NM_017763.5:c.252+2C>G is a canonical splice donor variant at the +2 position of intron 2 in RNF43, a gene where loss of function is an established mechanism for germline disease including serrated polyposis syndrome and colorectal cancer predisposition. Assessed under ClinGen SVI PVS1 recommendations (PMC6185798) as a null variant (PVS1).¹ The variant is extremely rare in population databases, with an allele frequency of 3.98e-06 in gnomAD v2.1 (1/251,184 alleles, 0 homozygotes) and 6.20e-07 in gnomAD v4.1 (1/1,613,886 alleles, 0 homozygotes), and is absent from gnomAD-Canada. Allele frequency is well below the 0.1% PM2 threshold (PM2).² ClinVar reports this variant as Uncertain significance (2 clinical laboratories, criteria provided, single submitter; Variation ID 3669600). No variant-specific functional studies, segregation data, or de novo observations were identified in the reviewed literature.³ SpliceAI predicts no significant splice impact (max delta = 0.0), which conflicts with the canonical splice site expectation. This discrepancy may reflect SpliceAI calibration for a non-canonical reference donor (C at +2 instead of the consensus T). RNA functional studies are recommended to resolve this conflict.⁴ Under ACMG/AMP 2015 generic classification rules, 1 Very Strong (PVS1) + 1 Moderate (PM2) supports a classification of Likely Pathogenic. However, the SpliceAI conflict warrants caution and human review.⁵