# NM_002746.3(MAPK3):c.92T>C (p.Val31Ala)

https://sugi.bio/variant/mapk3-p-val31ala

## Summary

**MAPK3 p.Val31Ala (c.92T>C)** is classified **Uncertain significance** in MAPK3 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-06). AlphaMissense: likely pathogenic (0.8488); Very rare (popmax 8.68e-05%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 8.68e-05%, nfe)

## For patients & families {#patients}

This is a change in the MAPK3 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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.Val31Ala |
| Coding change (HGVS c.) | c.92T>C |
| MANE Select transcript | [NM_002746](https://www.ncbi.nlm.nih.gov/nuccore/NM_002746) |
| Variant type | single nucleotide variant |
| Location | chr16:30123118-30123118 (GRCh38) |
| ClinVar | [VCV3293221](https://www.ncbi.nlm.nih.gov/clinvar/variation/3293221/) |

**All HGVS expressions:** `NC_000016.10:g.30123118A>G`, `NC_000016.9:g.30134439A>G`, `NG_029936.1:g.5192T>C`, `NG_193234.1:g.7A>G`, `NM_001040056.3:c.92T>C`, `NM_001109891.2:c.92T>C`, `NM_002746.3:c.92T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.8488)
- REVEL 0.318 (indeterminate)
- SaProt LLR -11.198 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- Conservation: phyloP 7.404, GERP 1.72, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 23.5**. 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 1.09** across the covering region of the MANE Select transcript (30,121,912–30,123,209), spanning 1,297 bp. Chi-square p 0.3. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **8.68e-05%** (nfe) · 1/1,152,502 in the highest group · 1/1,552,808 alleles overall — very rare (popmax 8.68e-05%, nfe).

*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 **31** lies in a β-strand.

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. 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-04-06.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-06 |

**Reported phenotype names (ClinVar):** not specified, AllHighlyPenetrant.

## Similar variants {#similar}

Related MAPK3 variant pages (same residue, condition, or type): [MAPK3 p.Val31Gly](/variant/mapk3-p-val31gly), [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).

### 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 3293221). 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.*