# NM_002755.4(MAP2K1):c.370C>T (p.Pro124Ser)

https://sugi.bio/variant/map2k1-p-pro124ser

## Summary

**MAP2K1 p.Pro124Ser (c.370C>T)** is classified **Pathogenic** in MAP2K1 (ClinVar, Expert panel, 7 submitters; last evaluated 2025-01-10). AlphaMissense: likely pathogenic (0.968); Absent from gnomAD v4.1; Associated with RASopathy.

**At a glance:** Pathogenic · review: Expert panel · rsID rs1057519732 · 7 submitters · 3 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the MAP2K1 gene that is considered disease-causing, submitted by 7 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 | [MAP2K1](https://sugi.bio/atlas/gene/MAP2K1/) |
| Protein change (HGVS p.) | p.Pro124Ser |
| Coding change (HGVS c.) | c.370C>T |
| MANE Select transcript | [NM_002755](https://www.ncbi.nlm.nih.gov/nuccore/NM_002755) |
| dbSNP | [rs1057519732](https://www.ncbi.nlm.nih.gov/snp/rs1057519732/) |
| Variant type | single nucleotide variant |
| Location | chr15:66436824-66436824 (GRCh38) |
| ClinVar | [VCV375981](https://www.ncbi.nlm.nih.gov/clinvar/variation/375981/) |

**All HGVS expressions:** `LRG_725:g.54952C>T`, `LRG_725t1:c.370C>T`, `NC_000015.10:g.66436824C>T`, `NC_000015.9:g.66729162C>T`, `NG_008305.1:g.54952C>T`, `NM_002755.3(MAP2K1):c.370C>T`, `NM_002755.4:c.370C>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.968) — concordant with the pathogenic call
- REVEL 0.855 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -12.521 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.639, GERP 2.21, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 27.4**. 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 0.46** across the covering region of the MANE Select transcript (66,387,415–66,481,789), spanning 94,374 bp. Chi-square p 1.7e-15. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for MAP2K1 (637 scored positions, the nearest 20 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**MAP2K1** population constraint: LOEUF 0.515, pLI 0.96737, missense-Z 3.7569; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *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)
- **Costello syndrome** — Disputed (AD)
- **Noonan syndrome with multiple lentigines** — Limited (AD)
- **cardiofaciocutaneous syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **124** lies in the protein kinase domain.

AlphaFold model confidence (whole protein): pLDDT 84.05, 63% of residues very-high.

**99 experimental structure(s)** (PDB): [1S9J](https://www.rcsb.org/structure/1S9J), [2P55](https://www.rcsb.org/structure/2P55), [3DV3](https://www.rcsb.org/structure/3DV3), [3DY7](https://www.rcsb.org/structure/3DY7), [3E8N](https://www.rcsb.org/structure/3E8N), [3EQB](https://www.rcsb.org/structure/3EQB) — incl. mutant structure 5YT3.

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

*Describes the biological roles of MAP2K1 (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:** MAP2K1's established molecular role includes MAP kinase kinase activity. p.Pro124Ser falls in the protein kinase domain. In Reactome, MAP2K1 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):** MAP2K1 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}

MAP2K1 participates in **15 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 |
| [MAPK3 (ERK1) activation](https://reactome.org/content/detail/R-HSA-110056) | 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 |
| [MAP3K8 (TPL2)-dependent MAPK1/3 activation](https://reactome.org/content/detail/R-HSA-5684264) | electronic |

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

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

**Biological process:** negative regulation of cell population proliferation, positive regulation of gene expression, positive regulation of DNA-templated transcription, positive regulation of ERK1 and ERK2 cascade, positive regulation of protein serine/threonine kinase activity, cellular senescence.

## Clinical significance {#significance}

**Pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2025-01-10.

**Submitter consensus:** conflicting (4 Pathogenic, 2 Likely pathogenic).

**Submission history:** 8 submissions (2019–2025); classifications have differed over time.

**ClinGen expert panel:** Pathogenic — RASopathy VCEP (RASopathy). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PS2_VeryStrong`, `PM2_Supporting`, `PS3_Supporting`, `PS4_Moderate`, `PM1`, `PP2`, `PP3`, `PM5`.
*Considered but not met:* `BS1`, `BA1`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The NM_002755.4:c.370C>T variant in MAP2K1 is a missense variant predicted to cause substitution of proline by serine at amino acid 124 (p.Pro124Ser). This variant was absent from gnomAD v2.1.1 (PM2_Supporting). The computational prediction tool REVEL gives a score of 0.855, suggesting that this variant may impact the protein (PP3). The p.Pro124Ser variant is located in the MAP2K1 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). The variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a critical domain of MAP2K1 (AA 124-134, PM1). Furthermore, 4 different (likely) pathogenic variants at this residue (Pro124Leu, Pro124Arg, Pro124Ala, Pro124Gln) have been identified in several patients with RASopathies (PM5). This variant has been observed in at least 7 probands with a RASopathy, of which 3 were reported as a de novo occurrence with confirmed parental relationships and 1 was assumed to be de novo (PS2_VeryStrong, PS4_Moderate; PMIDs: 36777711, 32978145, GeneDx, LabCorp, ClinVar SCV000572401.6, SCV003316958.3). In vitro functional studies showed that the p.Pro124Ser variant led to ERK1/2 phosphorylation indicating that the mutant was constitutively active (PS3_Supporting; PMID: 22197931). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2_VeryStrong, PS4_Moderate, PM1, PM5, PS3_Supporting PM2_Supporting, PP2, PP3 (Specification Version 2.3, 1/10/2025)
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50021 · approved 2025-01-10 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/5725ca85-ac7d-4884-bdcb-d5ee4a24cee6).*
*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 |
| --- | --- | --- | --- | --- |
| Mendelics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2019-05-28 |
| Service de Génétique Moléculaire, Hôpital Robert Debré | Pathogenic | no assertion criteria provided | clinical testing |  |
| ClinGen RASopathy Variant Curation Expert Panel | Pathogenic | reviewed by expert panel | curation | 2025-01-10 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-02-25 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2020-10-14 |
| Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital |  | criteria provided, single submitter | clinical testing | 2023-03-02 |
| Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital |  | criteria provided, single submitter | clinical testing | 2025-05-14 |
| Blueprint Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2020-02-05 |

## Associated conditions {#conditions}

[RASopathy](https://sugi.bio/atlas/disease/rasopathy/), [cardiofaciocutaneous syndrome 3](https://sugi.bio/atlas/disease/cardiofaciocutaneous-syndrome-3/), [Noonan syndrome](https://sugi.bio/atlas/disease/noonan-syndrome/).

**Reported phenotype names (ClinVar):** RASopathy, not provided, Noonan syndrome, Cardiofaciocutaneous syndrome 3, Spitz Melanocytoma, Metastatic melanoma, MAP2K1-related disorder, Noonan's syndrome, MAP2K1-related disorders, MAP2K1-related condition.

## Same-residue context {#hotspot}

Residue **124** carries **4 other pathogenic ClinVar variants** — a recurrently-mutated position: [MAP2K1 p.Pro124Ala](/variant/map2k1-p-pro124ala), [MAP2K1 p.Pro124Arg](/variant/map2k1-p-pro124arg), [MAP2K1 p.Pro124Gln](/variant/map2k1-p-pro124gln), [MAP2K1 p.Pro124Leu](/variant/map2k1-p-pro124leu). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Cancer therapy associations (CIViC) {#civic}

Curated clinical evidence for this variant from CIViC (profile *P124S*):

| Disease | Therapies | Type | Level | Significance |
| --- | --- | --- | --- | --- |
| Melanoma | Selumetinib | Predictive | D | Resistance |
| Cancer |  | Oncogenic | D | Oncogenicity |
| Melanoma | Vemurafenib,Dabrafenib | Predictive | C | Resistance |
*CIViC evidence levels A–E (A strongest). Therapy associations are context-specific — not a treatment recommendation.*

## Similar variants {#similar}

Related MAP2K1 variant pages (same residue, condition, or type): [MAP2K1 p.Pro124Leu](/variant/map2k1-p-pro124leu), [MAP2K1 p.Pro124=](/variant/map2k1-p-pro124), [MAP2K1 p.Pro124Ala](/variant/map2k1-p-pro124ala), [MAP2K1 p.Pro124Thr](/variant/map2k1-p-pro124thr), [MAP2K1 p.Pro124Gln](/variant/map2k1-p-pro124gln), [MAP2K1 p.Pro124Arg](/variant/map2k1-p-pro124arg), [MAP2K1 p.Arg108Leu](/variant/map2k1-p-arg108leu), [MAP2K1 p.Asn122Asp](/variant/map2k1-p-asn122asp).

### 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 375981). 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.*