MAP2K2 p.Pro128Gln
c.383C>A · rs267607230 · VCV8275
ClinGen expert panel — RASopathy VCEP
Pathogenic for RASopathy. Applied ACMG criteria (verbatim):
PP1_Strong PM2_Supporting PS4_Supporting PS3_Supporting PM1 PP3
Curation rationale (ClinGen, verbatim)
The c.383C>A variant in the MAP2K2 gene is a missense variant predicted to cause substitution of proline by glutamine at amino acid 128 (p.Pro128Gln). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.928 (PP3). This variant is located in a functional domain supporting pathogenicity (PM1). This variant has been reported to segregate with clinical features of a RASopathy in at least 7 family members of the proband (PS4_Supporting, PP1_Strong; 20358587). ERK phosphorylation assay showed that this variant led to increased ERK phosphorylation compared to wild-type (PS3_P; PMID 20358587). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PP1_Strong, PM1, PS3_Supporting, PS4_Supporting, PM2_Supporting, PP3 (Specification Version 2.1, 09/17/2024)
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9712 | likely pathogenic ✓ concordant with ClinVar |
|---|---|---|
| REVEL | 0.928 | moderately pathogenic-leaning |
| SaProt | LLR -11.88 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP 1.9, phastCons 1 |
| Regional constraint | o/e 0.67 | unconstrained · MANE · 18 kb · p 1.4e-08 · regional, not allelic |
| Overall | ||
| CADD | 26.5 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- MAP2K2
- Protein
- p.Pro128Gln
- Coding
- c.383C>A
- MANE Select
- NM_030662
- dbSNP
- rs267607230
- Type
- single nucleotide variant
- Location
- chr19:4110576 (GRCh38)
- Gene constraint
- LOEUF 0.858 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 82.54 · 3 PDB
- Residue 128
- the protein kinase domain; a UniProt-annotated variant site (in cfc4; results in increased kinase activity)
Similar variants
- MAP2K2 p.Pro128Leu Pathogenic/Likely pathogenic ★★ same residue
- MAP2K2 p.Pro128= Likely benign ★★ same residue
- MAP2K2 p.Pro128Arg 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.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-pro128gln (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown