# NM_030662.4(MAP2K2):c.1140C>T (p.Ala380=)

https://sugi.bio/variant/map2k2-p-ala380

## Summary

**MAP2K2 p.Ala380= (c.1140C>T)** is classified **Likely benign** in MAP2K2 (ClinVar, Expert panel, 10 submitters; last evaluated 2017-05-09). Ultra-rare (popmax 0.0666%, afr); Associated with RASopathy.

**At a glance:** Likely benign · review: Expert panel · rsID rs146618055 · 10 submitters · 2 linked conditions · ultra-rare (popmax 0.0666%, afr)

## For patients & families {#patients}

This is a change in the MAP2K2 gene that is classified as likely benign — not considered disease-causing, submitted by 10 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.Ala380= |
| Coding change (HGVS c.) | c.1140C>T |
| MANE Select transcript | [NM_030662](https://www.ncbi.nlm.nih.gov/nuccore/NM_030662) |
| dbSNP | [rs146618055](https://www.ncbi.nlm.nih.gov/snp/rs146618055/) |
| Variant type | single nucleotide variant |
| Location | chr19:4090661-4090661 (GRCh38) |
| ClinVar | [VCV50938](https://www.ncbi.nlm.nih.gov/clinvar/variation/50938/) |

**All HGVS expressions:** `LRG_750:g.38468C>T`, `LRG_750t1:c.1140C>T`, `NC_000019.10:g.4090661G>A`, `NC_000019.9:g.4090659G>A`, `NG_007996.1:g.38468C>T`, `NM_030662.4:c.1140C>T`

## 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 -8.048, GERP -3.85 — fast-evolving / accelerated position
- CADD: **PHRED 0.515**. 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.*
- 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 **0.0666%** (afr) · FAF95 0.0516% · FAF99 0.0464% · 49/73,606 in the highest group · 428/1,559,242 alleles overall — ultra-rare (popmax 0.0666%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.0666% | 1,502 |
| East Asian | 0.0407% | 2,454 |
| Middle Eastern | 0.0334% | 2,993 |
| European (non-Finnish) | 0.029% | 3,448 |
| Remaining individuals (not grpmax-eligible) | 0.0281% | 3,556 |
| Admixed American | 0.0116% | 8,656 |
| South Asian | 0.00354% | 28,235 |

*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 **380** lies in 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. 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}

**Likely benign** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2017-05-09.

**Submitter consensus:** conflicting (6 Benign, 4 Likely benign).

**Submission history:** 10 submissions (2012–2026); classifications have differed over time.

**ClinGen expert panel:** Likely Benign — RASopathy VCEP (RASopathy). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `BS1`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The filtering allele frequency of the c.1140C>T (p.Ala380=) variant in the MAP2K2 gene is 0.003% (2/796) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as likely benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1; PMID:29493581)
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50021 · approved 2017-05-09 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/b23e5835-5f83-4a46-b686-0e354d53e944).*
*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 |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2014-08-26 |
| Genome Diagnostics Laboratory, The Hospital for Sick Children | Benign | criteria provided, single submitter | clinical testing | 2020-01-01 |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2020-07-28 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2019-03-18 |
| ClinGen RASopathy Variant Curation Expert Panel | Likely benign | reviewed by expert panel | curation | 2017-05-09 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2022-06-30 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-08-23 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Likely benign | criteria provided, single submitter | clinical testing | 2012-10-18 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-10-23 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-07 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** RASopathy, not specified, Noonan syndrome and Noonan-related syndrome, Cardiovascular phenotype, MAP2K2-related disorder, MAP2K2-related condition, AllHighlyPenetrant, rasopathies, Noonan spectrum disorder.

## Similar variants {#similar}

Related MAP2K2 variant pages (same residue, condition, or type): [MAP2K2 p.Ala380Val](/variant/map2k2-p-ala380val), [MAP2K2 p.Ala380Thr](/variant/map2k2-p-ala380thr), [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 50938). 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.*