# NM_030662.4(MAP2K2):c.692G>A (p.Arg231His)

https://sugi.bio/variant/map2k2-p-arg231his

## Summary

**MAP2K2 p.Arg231His (c.692G>A)** is classified **Uncertain significance** in MAP2K2 (ClinVar, Expert panel, 7 submitters; last evaluated 2019-05-17). AlphaMissense: likely pathogenic (0.9878); Very rare (popmax 0.00769%, amr); Associated with Noonan syndrome and Noonan-related syndrome.

**At a glance:** Uncertain significance · review: Expert panel · rsID rs730880511 · 7 submitters · 3 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00769%, amr)

## For patients & families {#patients}

This is a change in the MAP2K2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 7 submitters, and is linked to Noonan syndrome and Noonan-related syndrome.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019561/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MAP2K2](https://sugi.bio/atlas/gene/MAP2K2/) |
| Protein change (HGVS p.) | p.Arg231His |
| Coding change (HGVS c.) | c.692G>A |
| MANE Select transcript | [NM_030662](https://www.ncbi.nlm.nih.gov/nuccore/NM_030662) |
| dbSNP | [rs730880511](https://www.ncbi.nlm.nih.gov/snp/rs730880511/) |
| Variant type | single nucleotide variant |
| Location | chr19:4101032-4101032 (GRCh38) |
| ClinVar | [VCV543999](https://www.ncbi.nlm.nih.gov/clinvar/variation/543999/) |

**All HGVS expressions:** `LRG_750:g.28097G>A`, `LRG_750t1:c.692G>A`, `NC_000019.10:g.4101032C>T`, `NC_000019.9:g.4101030C>T`, `NG_007996.1:g.28097G>A`, `NM_030662.4:c.692G>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9878)
- REVEL 0.803 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -13.581 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.659, GERP 1.92, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 27.3**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- Regional missense constraint: **o/e 0.67** across the covering region of the MANE Select transcript (4,099,368–4,117,616), spanning 18,248 bp. Chi-square p 1.4e-08. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00769%** (amr) · FAF95 0.00281% · FAF99 0.0025% · 4/52,044 in the highest group · 54/1,561,360 alleles overall — very rare (popmax 0.00769%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00769% | 13,011 |
| European (non-Finnish) | 0.00373% | 26,827 |
| South Asian | 0.00353% | 28,338 |
| Remaining individuals (not grpmax-eligible) | 0.0033% | 30,269 |
| East Asian | 0.0024% | 41,700 |
| African / African-American | 0.00136% | 73,324 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**MAP2K2** population constraint: LOEUF 0.858, pLI 1.581e-05, missense-Z 0.6256. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Noonan syndrome** — Limited (AD)
- **cardiofaciocutaneous syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **231** lies in the protein kinase domain.

AlphaFold model confidence (whole protein): pLDDT 82.54, 64% of residues very-high.

**3 experimental structure(s)** (PDB): [1S9I](https://www.rcsb.org/structure/1S9I), [4H3Q](https://www.rcsb.org/structure/4H3Q), [1JKY](https://www.rcsb.org/structure/1JKY).

## What this gene does {#gene-function}

*Describes the biological roles of MAP2K2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** MAP2K2's established molecular role includes MAP kinase kinase activity. p.Arg231His falls in the protein kinase domain. In Reactome, MAP2K2 is annotated in disease pathway(s) including **Paradoxical activation of RAF signaling by kinase inactive BRAF**, **Signaling by BRAF and RAF1 fusions**.

**Disease mechanism (Reactome):** MAP2K2 loss or alteration is curated in [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955), [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952), [Signaling by MAP2K mutants](https://reactome.org/content/detail/R-HSA-9652169).

