MAP2K2 p.Arg281Gln
c.842G>A · rs1332074575 · VCV569590
ClinGen expert panel — RASopathy VCEP
Uncertain Significance for RASopathy. Applied ACMG criteria (verbatim):
PP2 BP4
Curation rationale (ClinGen, verbatim)
The c.842G>A (p.Arg281Gln) variant in MAP2K2 was present in 0.007324% (1/13654) of Latino chromosomes in gnomAD v3. It was observed in one healthy adult male who did not have features of a RASopathy (BS2 not met; Baylor internal data). 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 variants are common (PP2; PMID: 29493581). Computational analysis and splice site predictors suggest that this variant does not impact the protein (BP4). In summary, the clinical significance of this variant is uncertain. RASopathy-specific ACMG/AMP criteria applied: PP2, BP4.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.0677 | likely benign |
|---|---|---|
| REVEL | 0.032 | moderately benign-leaning |
| SaProt | LLR -8.68 | tolerated |
| ⇒ AlphaMissense, REVEL and SaProt all call this tolerated. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 4 | GERP 0.8, phastCons 1 |
| Regional constraint | o/e 0.96 | unconstrained · MANE · 8,766 bp · p 0.55 · regional, not allelic |
| Overall | ||
| CADD | 21.3 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Remaining individualsnot grpmax-eligible | 0.00161% | 62,174 |
| European (non-Finnish)grpmax | 0.00085% | 117,680 |
Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.
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.Arg281Gln
- Coding
- c.842G>A
- MANE Select
- NM_030662
- dbSNP
- rs1332074575
- Type
- single nucleotide variant
- Location
- chr19:4099278 (GRCh38)
- Gene constraint
- LOEUF 0.858 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 82.54 · 3 PDB
- Residue 281
- the protein kinase domain
Similar variants
- MAP2K2 p.Arg281Pro Uncertain significance ★ ⚠ same residue
- MAP2K2 p.Arg281Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
- MAP2K2 p.Arg281= Likely benign ★ 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
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-arg281gln (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown