NM_198159.3:c.218G>A (p.Arg73His) is a missense variant in MITF exon 2, classified under the generic ACMG/AMP 2015 framework as no CSPEC/VCEP framework is available for this gene. The variant is present at extremely low frequency in gnomAD: v2.1 AF = 0.0018% (5/280628 alleles) and v4.1 AF = 0.0032% (51/1614094 alleles), with no homozygotes observed. This meets PM2 at supporting level.¹ Multiple lines of in silico evidence suggest a neutral effect: REVEL 0.285, BayesDel -0.025, and SpliceAI max delta 0.0, meeting BP4 at supporting benign level.² No variant-specific functional studies, case-control analyses, de novo reports, cosegregation data, or expert panel classifications were identified for this variant. The variant has been reported in ClinVar as Uncertain Significance by two clinical laboratories.³ PVS1 is not applicable as the variant is missense. PM5 is not applicable as no pathogenic comparator exists at p.Arg73. BP1 is not applicable as MITF has known pathogenic missense variants. BP7 is not applicable as the variant is not synonymous. BP3, PM3, and PM4 were trivially not applicable per the assessment scope.⁴ With one supporting pathogenic criterion (PM2_Supporting) and one supporting benign criterion (BP4_Supporting), the evidence is balanced. The variant is classified as a Variant of Uncertain Significance (VUS) under the ACMG/AMP 2015 generic framework.⁵