# NM_002755.4(MAP2K1):c.158T>C (p.Phe53Ser)

https://sugi.bio/variant/map2k1-p-phe53ser

## Summary

**MAP2K1 p.Phe53Ser (c.158T>C)** is classified **Likely pathogenic** in MAP2K1 (ClinVar, Expert panel, 5 submitters; last evaluated 2024-09-17). AlphaMissense: likely pathogenic (0.9995); Absent from gnomAD v4.1; Associated with RASopathy.

**At a glance:** Likely pathogenic · review: Expert panel · rsID rs121908594 · 5 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 likely disease-causing, submitted by 5 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.Phe53Ser |
| Coding change (HGVS c.) | c.158T>C |
| MANE Select transcript | [NM_002755](https://www.ncbi.nlm.nih.gov/nuccore/NM_002755) |
| dbSNP | [rs121908594](https://www.ncbi.nlm.nih.gov/snp/rs121908594/) |
| Variant type | single nucleotide variant |
| Location | chr15:66435104-66435104 (GRCh38) |
| ClinVar | [VCV13350](https://www.ncbi.nlm.nih.gov/clinvar/variation/13350/) |

**All HGVS expressions:** `LRG_725:g.53232T>C`, `LRG_725t1:c.158T>C`, `NC_000015.10:g.66435104T>C`, `NC_000015.9:g.66727442T>C`, `NG_008305.1:g.53232T>C`, `NM_002755.4:c.158T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9995) — concordant with the pathogenic call
- REVEL 0.938 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -16.227 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.862, GERP 1.9, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 9%** most-pathogenic-predicted substitutions in MAP2K1 (of 2,322 modeled).
- CADD: **PHRED 33.0**. 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 0.46** 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 22 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 **53** lies in a UniProt-annotated variant site (in cfc3); an α-helix.

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. 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}

**Likely pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2024-09-17.

**Submitter consensus:** conflicting (4 Pathogenic, 1 Likely Pathogenic).

**Submission history:** 5 submissions (2008–2024); classifications have differed over time.

**ClinGen expert panel:** Likely Pathogenic — RASopathy VCEP (RASopathy). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM6_Supporting`, `PM2_Supporting`, `PS3_Moderate`, `PS4_Moderate`, `PM1`, `PP2`, `PP3`.
*Considered but not met:* `BS1`, `BP4`, `BA1`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The c.158T>C variant in the MAP2K1 gene is a missense variant predicted to cause substitution of phenylalanine by serine at amino acid 53 (p.Phe53Ser). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). The computational predictor REVEL gives a score of 0.938 (PP3). The 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). Furthermore, the variant is in a location, analogous to MEK2 F57 residue, that has been defined by the ClinGen RASopathy Expert Panel functional domain of MAP2K1 (PM1). This variant has been reported in the literature in 4 individuals with clinical features of RASopathy with 1 unconfirmed de novo occurrence (PS4_Moderate, PM6_Supporting; PMIDs: 16439621, 18039235, 21062266, 30141192). ERK/MAPK phosphorylation assays showed that this variant led to significantly increased phosphorylation compared to wildtype (PS3_Moderate; PMID: 16439621, 17981815). In summary, this variant meets criteria to be classified as likely pathogenic for autosomal dominant RASopathies based on ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS3_Moderate, PS4_Moderate, PM1, PM2_Supporting, PM6_Supporting, PP2, PP3 (Specification Version 2.1, 9/17/2024)
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50021 · approved 2024-09-17 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/b78d797f-9630-4e8f-a1e3-8bf3ece401f5).*
*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 |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-01-02 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2008-02-01 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2016-06-02 |
| ClinGen RASopathy Variant Curation Expert Panel | Likely Pathogenic | reviewed by expert panel | curation | 2024-09-17 |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-03-01 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** RASopathy, Cardiofaciocutaneous syndrome 3, not provided, Cardio-facio-cutaneous syndrome, MAP2K1-related disorder, MAP2K1-related disorders, MAP2K1-related condition, MAP2K1-Related Cardiofaciocutaneous Syndrome, none provided, rasopathies.

## Same-residue context {#hotspot}

Residue **53** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MAP2K1 p.Phe53Tyr](/variant/map2k1-p-phe53tyr). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MAP2K1 variant pages (same residue, condition, or type): [MAP2K1 p.Phe53Tyr](/variant/map2k1-p-phe53tyr), [MAP2K1 p.Phe53Leu](/variant/map2k1-p-phe53leu), [MAP2K1 p.Arg108Leu](/variant/map2k1-p-arg108leu), [MAP2K1 p.Asn122Asp](/variant/map2k1-p-asn122asp), [MAP2K1 p.Asp67Asn](/variant/map2k1-p-asp67asn), [MAP2K1 p.Glu203Gly](/variant/map2k1-p-glu203gly), [MAP2K1 p.Leu42Arg](/variant/map2k1-p-leu42arg), [MAP2K1 p.Leu42Phe](/variant/map2k1-p-leu42phe).

### 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 13350). 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.*