MAP2K2 p.Arg231His
c.692G>A · rs730880511 · VCV543999
ClinGen expert panel — RASopathy VCEP
Uncertain Significance for RASopathy. Applied ACMG criteria (verbatim):
PP2 PP3
Curation rationale (ClinGen, verbatim)
The c.692G>A (p.Arg231His) variant in MAP2K2 has been identified in a patient with clinical features consistent with cardiomyopathy (PS4 not met; Invitae internal data, GTR Lab ID 500031; ClinVar SCV000776886.1). 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.Arg231His variant may impact the protein (PP3). In summary, the clinical significance of the p.Arg231His variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9878 | likely pathogenic |
|---|---|---|
| REVEL | 0.803 | moderately pathogenic-leaning |
| SaProt | LLR -13.58 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| 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 | 27.3 | 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
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.00769% | 13,011 |
| European (non-Finnish) | 0.00373% | 26,827 |
| South Asian | 0.00353% | 28,338 |
| Remaining individualsnot grpmax-eligible | 0.0033% | 30,269 |
| East Asian | 0.0024% | 41,700 |
| African / African-American | 0.00136% | 73,324 |
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.Arg231His
- Coding
- c.692G>A
- 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.Arg231Leu 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-arg231his (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown