NM_004333.6:c.1741A>T (p.Asn581Tyr) is a missense variant in exon 14 of BRAF, encoding a substitution at a highly conserved residue within the kinase domain. This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at Supporting strength per the ClinGen RASopathy VCEP v2.3.0 (PM2_Supporting).¹ BRAF exhibits strong constraint against missense variation in gnomAD (missense Z-score >3.09), and missense variants are a common mechanism of RASopathy, meeting PP2 at Supporting strength. The REVEL in silico prediction score is 0.978, exceeding the VCEP threshold of ≥0.7 for PP3 at Supporting strength. SpliceAI predicts no significant splicing impact (max delta = 0.07).² N581Y has been observed as a somatic variant in multiple cancer types: colorectal cancer cell line HT55 (Seth 2009, PMID:19474002), melanoma cell line WM3912 (Hutchinson 2015, PMID:26084293), and in a cfDNA NSCLC cohort where it was identified as a novel activating mutation by Ba/F3 assay (Negrao 2020, PMID:32540409). N581Y is catalogued in COSMIC (COSV56062673, n=7). OncoKB classifies it as Likely Oncogenic with Likely Gain-of-function effect.³ No germline RASopathy probands, de novo occurrences, or family segregation data are available for this variant. VCEP-approved functional assays (BRAF Kinase Activity, MEK/ERK Activation Assays) have no data for N581Y. The N581 residue lies in a statistically significant hotspot, but is outside the VCEP-specified PM1 domains (P-loop AA 459-474 and CR3 activation segment AA 594-627); PM1 is not met.