# NM_002745.5(MAPK1):c.968C>G (p.Pro323Arg)

https://sugi.bio/variant/mapk1-p-pro323arg

## Summary

**MAPK1 p.Pro323Arg (c.968C>G)** is classified **Pathogenic** in MAPK1 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-04-01). AlphaMissense: likely pathogenic (0.9504); Absent from gnomAD v4.1; Associated with Abnormal heart morphology.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2068678455 · 1 submitter · 3 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the MAPK1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Abnormal heart morphology.

*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.Pro323Arg |
| Coding change (HGVS c.) | c.968C>G |
| MANE Select transcript | [NM_002745](https://www.ncbi.nlm.nih.gov/nuccore/NM_002745) |
| dbSNP | [rs2068678455](https://www.ncbi.nlm.nih.gov/snp/rs2068678455/) |
| Variant type | single nucleotide variant |
| Location | chr22:21769319-21769319 (GRCh38) |
| ClinVar | [VCV917749](https://www.ncbi.nlm.nih.gov/clinvar/variation/917749/) |

**All HGVS expressions:** `LRG_786:g.103362C>G`, `LRG_786t1:c.968C>G`, `LRG_786t2:c.968C>G`, `NC_000022.10:g.22123608G>C`, `NC_000022.11:g.21769319G>C`, `NG_023054.2:g.103362C>G`, `NM_002745.5:c.968C>G`, `NM_138957.3:c.968C>G`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- AlphaMissense **likely pathogenic** (0.9504) — concordant with the pathogenic call
- REVEL 0.728 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.249 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.907, GERP 1.88, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 28.1**. 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 0.45** across the covering region of the MANE Select transcript (21,769,207–21,788,373), spanning 19,166 bp. Chi-square p 1.4e-10. 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: **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}

**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 **323** lies in a UniProt-annotated variant site (in ns13; results in increased mapk signaling; increased translocation to the nucleus; reduced interaction with dusp6; no effect on interaction with map2k1); 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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-04-01.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Tartaglia Lab, Genetics and Rare Diseases Research Division, Bambino Gesu' Children's Hospital | Pathogenic | criteria provided, single submitter | research | 2020-04-01 |

## Associated conditions {#conditions}

[Abnormal heart morphology](https://sugi.bio/atlas/disease/abnormal-heart-morphology/), [intellectual disability](https://sugi.bio/atlas/disease/intellectual-disability/), [specific learning disability](https://sugi.bio/atlas/disease/specific-learning-disability/).

**Reported phenotype names (ClinVar):** Abnormal heart morphology, Abnormal facial shape, Atypical behavior, Intellectual disability, Short stature, Specific learning disability, Heart, malformation of, Abnormality of cardiac morphology, Behavioral abnormality, Behavioral disorders.

## Same-residue context {#hotspot}

Residue **323** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MAPK1 p.Pro323His](/variant/mapk1-p-pro323his). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MAPK1 variant pages (same residue, condition, or type): [MAPK1 p.Pro323His](/variant/mapk1-p-pro323his), [MAPK1 p.Ala174Val](/variant/mapk1-p-ala174val), [MAPK1 p.Asp318Asn](/variant/mapk1-p-asp318asn), [MAPK1 p.Asp318Gly](/variant/mapk1-p-asp318gly), [MAPK1 p.Glu322Gln](/variant/mapk1-p-glu322gln), [MAPK1 p.His80Tyr](/variant/mapk1-p-his80tyr), [MAPK1 p.Ile74Asn](/variant/mapk1-p-ile74asn), [MAPK1 p.Arg135Thr](/variant/mapk1-p-arg135thr).

### 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 917749). 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.*