MAP2K2 p.Arg231Leu
c.692G>T · rs730880511 · VCV40818
ClinGen expert panel — RASopathy VCEP
Uncertain Significance for RASopathy. Applied ACMG criteria (verbatim):
PM2 PS4_Supporting PP2 PP3
Curation rationale (ClinGen, verbatim)
The c.692G>T (p.Arg231Leu) variant has been identified in at least 2 independent occurrences in patients with clinical features of RASopathies (PS4_Supporting GeneDx, Invitae internal data, GTR Lab IDs 26957, 500031; ClinVar SCV000207960.9, SCV000551455.2). This variant was absent from large population studies (PM2; gnomAD, http://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 the p.Arg231Leu variant may impact the protein (PP3).In summary, the clinical significance of the p.Arg231Leu variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Supporting, PM2, PP2, PP3.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9897 | likely pathogenic |
|---|---|---|
| REVEL | 0.839 | moderately pathogenic-leaning |
| SaProt | LLR -14.71 | 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 1.9, phastCons 1 |
| Regional constraint | o/e 0.67 | unconstrained · MANE · 18 kb · p 1.4e-08 · regional, not allelic |
| Overall | ||
| CADD | 25.9 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification
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.Arg231Leu
- Coding
- c.692G>T
- MANE Select
- NM_030662
- dbSNP
- rs730880511
- Type
- single nucleotide variant
- Location
- chr19:4101032 (GRCh38)
- Gene constraint
- LOEUF 0.858 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 82.54 · 3 PDB
- Residue 231
- the protein kinase domain
Similar variants
- MAP2K2 p.Arg231His Uncertain significance ★★★ ⚠ same residue
- MAP2K2 p.Arg231Cys 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-arg231leu (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown