NM_000044.4:c.2653T>C (p.Ser885Pro) is a missense variant in exon 8 of AR, encoding the androgen receptor. This variant is absent from gnomAD population databases (v2.1, v4.1, Canada v1.0), meeting PM2 at moderate strength.¹ The variant is located within the AR ligand-binding domain (residues ~671-919), a well-established critical functional domain where missense variants are a known cause of androgen insensitivity syndrome, meeting PM1 at supporting strength. Multiple computational predictors suggest no significant impact: SpliceAI delta score is 0.00 and BayesDel score is 0.335 (intermediate, not damaging), meeting BP4 at supporting strength.² The variant is classified as Uncertain significance in ClinVar (VariationID 1410073) by a single clinical laboratory (Labcorp Genetics/Invitae) with review status 'criteria provided, single submitter'. No expert panel classification is available.³ No functional studies, case-control data, segregation data, de novo reports, or variant-specific publications were identified for this variant. OncoKB reports Unknown Oncogenic Effect with no curated functional evidence.⁴ Applying the generic ACMG/AMP 2015 classification rules (Richards et al. 2015, PMID:25741868): PM2 (moderate) + PM1 (supporting) + BP4 (supporting benign) yields conflicting evidence insufficient to classify as Likely Pathogenic or Likely Benign. The overall classification is Variant of Uncertain Significance (VUS).⁵