# NM_002745.5(MAPK1):c.957G>A (p.Pro319=)

https://sugi.bio/variant/mapk1-p-pro319

## Summary

**MAPK1 p.Pro319= (c.957G>A)** is classified **Likely benign** in MAPK1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2021-08-23). Very rare (popmax 0.005%, amr); Associated with MAPK1-related disorder.

**At a glance:** Likely benign · review: No assertion criteria · rsID rs778814312 · 1 submitter · 1 linked condition · very rare (popmax 0.005%, amr)

## For patients & families {#patients}

This is a change in the MAPK1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to MAPK1-related disorder.

*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 | [MAPK1](https://sugi.bio/atlas/gene/MAPK1/) |
| Protein change (HGVS p.) | p.Pro319= |
| Coding change (HGVS c.) | c.957G>A |
| MANE Select transcript | [NM_002745](https://www.ncbi.nlm.nih.gov/nuccore/NM_002745) |
| dbSNP | [rs778814312](https://www.ncbi.nlm.nih.gov/snp/rs778814312/) |
| Variant type | single nucleotide variant |
| Location | chr22:21772882-21772882 (GRCh38) |
| ClinVar | [VCV3029212](https://www.ncbi.nlm.nih.gov/clinvar/variation/3029212/) |

**All HGVS expressions:** `LRG_786:g.99799G>A`, `LRG_786t1:c.957G>A`, `LRG_786t2:c.957G>A`, `NC_000022.10:g.22127171C>T`, `NC_000022.11:g.21772882C>T`, `NG_023054.2:g.99799G>A`, `NM_002745.5:c.957G>A`, `NM_138957.3:c.957G>A`

## 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 -4.707, GERP -3.76 — fast-evolving / accelerated position
- CADD: **PHRED 6.673**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for MAPK1 (869 scored positions, the nearest 9 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.005%** (amr) · FAF95 0.00133% · FAF99 0.000668% · 3/59,998 in the highest group · 12/1,612,982 alleles overall — very rare (popmax 0.005%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.005% | 19,999 |
| South Asian | 0.0011% | 91,036 |
| European (non-Finnish) | 0.000678% | 147,387 |

*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}

**MAPK1** population constraint: LOEUF 0.377, pLI 0.99854, missense-Z 3.6281. *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 **319** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 90.99, 79% of residues very-high.

**157 experimental structure(s)** (PDB): [1PME](https://www.rcsb.org/structure/1PME), [1TVO](https://www.rcsb.org/structure/1TVO), [1WZY](https://www.rcsb.org/structure/1WZY), [2OJG](https://www.rcsb.org/structure/2OJG), [2OJI](https://www.rcsb.org/structure/2OJI), [2OJJ](https://www.rcsb.org/structure/2OJJ) — incl. mutant structure 1PME.

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

*Describes the biological roles of MAPK1 (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:** MAPK1's established molecular role includes protein serine/threonine kinase activity. In Reactome, MAPK1 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):** MAPK1 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}

