# NM_030662.4(MAP2K2):c.707C>T (p.Pro236Leu)

https://sugi.bio/variant/map2k2-p-pro236leu

## Summary

**MAP2K2 p.Pro236Leu (c.707C>T)** is classified **Uncertain significance** in MAP2K2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-10-18). AlphaMissense: likely pathogenic (0.9944); Very rare (popmax 0.00134%, afr); Associated with RASopathy.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs1309234276 · 3 submitters · 1 linked condition · AlphaMissense likely pathogenic · very rare (popmax 0.00134%, afr)

## 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 3 submitters, 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.Pro236Leu |
| Coding change (HGVS c.) | c.707C>T |
| MANE Select transcript | [NM_030662](https://www.ncbi.nlm.nih.gov/nuccore/NM_030662) |
| dbSNP | [rs1309234276](https://www.ncbi.nlm.nih.gov/snp/rs1309234276/) |
| Variant type | single nucleotide variant |
| Location | chr19:4099413-4099413 (GRCh38) |
| ClinVar | [VCV591250](https://www.ncbi.nlm.nih.gov/clinvar/variation/591250/) |

**All HGVS expressions:** `LRG_750:g.29716C>T`, `LRG_750t1:c.707C>T`, `NC_000019.10:g.4099413G>A`, `NC_000019.9:g.4099411G>A`, `NG_007996.1:g.29716C>T`, `NM_030662.3:c.707C>T`, `NM_030662.4:c.707C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9944)
- REVEL 0.964 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -16.995 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.733, GERP 1.92, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 35.0**. 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: **below the reporting threshold**. This position is scored for a different substitution (G>T, Δ0.67 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00134%** (afr) · FAF95 0.000184% · FAF99 0.000121% · 1/74,564 in the highest group · 8/1,599,314 alleles overall — very rare (popmax 0.00134%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.00162% | 61,896 |
| African / African-American (grpmax) | 0.00134% | 74,564 |
| European (non-Finnish) | 0.000511% | 195,536 |

Remaining individuals shows a higher raw frequency than the grpmax group. 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.

*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 **236** lies in the protein kinase domain; an α-helix.

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.Pro236Leu 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 Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-10-18.

**Submitter consensus:** unanimous (3/3 Uncertain significance).

**Submission history:** 3 submissions (2018–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Gharavi Laboratory, Columbia University | Uncertain significance | no assertion criteria provided | research | 2018-09-16 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-07-29 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-18 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** RASopathy, not provided, Cardiovascular phenotype, none provided, Noonan spectrum disorder, rasopathies.

## Similar variants {#similar}

Related MAP2K2 variant pages (same residue, condition, or type): [MAP2K2 p.Pro236=](/variant/map2k2-p-pro236), [MAP2K2 p.Pro236Ser](/variant/map2k2-p-pro236ser), [MAP2K2 p.Glu207Lys](/variant/map2k2-p-glu207lys), [MAP2K2 p.Phe57Cys](/variant/map2k2-p-phe57cys), [MAP2K2 p.Pro128Gln](/variant/map2k2-p-pro128gln), [MAP2K2 p.Tyr134Cys](/variant/map2k2-p-tyr134cys), [MAP2K2 p.Tyr134His](/variant/map2k2-p-tyr134his), [MAP2K2 p.Arg231His](/variant/map2k2-p-arg231his).

### 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 591250). 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.*