MAP2K2 p.Val262Ile
c.784G>A · rs138873805 · VCV46242
ClinGen expert panel — RASopathy VCEP
Uncertain Significance for RASopathy. Applied ACMG criteria (verbatim):
BP4
Curation rationale (ClinGen, verbatim)
The c.784G>A variant in the MAP2K2 gene is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 262 (p.Val262Ile). The filtering allele frequency in gnomAD v4.1.0 is 0.01543% (201/1178752 alleles) in the European (non-Finnish) population (PM2_Supporting/BS1/BA1 are not met). The computational predictor REVEL gives a score of 0.219, which predicts no impact on protein function (BP4). This variant has been identified in 4 independent occurrences in patients with disparate phenotypes of RASopathy (PS4 not met; GeneDx, LMM internal data; GTR ID's 26957, 21766; SCV000207950.9, SCV000063182.5). In summary, this variant meets criteria to be classified as variant of uncertain significance for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BP4 (Specification Version 2.1, 9/17/2024)
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.0582 | likely benign |
|---|---|---|
| REVEL | 0.219 | benign-leaning |
| SaProt | LLR -5.12 | 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 0.69 | GERP -1.2, phastCons 1 |
| Regional constraint | o/e 0.96 | unconstrained · MANE · 8,766 bp · p 0.55 · regional, not allelic |
| Overall | ||
| CADD | 12.78 | 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 |
|---|---|---|
| Admixed Americangrpmax | 0.0235% | 4,258 |
| Remaining individualsnot grpmax-eligible | 0.0209% | 4,796 |
| European (non-Finnish) | 0.0171% | 5,864 |
| African / African-American | 0.00935% | 10,700 |
| South Asian | 0.00662% | 15,108 |
| Ashkenazi Jewishnot grpmax-eligible | 0.00338% | 29,550 |
| Finnishnot grpmax-eligible | 0.00159% | 62,810 |
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.Val262Ile
- Coding
- c.784G>A
- MANE Select
- NM_030662
- dbSNP
- rs138873805
- Type
- single nucleotide variant
- Location
- chr19:4099336 (GRCh38)
- Gene constraint
- LOEUF 0.858 · pLI <0.01 (gnomAD)
- Structure
- AlphaFold pLDDT 82.54 · 3 PDB
- Residue 262
- the protein kinase domain; an α-helix
Similar variants
- MAP2K2 p.Val262= Likely benign ★★ same residue
- MAP2K2 p.Glu207Lys Likely pathogenic ★★★ same condition
- MAP2K2 p.Phe57Cys 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
- MAP2K2 p.Arg231Leu 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-val262ile (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown