# NM_002755.4(MAP2K1):c.510C>T (p.Ser170=)

https://sugi.bio/variant/map2k1-p-ser170

## Summary

**MAP2K1 p.Ser170= (c.510C>T)** is classified **Uncertain significance** in MAP2K1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-06-10). Very rare (popmax 0.00333%, amr); Associated with RASopathy.

**At a glance:** Uncertain significance · review: Multiple submitters · 2 submitters · 3 linked conditions · very rare (popmax 0.00333%, amr)

## For patients & families {#patients}

This is a change in the MAP2K1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 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.Ser170= |
| Coding change (HGVS c.) | c.510C>T |
| MANE Select transcript | [NM_002755](https://www.ncbi.nlm.nih.gov/nuccore/NM_002755) |
| Variant type | single nucleotide variant |
| Location | chr15:66443351-66443351 (GRCh38) |
| ClinVar | [VCV3577603](https://www.ncbi.nlm.nih.gov/clinvar/variation/3577603/) |

**All HGVS expressions:** `LRG_725:g.61479C>T`, `LRG_725t1:c.510C>T`, `NC_000015.10:g.66443351C>T`, `NC_000015.9:g.66735689C>T`, `NG_008305.1:g.61479C>T`, `NM_001411065.1:c.373-1305C>T`, `NM_002755.4:c.510C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.47) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.876, GERP 2, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 19.61**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.03**, acceptor gain **0.00**, donor gain **0.47**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.47**.
- Pangolin: Δ**0.46** (gain), gain 0.46 / loss 0.08. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00333%** (amr) · FAF95 0.000553% · FAF99 0.000207% · 2/59,976 in the highest group · 2/1,601,644 alleles overall — very rare (popmax 0.00333%, amr).

*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 **170** lies in the protein kinase domain; 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. p.Ser170= 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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-06-10.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-06-10 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** RASopathy, Cardiofaciocutaneous syndrome 3, Melorheostosis, rasopathies, Noonan spectrum disorder, MAP2K1-Related Cardiofaciocutaneous Syndrome, MELORHEOSTOSIS, ISOLATED.

## Similar variants {#similar}

Related MAP2K1 variant pages (same residue, condition, or type): [MAP2K1 p.Ser170Asn](/variant/map2k1-p-ser170asn), [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), [MAP2K1 p.Leu92Arg](/variant/map2k1-p-leu92arg).

### 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 3577603). 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.*