MAP2K2 p.Pro269Arg
c.806C>G · rs368064728 · VCV177876
ClinGen expert panel — RASopathy VCEP
Uncertain Significance for RASopathy. Applied ACMG criteria (verbatim):
PM2 PP3 BP5
Curation rationale (ClinGen, verbatim)
The c.806C>G (p.Pro269Arg) variant in MAP2K2 is absent from gnomAD (PM2). This variant has been observed in an individual with an alternate mechanism of disease (VCV000013329.8; Laboratory for Molecular Medicine internal data; BP5). Four apparently unaffected parental samples involved in whole exome testing were observed with this variant supporting that this variant is likely benign; however, this evidence does not meet current scoring criteria for BS2 at this time. Computational prediction tools and conservation analysis suggest that the p.Pro269Arg variant may impact the protein (PP3). In summary, the clinical significance of the p.Pro269Arg variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP3, PM2, BP5.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.6131 | likely pathogenic |
|---|---|---|
| REVEL | 0.711 | pathogenic-leaning |
| SaProt | LLR -9.91 | tolerated |
| ⇒ AlphaMissense and REVEL call this damaging; SaProt does not. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 12 | GERP 0.8, phastCons 1 |
| Regional constraint | o/e 0.96 | unconstrained · MANE · 8,766 bp · p 0.55 · 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
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Remaining individualsnot grpmax-eligible | 0.00321% | 31,110 |
| European (non-Finnish)grpmax | 0.00144% | 69,259 |
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.Pro269Arg
- Coding
- c.806C>G
- MANE Select
- NM_030662
- dbSNP
- rs368064728
- Type
- single nucleotide variant
- Location
- chr19:4099314 (GRCh38)
- Gene constraint
- LOEUF 0.858 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 82.54 · 3 PDB
- Residue 269
- the protein kinase domain; an α-helix
Similar variants
- MAP2K2 p.Pro269Gln Uncertain significance ★★ ⚠ same residue
- MAP2K2 p.Pro269Leu Uncertain significance ★★ ⚠ same residue
- MAP2K2 p.Pro269= 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-pro269arg (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown