# NM_002746.3(MAPK3):c.417C>T (p.Ser139=)

https://sugi.bio/variant/mapk3-p-ser139

## Summary

**MAPK3 p.Ser139= (c.417C>T)** is classified **Likely benign** in MAPK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-03-29). Absent from gnomAD v4.1.

**At a glance:** Likely benign · review: Single submitter · rsID rs1596880352 · 1 submitter · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the MAPK3 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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 | [MAPK3](https://sugi.bio/atlas/gene/MAPK3/) |
| Protein change (HGVS p.) | p.Ser139= |
| Coding change (HGVS c.) | c.417C>T |
| MANE Select transcript | [NM_002746](https://www.ncbi.nlm.nih.gov/nuccore/NM_002746) |
| dbSNP | [rs1596880352](https://www.ncbi.nlm.nih.gov/snp/rs1596880352/) |
| Variant type | single nucleotide variant |
| Location | chr16:30118475-30118475 (GRCh38) |
| ClinVar | [VCV736303](https://www.ncbi.nlm.nih.gov/clinvar/variation/736303/) |

**All HGVS expressions:** `NC_000016.10:g.30118475G>A`, `NC_000016.9:g.30129796G>A`, `NG_029936.1:g.9835C>T`, `NM_001040056.3:c.417C>T`, `NM_001109891.2:c.417C>T`, `NM_002746.3:c.417C>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 **acceptor loss** (Δ 0.43) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 8.578, GERP 1.94, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 13.86**. 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 **0.43**, donor loss **0.00**, acceptor gain **0.02**, donor gain **0.00**. Largest is acceptor loss, 50 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.02**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.26** (gain), gain 0.26 / loss 0.00. SpliceAI calls loss. 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: **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}

**MAPK3** population constraint: LOEUF 0.935, pLI 8.5101e-07, missense-Z 2.018. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **139** lies in the protein kinase domain; an α-helix.

AlphaFold model confidence (whole protein): pLDDT 89.09, 76% of residues very-high.

**8 experimental structure(s)** (PDB): [2ZOQ](https://www.rcsb.org/structure/2ZOQ), [4QTB](https://www.rcsb.org/structure/4QTB), [6GES](https://www.rcsb.org/structure/6GES), [9TU0](https://www.rcsb.org/structure/9TU0), [9UUR](https://www.rcsb.org/structure/9UUR), [9UUX](https://www.rcsb.org/structure/9UUX).

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

*Describes the biological roles of MAPK3 (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:** MAPK3's established molecular role includes protein serine/threonine kinase activity. p.Ser139= falls in the protein kinase domain. In Reactome, MAPK3 is annotated in disease pathway(s) including **FCGR3A-mediated phagocytosis**, **Nuclear events stimulated by ALK signaling in cancer**.

**Disease mechanism (Reactome):** MAPK3 loss or alteration is curated in [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422), [Nuclear events stimulated by ALK signaling in cancer](https://reactome.org/content/detail/R-HSA-9725371), [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955).

