NM_004333.5:c.1661T>C (p.Ile554Thr) is a missense variant in BRAF exon 13, located in the kinase domain between the P-loop and CR3 activation segment. This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=3.98e-6 (1/251,340 alleles) and v4.1 AF=1.43e-5 (23/1,613,478 alleles), with no homozygotes observed.¹ ClinVar reports conflicting interpretations: Likely benign (2 clinical laboratories) and Uncertain significance (1 clinical laboratory), with no expert panel review (ClinVar Variation ID 239870).² PP3 (supporting): REVEL score of 0.885 exceeds the VCEP threshold of ≥0.7 for pathogenic computational prediction. SpliceAI predicts no splicing impact (max delta 0.00).³ PP2 (supporting): BRAF has a high missense constraint Z-score in gnomAD (>3.09), indicating a low rate of benign missense variation consistent with a gene where missense variants are a common disease mechanism.⁴ PM1 is not met because amino acid 554 lies outside the VCEP-specified domains (exon 6, exon 11, P-loop AA 459-474, CR3 activation segment AA 594-627).⁵ PM2 is not met because the RASopathy VCEP requires absence from gnomAD controls, and this variant is observed in both gnomAD v2.1 and v4.1.⁶ PM5 is not met because no other [likely] pathogenic missense variant at codon 554 was identified in ClinVar or the VCEP supplementary materials.⁷ BS1 is not met because the allele frequency (max 9.92e-5) is below the VCEP threshold of ≥0.025%.⁸ No benign criteria are met. Two pathogenic supporting criteria (PP2, PP3) are met. Under the RASopathy VCEP v2.3.0 combination rules, this does not reach the threshold for Likely Pathogenic (which requires at minimum 1 moderate + 4 supporting, or 1 strong + 1 moderate, or comparable combinations).⁹ Insufficient evidence exists to classify this variant as either pathogenic or benign. With only two supporting-level pathogenic criteria and no benign criteria, this variant is classified as a Variant of Uncertain Significance (VUS).