# NM_030662.4(MAP2K2):c.639del (p.Phe213fs)

https://sugi.bio/variant/map2k2-p-phe213fs

## Summary

**MAP2K2 p.Phe213fs (c.639del)** is classified **Uncertain significance** in MAP2K2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-04). No gnomAD frequency available for this variant; Associated with RASopathy.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2145054190 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## 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 1 submitter, and is linked to RASopathy.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 9 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0022213/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.Phe213fs |
| Coding change (HGVS c.) | c.639del |
| MANE Select transcript | [NM_030662](https://www.ncbi.nlm.nih.gov/nuccore/NM_030662) |
| dbSNP | [rs2145054190](https://www.ncbi.nlm.nih.gov/snp/rs2145054190/) |
| Variant type | Deletion |
| Location | chr19:4101085-4101085 (GRCh38) |
| ClinVar | [VCV1384483](https://www.ncbi.nlm.nih.gov/clinvar/variation/1384483/) |

**All HGVS expressions:** `LRG_750:g.28044del`, `NC_000019.10:g.4101085del`, `NC_000019.9:g.4101083del`, `NG_007996.1:g.28044del`, `NM_030662.4:c.639del`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 7.657, GERP 1.92, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 0.858, pLI 1.581e-05. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 6 of 11**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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 **213** 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.Phe213fs 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 Single submitter *(criteria provided, single submitter)*, last evaluated 2021-10-04.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-10-04 |

## Associated conditions {#conditions}

[RASopathy](https://sugi.bio/atlas/disease/rasopathy/).

**Reported phenotype names (ClinVar):** RASopathy, rasopathies, Noonan spectrum disorder.

## Similar variants {#similar}

Related MAP2K2 variant pages (same residue, condition, or type): [MAP2K2 p.Phe213=](/variant/map2k2-p-phe213), [MAP2K2 p.Leu54fs](/variant/map2k2-p-leu54fs), [MAP2K2 c.303+15del](/variant/map2k2-c-303-plus-15del), [MAP2K2 c.1046+5_1046+8del](/variant/map2k2-c-1046-plus-5-1046-plus-8del), [MAP2K2 c.1046+5del](/variant/map2k2-c-1046-plus-5del), [MAP2K2 c.578_580+9del](/variant/map2k2-c-578-580-plus-9del), [MAP2K2 p.Ala162fs](/variant/map2k2-p-ala162fs), [MAP2K2 p.Arg303fs](/variant/map2k2-p-arg303fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 1384483). 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.*