# NM_139012.3(MAPK14):c.29G>C (p.Arg10Pro)

https://sugi.bio/variant/mapk14-p-arg10pro

## Summary

**MAPK14 p.Arg10Pro (c.29G>C)** is classified **Uncertain significance** in MAPK14 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-15). AlphaMissense: likely pathogenic (0.9068); Very rare (popmax 0.000424%, nfe).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely pathogenic · very rare (popmax 0.000424%, nfe)

## For patients & families {#patients}

This is a change in the MAPK14 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 | [MAPK14](https://sugi.bio/atlas/gene/MAPK14/) |
| Protein change (HGVS p.) | p.Arg10Pro |
| Coding change (HGVS c.) | c.29G>C |
| MANE Select transcript | [NM_139012](https://www.ncbi.nlm.nih.gov/nuccore/NM_139012) |
| Variant type | single nucleotide variant |
| Location | chr6:36028186-36028186 (GRCh38) |
| ClinVar | [VCV4103755](https://www.ncbi.nlm.nih.gov/clinvar/variation/4103755/) |

**All HGVS expressions:** `NC_000006.11:g.35995963G>C`, `NC_000006.12:g.36028186G>C`, `NG_033897.1:g.1451C>G`, `NG_175710.1:g.238G>C`, `NM_001315.3:c.29G>C`, `NM_139012.3:c.29G>C`, `NM_139013.3:c.29G>C`, `NM_139014.3:c.29G>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.9068)
- REVEL 0.258 (benign-leaning) — differs from AlphaMissense
- SaProt LLR -14.813 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt call this damaging; REVEL does not
- SpliceAI predicts **acceptor gain** (Δ 0.37) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 4.997, GERP 4.79, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 34.0**. 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 0.88** across the covering region of the MANE Select transcript (36,028,158–36,028,243), spanning 85 bp. Chi-square p 0.47. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.37**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.37**, donor gain **0.00**.
- Pangolin: Δ**0.46** (gain), gain 0.46 / loss 0.00. 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 **0.000424%** (nfe) · FAF95 0.000124% · FAF99 9e-05% · 5/1,179,698 in the highest group · 5/1,613,630 alleles overall — very rare (popmax 0.000424%, 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}

**MAPK14** population constraint: LOEUF 0.564, pLI 0.90557, missense-Z 2.9352. *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 **10** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 89.91, 75% of residues very-high.

**267 experimental structure(s)** (PDB): [1A9U](https://www.rcsb.org/structure/1A9U), [1BL6](https://www.rcsb.org/structure/1BL6), [1BL7](https://www.rcsb.org/structure/1BL7), [1BMK](https://www.rcsb.org/structure/1BMK), [1DI9](https://www.rcsb.org/structure/1DI9), [1IAN](https://www.rcsb.org/structure/1IAN) — incl. mutant structure 1R3C.

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

*Describes the biological roles of MAPK14 (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:** MAPK14's established molecular role includes protein serine/threonine kinase activity. In Reactome, MAPK14 is annotated in disease pathway(s) including **CD163 mediating an anti-inflammatory response**.

**Disease mechanism (Reactome):** MAPK14 loss or alteration is curated in [CD163 mediating an anti-inflammatory response](https://reactome.org/content/detail/R-HSA-9662834).

### Pathways affected {#pathways}

MAPK14 participates in **18 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [CD163 mediating an anti-inflammatory response](https://reactome.org/content/detail/R-HSA-9662834) | other |
| [ADP signalling through P2Y purinoceptor 1](https://reactome.org/content/detail/R-HSA-418592) | other |
| [Activation of PPARGC1A (PGC-1alpha) by phosphorylation](https://reactome.org/content/detail/R-HSA-2151209) | other |
| [Activation of the AP-1 family of transcription factors](https://reactome.org/content/detail/R-HSA-450341) | other |
| [ERK/MAPK targets](https://reactome.org/content/detail/R-HSA-198753) | other |
| [KSRP (KHSRP) binds and destabilizes mRNA](https://reactome.org/content/detail/R-HSA-450604) | other |
| [Myogenesis](https://reactome.org/content/detail/R-HSA-525793) | other |
| [NOD1/2 Signaling Pathway](https://reactome.org/content/detail/R-HSA-168638) | other |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | other |
| [Oxidative Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559580) | other |
| [Platelet sensitization by LDL](https://reactome.org/content/detail/R-HSA-432142) | other |
| [RHO GTPases Activate NADPH Oxidases](https://reactome.org/content/detail/R-HSA-5668599) | other |
| [Regulation of MITF-M-dependent genes involved in pigmentation](https://reactome.org/content/detail/R-HSA-9824585) | other |
| [Regulation of TP53 Activity through Phosphorylation](https://reactome.org/content/detail/R-HSA-6804756) | other |
| [Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A](https://reactome.org/content/detail/R-HSA-69601) | other |
| [VEGFA-VEGFR2 Pathway](https://reactome.org/content/detail/R-HSA-4420097) | other |
| [activated TAK1 mediates p38 MAPK activation](https://reactome.org/content/detail/R-HSA-450302) | other |
| [p38MAPK events](https://reactome.org/content/detail/R-HSA-171007) | other |

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

**Molecular function:** protein serine/threonine kinase activity, MAP kinase activity, enzyme binding, protein phosphatase binding, mitogen-activated protein kinase p38 binding.

**Biological process:** positive regulation of gene expression, stress-activated protein kinase signaling cascade, positive regulation of cyclase activity, positive regulation of interleukin-12 production, negative regulation of hippo signaling, intracellular signal transduction.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-07-15.

**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 | 2025-07-15 |

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

## Similar variants {#similar}

Related MAPK14 variant pages (same residue, condition, or type): [MAPK14 p.Arg10Trp](/variant/mapk14-p-arg10trp), [MAPK14 c.763-2308A>G](/variant/mapk14-c-763-minus-2308a-g), [MAPK14 c.763-2312A>G](/variant/mapk14-c-763-minus-2312a-g), [MAPK14 c.763-2316G>A](/variant/mapk14-c-763-minus-2316g-a), [MAPK14 c.763-2341C>G](/variant/mapk14-c-763-minus-2341c-g), [MAPK14 c.763-2356G>A](/variant/mapk14-c-763-minus-2356g-a), [MAPK14 p.Ala304Val](/variant/mapk14-p-ala304val), [MAPK14 p.Ala41Thr](/variant/mapk14-p-ala41thr).

### 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 4103755). 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.*