NM_000500.9:c.1439G>T (p.Arg480Leu) is a missense variant in exon 10 of CYP21A2, a gene associated with autosomal recessive congenital adrenal hyperplasia due to 21-hydroxylase deficiency. The variant is present in gnomAD at an appreciable global allele frequency of 0.62% (v2.1, 1521/244182 alleles) and 0.33% (v4.1, 5128/1571116 alleles), exceeding the BS1 threshold (>0.3%) for a recessive disorder.¹ In silico predictions are uniformly benign: REVEL score 0.334, BayesDel score -0.316 (predicting benign), and SpliceAI detects no splice alteration (max delta 0.00), satisfying BP4.² ClinVar reports this variant as Benign by three clinical laboratories and Likely benign by three additional laboratories, with two VUS submissions, supporting BP6.³ Functional studies demonstrate the variant retains ~75-80% of wild-type 21-hydroxylase activity in transfected COS-1 cells, consistent with a mild functional impact, providing PS3 at the supporting level.⁴ Applying the generic ACMG/AMP 2015 combination rules (PMID:25741868), the criteria met are three supporting benign (BS1, BP4, BP6) and one supporting pathogenic (PS3). Likely benign requires at least two supporting benign criteria, which is satisfied.⁵