufficient to meet BS1 criteria). In summary, this variant meets the criteria to be classified as Likely Benign. Although there are both pathogenic and benign types of evidence for this variant, the pathogenic evidence is not considered inconsistent with the final classification. ACMG/AMP criteria applied, as specified by the ClinGen Rett/Angelman-like expert panel: PM6, BS2, BP5 (ClinGen Rett and Angelman-like Disorders Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 2; date of approval 12/13/2021).