NM_005732.3:c.221A>C (p.Gln74Pro) is a missense variant in RAD50, a gene in which biallelic loss-of-function variants cause RAD50 deficiency (OMIM #613078), an autosomal recessive disorder of DNA double-strand break repair.¹ This variant is absent from gnomAD v2.1 and observed at extremely low frequency in gnomAD v4.1 (3/1,594,676 total alleles, AF=1.88e-6, 0 homozygotes), with all three alleles restricted to the European (non-Finnish) subpopulation (grpmax FAF=6.9e-7). This extreme rarity meets PM2 at moderate strength.² REVEL (0.263), BayesDel (-0.354), and SpliceAI (max delta 0.01) all predict no damaging effect on protein function or splicing, meeting BP4 at supporting benign strength.³ As a missense variant in a gene where truncating variants are the established disease mechanism, BP1 applies at supporting benign strength.⁴ ClinVar reports this variant as Uncertain Significance (variation ID 1053169) based on two clinical laboratory submissions (Ambry Genetics and Invitae/Labcorp); no expert panel review is available. This does not meet criteria for PP5 or BP6, as neither pathogenic nor benign consensus has been reached.⁵ No variant-specific functional studies, de novo observations, case-control data, segregation data, or published case reports were identified for this variant. OncoKB reports unknown oncogenic effect with no curated functional evidence.⁶ Overall, the evidence profile consists of one moderate pathogenic criterion (PM2) and two supporting benign criteria (BP1, BP4). The net classification is Variant of Uncertain Significance (VUS) under the ACMG/AMP 2015 framework.⁷