MAPK1 participates in **63 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 MAPK mutants](https://reactome.org/content/detail/R-HSA-9652817) | 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 |
| ⚕ [FCGR3A-mediated phagocytosis](https://reactome.org/content/detail/R-HSA-9664422) | other |
| ⚕ [Nuclear events stimulated by ALK signaling in cancer](https://reactome.org/content/detail/R-HSA-9725371) | other |
| ⚕ [Signaling by LTK in cancer](https://reactome.org/content/detail/R-HSA-9842640) | other |
| ⚕ [Signaling by RAF1 mutants](https://reactome.org/content/detail/R-HSA-9656223) | other |
| [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 |
| [ESR-mediated signaling](https://reactome.org/content/detail/R-HSA-8939211) | curated |
| [Estrogen-stimulated signaling through PRKCZ](https://reactome.org/content/detail/R-HSA-9634635) | curated |
| [FCERI mediated MAPK activation](https://reactome.org/content/detail/R-HSA-2871796) | curated |
| [Gastrin-CREB signalling pathway via PKC and MAPK](https://reactome.org/content/detail/R-HSA-881907) | 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 |
| [NCAM signaling for neurite out-growth](https://reactome.org/content/detail/R-HSA-375165) | 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 |
| [Neutrophil degranulation](https://reactome.org/content/detail/R-HSA-6798695) | 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/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 |
| [Recycling pathway of L1](https://reactome.org/content/detail/R-HSA-437239) | 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 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 |
| [Thrombin signalling through proteinase activated receptors (PARs)](https://reactome.org/content/detail/R-HSA-456926) | 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) | other |
| [ERKs are inactivated](https://reactome.org/content/detail/R-HSA-202670) | other |
| [Estrogen-dependent nuclear events downstream of ESR-membrane signaling](https://reactome.org/content/detail/R-HSA-9634638) | electronic |
| [Frs2-mediated activation](https://reactome.org/content/detail/R-HSA-170968) | other |
| [Golgi Cisternae Pericentriolar Stack Reorganization](https://reactome.org/content/detail/R-HSA-162658) | other |
| [Growth hormone receptor signaling](https://reactome.org/content/detail/R-HSA-982772) | other |
| [IFNG signaling activates MAPKs](https://reactome.org/content/detail/R-HSA-9732724) | other |
| [MAPK1 (ERK2) activation](https://reactome.org/content/detail/R-HSA-112411) | other |
| [NPAS4 regulates expression of target genes](https://reactome.org/content/detail/R-HSA-9768919) | other |
| [Negative Regulation of CDH1 Gene Transcription](https://reactome.org/content/detail/R-HSA-9764725) | other |
| [Oncogene Induced Senescence](https://reactome.org/content/detail/R-HSA-2559585) | electronic |
| [RAF-independent MAPK1/3 activation](https://reactome.org/content/detail/R-HSA-112409) | other |
| [RSK activation](https://reactome.org/content/detail/R-HSA-444257) | electronic |
| [RUNX2 regulates osteoblast differentiation](https://reactome.org/content/detail/R-HSA-8940973) | electronic |
| [Regulation of actin dynamics for phagocytic cup formation](https://reactome.org/content/detail/R-HSA-2029482) | other |
| [Signaling by Activin](https://reactome.org/content/detail/R-HSA-1502540) | other |
| [Signaling by NODAL](https://reactome.org/content/detail/R-HSA-1181150) | other |
| [Spry regulation of FGF signaling](https://reactome.org/content/detail/R-HSA-1295596) | other |
| [Transcriptional and post-translational regulation of MITF-M expression and activity](https://reactome.org/content/detail/R-HSA-9856649) | other |
| [phospho-PLA2 pathway](https://reactome.org/content/detail/R-HSA-111995) | other |

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

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

**Biological process:** MAPK cascade, protein phosphorylation, epidermal growth factor receptor signaling pathway, positive regulation of macrophage chemotaxis, positive regulation of peptidyl-threonine phosphorylation, positive regulation of telomere maintenance.

## Clinical significance {#significance}

**Likely benign** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2021-08-23.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2021-08-23 |

## Associated conditions {#conditions}

[MAPK1-related disorder](https://sugi.bio/atlas/disease/mapk1-related-disorder/).

**Reported phenotype names (ClinVar):** MAPK1-related disorder, MAPK1-related condition.

## Similar variants {#similar}

Related MAPK1 variant pages (same residue, condition, or type): [MAPK1 p.Pro319Leu](/variant/mapk1-p-pro319leu), [MAPK1 c.725-4A>G](/variant/mapk1-c-725-minus-4a-g), [MAPK1 c.492+10G>A](/variant/mapk1-c-492-plus-10g-a), [MAPK1 c.610-9C>T](/variant/mapk1-c-610-minus-9c-t), [MAPK1 p.Thr94Ala](/variant/mapk1-p-thr94ala), [MAPK1 p.Ala7_Gly8insAlaAla](/variant/mapk1-p-ala7-gly8insalaala), [MAPK1 c.120-20CT[5]](/variant/mapk1-c-120-minus-20ct-5), [MAPK1 p.Ala7del](/variant/mapk1-p-ala7del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 3029212). 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.*