### Pathways affected {#pathways}

MAP2K2 participates in **14 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955) | curated |
| ⚕ [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952) | curated |
| ⚕ [Signaling by MAP2K mutants](https://reactome.org/content/detail/R-HSA-9652169) | curated |
| ⚕ [Signaling by RAF1 mutants](https://reactome.org/content/detail/R-HSA-9656223) | curated |
| ⚕ [Signaling by high-kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802948) | curated |
| ⚕ [Signaling by moderate kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802946) | curated |
| ⚕ [Signaling downstream of RAS mutants](https://reactome.org/content/detail/R-HSA-9649948) | curated |
| ⚕ [Uptake and function of anthrax toxins](https://reactome.org/content/detail/R-HSA-5210891) | curated |
| [Frs2-mediated activation](https://reactome.org/content/detail/R-HSA-170968) | curated |
| [MAP2K and MAPK activation](https://reactome.org/content/detail/R-HSA-5674135) | curated |
| [MAPK1 (ERK2) activation](https://reactome.org/content/detail/R-HSA-112411) | curated |
| [Negative feedback regulation of MAPK pathway](https://reactome.org/content/detail/R-HSA-5674499) | curated |
| [RAF activation](https://reactome.org/content/detail/R-HSA-5673000) | curated |
| [Signal transduction by L1](https://reactome.org/content/detail/R-HSA-445144) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** MAP kinase kinase activity, MAP kinase scaffold activity, PDZ domain binding, protein serine/threonine kinase activator activity, scaffold protein binding.

**Biological process:** positive regulation of gene expression, peptidyl-serine autophosphorylation, positive regulation of DNA-templated transcription, ERK1 and ERK2 cascade, positive regulation of protein serine/threonine kinase activity.

## Clinical significance {#significance}

**Uncertain significance** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2019-05-17.

**Submitter consensus:** conflicting (6 Uncertain significance, 1 Likely benign).

**Submission history:** 7 submissions (2019–2026); classifications have differed over time.

**ClinGen expert panel:** Uncertain Significance — RASopathy VCEP (RASopathy). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PP2`, `PP3`.
*Considered but not met:* `PM6`, `PM2`, `PS1`, `PS2`, `PS3`, `PS4`, `PM1`, `PP1`, `BS2`, `BS1`, `BS4`, `BS3`, `BP5`, `BP7`, `PM5`, `BP4`, `BP3`, `BP1`, `BP2`, `BA1`, `PM4`.
Inheritance: Autosomal dominant inheritance.

> **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.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50021 · approved 2019-05-17 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/9f74ed62-a0c3-40e1-b0b2-7aa680c29fe2).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| ClinGen RASopathy Variant Curation Expert Panel | Uncertain significance | reviewed by expert panel | curation | 2019-05-17 |
| AiLife Diagnostics, AiLife Diagnostics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-01-10 |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2024-09-06 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-12-09 |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-01-29 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-01-25 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-10-03 |

## Associated conditions {#conditions}

[Noonan syndrome and Noonan-related syndrome](https://sugi.bio/atlas/disease/noonan-syndrome-and-noonan-related-syndrome/), [cardiofaciocutaneous syndrome 4](https://sugi.bio/atlas/disease/cardiofaciocutaneous-syndrome-4/), [RASopathy](https://sugi.bio/atlas/disease/rasopathy/).

**Reported phenotype names (ClinVar):** Noonan syndrome and Noonan-related syndrome, RASopathy, not provided, MAP2K2-related disorder, Cardiofaciocutaneous syndrome 4, not specified, MAP2K2-Related Cardiofaciocutaneous Syndrome, none provided, MAP2K2-related condition, AllHighlyPenetrant.

## Similar variants {#similar}

Related MAP2K2 variant pages (same residue, condition, or type): [MAP2K2 p.Arg231Leu](/variant/map2k2-p-arg231leu), [MAP2K2 p.Arg231Cys](/variant/map2k2-p-arg231cys), [MAP2K2 p.Glu207Lys](/variant/map2k2-p-glu207lys), [MAP2K2 p.Phe57Cys](/variant/map2k2-p-phe57cys), [MAP2K2 p.Phe57Val](/variant/map2k2-p-phe57val), [MAP2K2 p.Pro128Gln](/variant/map2k2-p-pro128gln), [MAP2K2 p.Tyr134Cys](/variant/map2k2-p-tyr134cys), [MAP2K2 p.Tyr134His](/variant/map2k2-p-tyr134his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 543999). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*