# NM_002755.4(MAP2K1):c.198C>T (p.Asp66=)

https://sugi.bio/variant/map2k1-p-asp66

## Summary

**MAP2K1 p.Asp66= (c.198C>T)** is classified **Conflicting classifications of pathogenicity** in MAP2K1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-06-19). Ultra-rare (popmax 0.0156%, eas); Associated with Cardiovascular phenotype.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs56200325 · 4 submitters · 3 linked conditions · ultra-rare (popmax 0.0156%, eas)

## For patients & families {#patients}

This is a change in the MAP2K1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, and is linked to Cardiovascular phenotype.

*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.*

**Support & next steps:** [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.Asp66= |
| Coding change (HGVS c.) | c.198C>T |
| MANE Select transcript | [NM_002755](https://www.ncbi.nlm.nih.gov/nuccore/NM_002755) |
| dbSNP | [rs56200325](https://www.ncbi.nlm.nih.gov/snp/rs56200325/) |
| Variant type | single nucleotide variant |
| Location | chr15:66435144-66435144 (GRCh38) |
| ClinVar | [VCV1334250](https://www.ncbi.nlm.nih.gov/clinvar/variation/1334250/) |

**All HGVS expressions:** `LRG_725:g.53272C>T`, `LRG_725t1:c.198C>T`, `NC_000015.10:g.66435144C>T`, `NC_000015.9:g.66727482C>T`, `NG_008305.1:g.53272C>T`, `NM_002755.4:c.198C>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 -11.285, GERP -3.8 — fast-evolving / accelerated position
- CADD: **PHRED 1.785**. 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 **0.0156%** (eas) · FAF95 0.00726% · FAF99 0.00514% · 7/44,890 in the highest group · 28/1,613,950 alleles overall — ultra-rare (popmax 0.0156%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0156% | 6,413 |
| South Asian | 0.00769% | 13,012 |
| Admixed American | 0.005% | 19,996 |
| African / African-American | 0.00134% | 74,886 |
| European (non-Finnish) | 0.000847% | 118,000 |

*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, triplosensitivity 0 (0–3 scale). *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 **66** lies in 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-06-19.

**Submitter consensus:** conflicting (3 Likely benign, 1 Uncertain significance).

**Submission history:** 4 submissions (2017–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Genome Diagnostics Laboratory, The Hospital for Sick Children | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-11-01 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2020-07-05 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-06-19 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-08-15 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related MAP2K1 variant pages (same residue, condition, or type): [MAP2K1 p.Asp66Glu](/variant/map2k1-p-asp66glu), [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 2026-10-06); 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 2026-07-14); 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 1334250). 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.*