MAP2K2 p.Glu207Lys
c.619G>A · rs727504382 · VCV40813
ClinGen expert panel — RASopathy VCEP
Pathogenic for cardiofaciocutaneous syndrome. Applied ACMG criteria (verbatim):
PM6 PM2 PS2 PS4 PP2
Curation rationale (ClinGen, verbatim)
The c.619G>A (p.Glu207Lys) variant in MAP2K2 was absent from large population studies (PM2; gnomAD.broadinstitute.org). It has been identified in 6 individuals with clinical features of a RASopathy (PS4; SCV000204213.4, SCV000207959.10, SCV000815593.1, Otto von Guericke University Magdeburg internal data). One of these cases was a confirmed de novo occurrence and another was an unconfirmed de novo occurrence (PS2; PM6; SCV000815593.1, Otto von Guericke University Magdeburg internal data). Additionally, the c.619G>A (p.Glu207Lys) is located in MAP2K2, 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). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4, PS2, PM6, PM2, PP2.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9868 | likely pathogenic ✓ concordant with ClinVar |
|---|---|---|
| REVEL | 0.657 | pathogenic-leaning |
| SaProt | LLR -13.63 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | <0.2 | no splice effect predicted · four deltas, not one · how we know |
| Constraint at this position | ||
| Conservation | phyloP 7.7 | GERP -0.66, phastCons 1 |
| Regional constraint | o/e 0.67 | unconstrained · MANE · 18 kb · p 1.4e-08 · regional, not allelic |
| Overall | ||
| CADD | 32.0 | 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.Glu207Lys
- Coding
- c.619G>A
- MANE Select
- NM_030662
- dbSNP
- rs727504382
- Type
- single nucleotide variant
- Location
- chr19:4101105 (GRCh38)
- Gene constraint
- LOEUF 0.858 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 82.54 · 3 PDB
- Residue 207
- the protein kinase domain
Similar variants
- MAP2K2 p.Glu207= Benign/Likely benign ★★ same residue
- MAP2K2 p.Glu207Val Uncertain significance ★ ⚠ same residue
- 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
- MAP2K2 p.Arg231His Uncertain significance ★★★ ⚠ 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-glu207lys (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown