The c.323G>T variant in MAP2K1 is a missense variant predicted to cause substitution of arginine by leucine at amino acid 108 (p.Arg108Leu, NM_002755.4). This variant is absent from gnomAD v2.1.1 (PM2_supporting). The computational predictor REVEL gives a score of 0.831, which is above the RASopathy VCEP threshold of 0.7, evidence that correlates with impact to MAP2K1 function (PP3). MAP2K1, in which the variant was identified, is defined by the ClinGen RASopathy VCEP as a gene that has a low rate of benign missense variation and where pathogenic missense variants are a common mechanism of disease (PP2). This variant has been reported in 3 probands with features of RASopathy (PS4_supporting; 2.5 pts.; PMID: 35524774, Fulgent Genetics & Baylor College of Medicine internal data (SCV000894927 & SCV005871135, respectively)). This variant has been identified as a de novo occurrence with confirmed parental relationships in 1 individual and as a de novo occurrence with unconfirmed parental relationships in 1 individual with features of RASopathy (PS2; 3.0 pts.; Fulgent Genetics & Baylor College of Medicine internal data (SCV000894927 & SCV005871135, respectively)). In summary, this variant meets the criteria to be classified as likely pathogenic for autosomal dominant RASopathy, based on the ACMG/AMP Criteria applied, as specified by the ClinGen RASopathy VCEP: PM2_supporting, PP3, PP2, PS4_supporting, PS2; Specifications Version 2.3.0). This variant was originally evaluated by the VCEP as pathogenic on 06/25/2020. It was re-evaluated on 07/08/2025 and downgraded to likely pathogenic, despite one new case of genetic evidence (PMID: 35524774). The change in classification was due to changes in guidelines (downgrading PM2 to PM2_supporting and combining PS2 & PM6).