NM_006231.4:c.1474-9C>T is an intronic substitution in POLE located 9 bases upstream of exon 14. SpliceAI predicts no significant splicing impact (max delta score = 0.01), indicating the variant is unlikely to alter normal splicing.

This variant is extremely rare in population databases, with an allele frequency of 4.10e-06 in gnomAD v2.1 (1/244,126 alleles) and 6.20e-07 in gnomAD v4.1 (1/1,611,808 alleles), both meeting the PM2_Supporting threshold for absence from population databases.

ClinVar classifies this variant as Likely benign (VariationID 2897960, Labcorp Genetics, criteria provided, single submitter), supporting benign interpretation under BP6_Supporting.

SpliceAI predicts no significant splice impact (max delta score = 0.01), consistent with a neutral computational assessment under BP4_Supporting.

No pathogenic evidence criteria are met. The custom León-Castillo PM1 and PS4 rules are missense-specific and do not apply to this intronic substitution. The variant is absent from COSMIC and the León-Castillo supplementary tables. No de novo observations, functional studies, or segregation data are available.

Applying the custom León-Castillo framework with generic ACMG/AMP 2015 fallback: the variant accrues one pathogenic supporting criterion (PM2_Supporting) and two benign supporting criteria (BP4_Supporting, BP6_Supporting). Under the likely_benign combination rules of the framework, two supporting benign criteria are sufficient for a classification of Likely benign. This classification is consistent with the existing ClinVar classification.