### Pathways affected {#pathways}

MAPK3 participates in **60 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422) | curated |
| ⚕ [Nuclear events stimulated by ALK signaling in cancer](https://reactome.org/content/detail/R-HSA-9725371) | curated |
| ⚕ [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 LTK in cancer](https://reactome.org/content/detail/R-HSA-9842640) | 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 |
| ⚕ [Suppression of apoptosis](https://reactome.org/content/detail/R-HSA-9635465) | curated |
| [Activation of the AP-1 family of transcription factors](https://reactome.org/content/detail/R-HSA-450341) | curated |
| [Downregulation of SMAD2/3:SMAD4 transcriptional activity](https://reactome.org/content/detail/R-HSA-2173795) | curated |
| [ERKs are inactivated](https://reactome.org/content/detail/R-HSA-202670) | curated |
| [ESR-mediated signaling](https://reactome.org/content/detail/R-HSA-8939211) | curated |
| [FCERI mediated MAPK activation](https://reactome.org/content/detail/R-HSA-2871796) | curated |
| [Frs2-mediated activation](https://reactome.org/content/detail/R-HSA-170968) | curated |
| [Gastrin-CREB signalling pathway via PKC and MAPK](https://reactome.org/content/detail/R-HSA-881907) | curated |
| [Growth hormone receptor signaling](https://reactome.org/content/detail/R-HSA-982772) | curated |
| [IFNG signaling activates MAPKs](https://reactome.org/content/detail/R-HSA-9732724) | curated |
| [ISG15 antiviral mechanism](https://reactome.org/content/detail/R-HSA-1169408) | curated |
| [Interferon gamma signaling](https://reactome.org/content/detail/R-HSA-877300) | 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 |
| [NCAM signaling for neurite out-growth](https://reactome.org/content/detail/R-HSA-375165) | curated |
| [Negative Regulation of CDH1 Gene Transcription](https://reactome.org/content/detail/R-HSA-9764725) | curated |
| [Negative feedback regulation of MAPK pathway](https://reactome.org/content/detail/R-HSA-5674499) | curated |
| [Negative regulation of FGFR1 signaling](https://reactome.org/content/detail/R-HSA-5654726) | curated |
| [Negative regulation of FGFR2 signaling](https://reactome.org/content/detail/R-HSA-5654727) | curated |
| [Negative regulation of FGFR3 signaling](https://reactome.org/content/detail/R-HSA-5654732) | curated |
| [Negative regulation of FGFR4 signaling](https://reactome.org/content/detail/R-HSA-5654733) | curated |
| [Negative regulation of MAPK pathway](https://reactome.org/content/detail/R-HSA-5675221) | curated |
| [Oxidative Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559580) | curated |
| [PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling](https://reactome.org/content/detail/R-HSA-6811558) | curated |
| [RAF-independent MAPK1/3 activation](https://reactome.org/content/detail/R-HSA-112409) | curated |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [RHO GTPases Activate NADPH Oxidases](https://reactome.org/content/detail/R-HSA-5668599) | curated |
| [RHO GTPases Activate WASPs and WAVEs](https://reactome.org/content/detail/R-HSA-5663213) | curated |
| [RNA Polymerase I Promoter Opening](https://reactome.org/content/detail/R-HSA-73728) | curated |
| [Regulation of HSF1-mediated heat shock response](https://reactome.org/content/detail/R-HSA-3371453) | curated |
| [Regulation of PTEN gene transcription](https://reactome.org/content/detail/R-HSA-8943724) | curated |
| [Regulation of actin dynamics for phagocytic cup formation](https://reactome.org/content/detail/R-HSA-2029482) | curated |
| [Regulation of the apoptosome activity](https://reactome.org/content/detail/R-HSA-9627069) | curated |
| [SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription](https://reactome.org/content/detail/R-HSA-2173796) | curated |
| [Senescence-Associated Secretory Phenotype (SASP)](https://reactome.org/content/detail/R-HSA-2559582) | curated |
| [Signal attenuation](https://reactome.org/content/detail/R-HSA-74749) | curated |
| [Signal transduction by L1](https://reactome.org/content/detail/R-HSA-445144) | curated |
| [Signaling by Activin](https://reactome.org/content/detail/R-HSA-1502540) | curated |
| [Signaling by NODAL](https://reactome.org/content/detail/R-HSA-1181150) | curated |
| [Spry regulation of FGF signaling](https://reactome.org/content/detail/R-HSA-1295596) | curated |
| [Thrombin signalling through proteinase activated receptors (PARs)](https://reactome.org/content/detail/R-HSA-456926) | curated |
| [Transcriptional and post-translational regulation of MITF-M expression and activity](https://reactome.org/content/detail/R-HSA-9856649) | curated |
| [Advanced glycosylation endproduct receptor signaling](https://reactome.org/content/detail/R-HSA-879415) | electronic |
| [ERK/MAPK targets](https://reactome.org/content/detail/R-HSA-198753) | electronic |
| [Estrogen-dependent nuclear events downstream of ESR-membrane signaling](https://reactome.org/content/detail/R-HSA-9634638) | electronic |
| [Golgi Cisternae Pericentriolar Stack Reorganization](https://reactome.org/content/detail/R-HSA-162658) | other |
| [NPAS4 regulates expression of target genes](https://reactome.org/content/detail/R-HSA-9768919) | electronic |
| [Oncogene Induced Senescence](https://reactome.org/content/detail/R-HSA-2559585) | electronic |
| [RSK activation](https://reactome.org/content/detail/R-HSA-444257) | electronic |
| [RUNX2 regulates osteoblast differentiation](https://reactome.org/content/detail/R-HSA-8940973) | electronic |

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

**Molecular function:** protein serine/threonine kinase activity, MAP kinase activity, phosphatase binding, identical protein binding, DNA-binding transcription factor binding.

**Biological process:** MAPK cascade, negative regulation of T cell mediated immune response to tumor cell, protein phosphorylation, epidermal growth factor receptor signaling pathway, positive regulation of macrophage chemotaxis, phosphorylation.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-03-29.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2018-03-29 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related MAPK3 variant pages (same residue, condition, or type): [MAPK3 p.Gly11=](/variant/mapk3-p-gly11), [MAPK3 p.Pro336=](/variant/mapk3-p-pro336), [MAPK3 p.Tyr148Cys](/variant/mapk3-p-tyr148cys), [MAPK3 p.Ala378Asp](/variant/mapk3-p-ala378asp), [MAPK3 p.Arg15Ser](/variant/mapk3-p-arg15ser), [MAPK3 p.Arg242Gln](/variant/mapk3-p-arg242gln), [MAPK3 p.Arg309Gln](/variant/mapk3-p-arg309gln), [MAPK3 p.Arg309Gly](/variant/mapk3-p-arg309gly).

### 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 736303). 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.*