# NM_001006617.3(MAPKAP1):c.860A>G (p.His287Arg)

https://sugi.bio/variant/mapkap1-p-his287arg

## Summary

**MAPKAP1 p.His287Arg (c.860A>G)** is classified **Uncertain significance** in MAPKAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-21). AlphaMissense: likely benign (0.2868); Absent from gnomAD v4.1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the MAPKAP1 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 | [MAPKAP1](https://sugi.bio/atlas/gene/MAPKAP1/) |
| Protein change (HGVS p.) | p.His287Arg |
| Coding change (HGVS c.) | c.860A>G |
| MANE Select transcript | [NM_001006617](https://www.ncbi.nlm.nih.gov/nuccore/NM_001006617) |
| Variant type | single nucleotide variant |
| Location | chr9:125543157-125543157 (GRCh38) |
| ClinVar | [VCV4103868](https://www.ncbi.nlm.nih.gov/clinvar/variation/4103868/) |

**All HGVS expressions:** `NC_000009.11:g.128305436T>C`, `NC_000009.12:g.125543157T>C`, `NM_001006617.3:c.860A>G`, `NM_001006618.2:c.860A>G`, `NM_001006619.2:c.860A>G`, `NM_001006620.2:c.284A>G`, `NM_001006621.2:c.284A>G`, `NM_024117.4:c.860A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.2868)
- REVEL 0.212 (benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.24 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- SpliceAI predicts **acceptor loss** (Δ 0.41) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.717, GERP 2.78, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.7**. 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 0.49** across the covering region of the MANE Select transcript (125,543,076–125,657,689), spanning 114,613 bp. Chi-square p 4.5e-13. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.41**, donor loss **0.00**, acceptor gain **0.05**, donor gain **0.00**. Largest is acceptor loss, 20 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, 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.*
- 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}

**MAPKAP1** population constraint: LOEUF 0.369, pLI 0.99999, missense-Z 3.5846. *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 **287** lies in the 'sin1-type rbd' region.

AlphaFold model confidence (whole protein): pLDDT 69.55, 9% of residues very-high.

**23 experimental structure(s)** (PDB): [3VOQ](https://www.rcsb.org/structure/3VOQ), [5ZCS](https://www.rcsb.org/structure/5ZCS), [6ZWM](https://www.rcsb.org/structure/6ZWM), [6ZWO](https://www.rcsb.org/structure/6ZWO), [7LC1](https://www.rcsb.org/structure/7LC1), [7LC2](https://www.rcsb.org/structure/7LC2).

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

*Describes the biological roles of MAPKAP1 (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:** MAPKAP1's established molecular role includes phosphatidylinositol-4,5-bisphosphate binding. p.His287Arg falls in the sin1-type rbd region. In Reactome, MAPKAP1 is annotated in disease pathway(s) including **Constitutive Signaling by AKT1 E17K in Cancer**, **Dengue virus modulates apoptosis**.

**Disease mechanism (Reactome):** MAPKAP1 loss or alteration is curated in [Constitutive Signaling by AKT1 E17K in Cancer](https://reactome.org/content/detail/R-HSA-5674400), [Dengue virus modulates apoptosis](https://reactome.org/content/detail/R-HSA-9920951).

### Pathways affected {#pathways}

MAPKAP1 participates in **7 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by AKT1 E17K in Cancer](https://reactome.org/content/detail/R-HSA-5674400) | curated |
| ⚕ [Dengue virus modulates apoptosis](https://reactome.org/content/detail/R-HSA-9920951) | curated |
| [CD28 dependent PI3K/Akt signaling](https://reactome.org/content/detail/R-HSA-389357) | curated |
| [High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells](https://reactome.org/content/detail/R-HSA-9856530) | curated |
| [PIP3 activates AKT signaling](https://reactome.org/content/detail/R-HSA-1257604) | curated |
| [Regulation of TP53 Degradation](https://reactome.org/content/detail/R-HSA-6804757) | curated |
| [VEGFR2 mediated vascular permeability](https://reactome.org/content/detail/R-HSA-5218920) | curated |

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

**Molecular function:** phosphatidylinositol-4,5-bisphosphate binding, phosphatidylinositol-3,4,5-trisphosphate binding, protein kinase binding, small GTPase binding, phosphatidylinositol-3,4-bisphosphate binding, molecular adaptor activity.

**Biological process:** substantia nigra development, TORC2 signaling, negative regulation of Ras protein signal transduction.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-21.

**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 | 2025-08-21 |

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

## Similar variants {#similar}

Related MAPKAP1 variant pages (same residue, condition, or type): [MAPKAP1 p.Ser488=](/variant/mapkap1-p-ser488), [MAPKAP1 p.Ala201Thr](/variant/mapkap1-p-ala201thr), [MAPKAP1 p.Ala229Asp](/variant/mapkap1-p-ala229asp), [MAPKAP1 p.Ala286Thr](/variant/mapkap1-p-ala286thr), [MAPKAP1 p.Arg15Gln](/variant/mapkap1-p-arg15gln), [MAPKAP1 p.Arg202Lys](/variant/mapkap1-p-arg202lys), [MAPKAP1 p.Arg503Ile](/variant/mapkap1-p-arg503ile), [MAPKAP1 p.Asn476Ser](/variant/mapkap1-p-asn476ser).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2026-07-14); 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 4103868). 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.*