NM_002755.3:c.146G>A (p.Arg49His) in MAP2K1 is a missense variant located within the VCEP-designated critical functional domain spanning amino acids 43-61, satisfying PM1 at Moderate strength.¹ A confirmed de novo occurrence of this variant was reported in a patient with cardio-facio-cutaneous syndrome, with both maternity and paternity confirmed, satisfying PS2 at Moderate strength (1 point under VCEP scoring). The REVEL in silico score is 0.707, meeting the VCEP PP3 threshold of ≥0.7 for missense variants at Supporting strength.² This variant is present at extremely low frequency in gnomAD (AF ~0.0004%), far below both the BA1 (≥0.05%) and BS1 (≥0.025%) thresholds, and present in only 1 allele in v2.1 and 5 alleles in v4.1.³ No alternative pathogenic missense change at codon 49 was identified (PM5 not met), and the variant is not absent from gnomAD controls (PM2 not met per VCEP requirement for complete absence).⁴ PP2 (missense constraint z-score) remains unassessed pending gnomAD constraint data retrieval. If the MAP2K1 missense z-score exceeds 3.09, PP2_Supporting would also be met.⁵ ClinVar lists this variant as Uncertain significance (1 submitter, SCV003504233, Labcorp Genetics). No expert panel classification is available.⁶ Under the RASopathy VCEP v2.3.0 combination rules, the current met criteria (PM1_Moderate + PS2_Moderate + PP3_Supporting) do not satisfy any rule for Likely Pathogenic or Pathogenic classification. If PP2_Supporting is also met, Rule14 (2 Moderate + ≥2 Supporting) would be satisfied, yielding Likely Pathogenic.⁷