NM_177438.2:c.4199A>G (p.Asp1400Gly) is a missense variant in exon 22 of DICER1. This variant is present in gnomAD v4.1 at an allele frequency of 4.71e-05 (76/1,612,760 alleles, 0 homozygotes), with a grpmax filtering allele frequency of 4.511e-05. It has been observed across multiple subpopulations, including 7 alleles in the South Asian population (AF=7.69e-05). These frequencies exceed the DICER1 VCEP PM2_Supporting threshold of <5e-06.¹ This variant has been reported in ClinVar as Likely Benign following review by the ClinGen DICER1 and miRNA-Processing Gene Variant Curation Expert Panel (ClinVar Variation ID: 412173). Individual clinical laboratory submissions include Uncertain Significance (4 laboratories) and Likely Benign (2 laboratories).² In silico predictors support a benign interpretation: REVEL score is 0.142, well below the DICER1 VCEP BP4_Supporting threshold of <0.500. SpliceAI predicts no splicing impact (max delta = 0.12). These findings meet BP4_Supporting per DICER1 VCEP criteria.³ The variant has been observed in two siblings with pleuropulmonary blastoma (Leckey et al. 2019, PMID:30665929). However, both siblings also carried a pathogenic DICER1 splice variant (c.2437-2A>G), and the authors explicitly state that c.4199A>G 'has not been associated with DICER1-associated phenotypic features.' In silico algorithms reportedly suggest the variant 'is likely to be tolerated.' No functional studies have been performed.⁴ Residue Asp1400 lies outside the RNase IIIb domain (p.Y1682–S1846) and is not one of the seven metal ion-binding residues defined by the DICER1 VCEP for PM1. No pathogenic variant at the same residue is known for PS1 or PM5 application. No functional, segregation, de novo, or case-control data support application of any pathogenic criterion.⁵ Applying the DICER1 VCEP (version 1.4.0) point-based Tavtigian framework: only BP4_Supporting (−1 point) is met. All other applicable criteria are not met. Total point value = −1, which falls within the Uncertain Significance range (Rule 3: ≥−1 and ≤5).⁶