NM_024408.3:c.782T>G (p.Ile261Ser) is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (0 alleles), meeting PM2 at supporting strength.¹ This variant has been reported in ClinVar (Variation ID 591665) as Uncertain significance by a single clinical testing laboratory (Labcorp Genetics, criteria provided, single submitter); no submitter has classified it as pathogenic or benign.² No published functional studies, de novo observations, case-control enrichment, or family segregation data exist for this specific variant.³ In silico predictions are discordant: REVEL (0.80) supports a deleterious effect while BayesDel (0.402) does not; SpliceAI predicts no splicing impact (max delta 0.02). Neither PP3 nor BP4 can be applied.⁴ PVS1 is not applicable as this is a missense variant outside the null-variant buckets defined by ClinGen SVI PVS1 recommendations (PMC6185798).⁵ The only applicable criterion is PM2 (supporting); one supporting pathogenic criterion is insufficient to classify this variant above Variant of Uncertain Significance per ACMG/AMP 2015 combination rules.⁶