MAP2K2 p.Ser94Leu
c.281C>T · rs202220799 · VCV40786
ClinGen expert panel — RASopathy VCEP
Uncertain Significance for RASopathy. Applied ACMG criteria (verbatim):
PP2 PP3
Curation rationale (ClinGen, verbatim)
The c.281C>T (p.Ser94Leu) variant in MAP2K2 has been identified in 2 independent occurrences in patients with a RASopathy; however, in both cases it was inherited from an apparently unaffected parent (BS2 not met; GeneDx, LMM internal data; ClinVar SCV000204231.4; SCV000207977.8). The p.Ser94Leu variant was present in 0.012% (3/24906) of African alleles in gnomAD (PM2 not met, gnomad.broadinstitute.org). The variant is located in the MAP2K2 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that this variant may impact protein function (PP3). In summary, the clinical significance of the p.Ser94Leu variant is uncertain. ACMG/AMP criteria applied: PP2, PP3.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.3557 | ambiguous |
|---|---|---|
| REVEL | 0.734 | pathogenic-leaning |
| SaProt | LLR -16.12 | damaging |
| ⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP -0.66, phastCons 1 |
| Regional constraint | o/e 0.67 | unconstrained · MANE · 18 kb · p 1.4e-08 · regional, not allelic |
| Overall | ||
| CADD | 29.9 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.012% | 8,322 |
| Admixed American | 0.00833% | 11,999 |
| European (non-Finnish) | 0.00314% | 31,889 |
| Remaining individualsnot grpmax-eligible | 0.0016% | 62,438 |
| South Asian | 0.0011% | 91,072 |
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- MAP2K2
- Protein
- p.Ser94Leu
- Coding
- c.281C>T
- MANE Select
- NM_030662
- dbSNP
- rs202220799
- Type
- single nucleotide variant
- Location
- chr19:4117441 (GRCh38)
- Gene constraint
- LOEUF 0.858 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 82.54 · 3 PDB
- Residue 94
- the protein kinase domain; a turn
Similar variants
- MAP2K2 p.Ser94= Likely benign ★★ same residue
- MAP2K2 p.Ser94Pro Uncertain significance ★ ⚠ same residue
- MAP2K2 p.Glu207Lys Likely pathogenic ★★★ same condition
- MAP2K2 p.Phe57Cys Pathogenic ★★★ same condition
- MAP2K2 p.Phe57Val Pathogenic ★★★ same condition
- MAP2K2 p.Pro128Gln Pathogenic ★★★ same condition
- MAP2K2 p.Tyr134Cys Likely pathogenic ★★★ same condition
- MAP2K2 p.Tyr134His Pathogenic ★★★ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/map2k2-p-ser94leu (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown