# NM_030662.4(MAP2K2):c.170T>G (p.Phe57Cys)

https://sugi.bio/variant/map2k2-p-phe57cys

## Summary

**MAP2K2 p.Phe57Cys (c.170T>G)** is classified **Pathogenic** in MAP2K2 (ClinVar, Expert panel, 5 submitters; last evaluated 2024-12-03). AlphaMissense: likely pathogenic (0.9973); Absent from gnomAD v4.1; Associated with RASopathy.

**At a glance:** Pathogenic · review: Expert panel · rsID rs121434497 · 5 submitters · 3 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the MAP2K2 gene that is considered 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 | [MAP2K2](https://sugi.bio/atlas/gene/MAP2K2/) |
| Protein change (HGVS p.) | p.Phe57Cys |
| Coding change (HGVS c.) | c.170T>G |
| MANE Select transcript | [NM_030662](https://www.ncbi.nlm.nih.gov/nuccore/NM_030662) |
| dbSNP | [rs121434497](https://www.ncbi.nlm.nih.gov/snp/rs121434497/) |
| Variant type | single nucleotide variant |
| Location | chr19:4117552-4117552 (GRCh38) |
| ClinVar | [VCV8272](https://www.ncbi.nlm.nih.gov/clinvar/variation/8272/) |

**All HGVS expressions:** `LRG_750:g.11577T>G`, `LRG_750t1:c.170T>G`, `NC_000019.10:g.4117552A>C`, `NC_000019.9:g.4117550A>C`, `NG_007996.1:g.11577T>G`, `NM_030662.4:c.170T>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9973) — concordant with the pathogenic call
- REVEL 0.959 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -16.781 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 10.972, GERP 1.61, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 29.4**. 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 0.67** 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: **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 MAP2K2 (940 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}

**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 **57** lies in a UniProt-annotated variant site (in cfc4).

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}

**Pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2024-12-03.

**Submitter consensus:** conflicting (3 Pathogenic, 2 not provided).

**Submission history:** 5 submissions (2008–2024); 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):** `PM6`, `PM2_Supporting`, `PS3_Supporting`, `PS4_Moderate`, `PM1`, `PP3`, `PM5`.
*Considered but not met:* `BS1`, `BS3`, `BP4`, `BA1`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The c.170T>G variant in the MAP2K2 gene is a missense variant predicted to cause substitution of phenylalanine by cysteine at amino acid 57 (p.Phe57Cys). This variant is absent from gnomAD v2.1.1 (PM2_Supporting). The computational predictor REVEL gives a score of 0.959, predicting a damaging impact on protein function (PP3). This variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a critical functional domain of MAP2K2 (PM1, AA 47-65). Furthermore, other pathogenic missense variants has been previously identified at this codon of MAP2K2 (Phe57Val, Phe57Ile, Phe57Leu) and in nearby residues in association with CFC syndrome, which may indicate that this residue is critical to the function of the protein (PM5). This variant has been identified in at least 4 patients with RASopathy, of which 1 was an unconfirmed de novo occurrence (PS4_Moderate, PM6; GenomeConnect, ClinVar: SCV002047662.1; PMID: 16439621, 18039235, 21062266). ERK phosphorylation assays showed that this variant led to increased phosphorylation compared to wild-type (PS3_Supporting; PMID: 16439621, 17981815). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS4_Moderate, PM1, PM5, PM6, PS3_Supporting, PM2_Supporting, PP3 (Specification Version 2.3, 12/3/2024)
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50021 · approved 2024-12-03 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/07aecf91-9cf2-48c7-b101-b21e809f57a4).*
*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 |
| --- | --- | --- | --- | --- |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2008-02-01 |
| GeneReviews | not provided | no classification provided | literature only |  |
| ClinGen RASopathy Variant Curation Expert Panel | Pathogenic | reviewed by expert panel | curation | 2024-12-03 |
| GenomeConnect - CFC International | not provided | no classification provided | phenotyping only |  |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2024-07-24 |

## Associated conditions {#conditions}

[RASopathy](https://sugi.bio/atlas/disease/rasopathy/), [cardiofaciocutaneous syndrome 4](https://sugi.bio/atlas/disease/cardiofaciocutaneous-syndrome-4/), [cardiofaciocutaneous syndrome](https://sugi.bio/atlas/disease/cardiofaciocutaneous-syndrome/).

**Reported phenotype names (ClinVar):** RASopathy, Cardiofaciocutaneous syndrome 4, not provided, Cardio-facio-cutaneous syndrome, Cardiofaciocutaneous syndrome, CFC syndrome, MAP2K2-Related Cardiofaciocutaneous Syndrome, none provided, Noonan spectrum disorder, rasopathies.

## Same-residue context {#hotspot}

Residue **57** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [MAP2K2 p.Phe57Leu](/variant/map2k2-p-phe57leu), [MAP2K2 p.Phe57Val](/variant/map2k2-p-phe57val). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MAP2K2 variant pages (same residue, condition, or type): [MAP2K2 p.Phe57Val](/variant/map2k2-p-phe57val), [MAP2K2 p.Phe57Leu](/variant/map2k2-p-phe57leu), [MAP2K2 p.Phe57Ile](/variant/map2k2-p-phe57ile), [MAP2K2 p.Phe57Tyr](/variant/map2k2-p-phe57tyr), [MAP2K2 p.Phe57=](/variant/map2k2-p-phe57), [MAP2K2 p.Glu207Lys](/variant/map2k2-p-glu207lys), [MAP2K2 p.Pro128Gln](/variant/map2k2-p-pro128gln), [MAP2K2 p.Tyr134Cys](/variant/map2k2-p-tyr134cys).

### 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 8272). 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.*