# NM_145160.3(MAP2K5):c.849C>T (p.Asp283=)

https://sugi.bio/variant/map2k5-p-asp283

## Summary

**MAP2K5 p.Asp283= (c.849C>T)** is classified **Benign** in MAP2K5 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-07-31). Low-frequency (popmax 1.3%, nfe).

**At a glance:** Benign · review: Single submitter · rsID rs55966838 · 1 submitter · low-frequency (popmax 1.3%, nfe)

## For patients & families {#patients}

This is a change in the MAP2K5 gene that is classified as benign — not considered disease-causing, 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 | [MAP2K5](https://sugi.bio/atlas/gene/MAP2K5/) |
| Protein change (HGVS p.) | p.Asp283= |
| Coding change (HGVS c.) | c.849C>T |
| MANE Select transcript | [NM_145160](https://www.ncbi.nlm.nih.gov/nuccore/NM_145160) |
| dbSNP | [rs55966838](https://www.ncbi.nlm.nih.gov/snp/rs55966838/) |
| Variant type | single nucleotide variant |
| Location | chr15:67692480-67692480 (GRCh38) |
| ClinVar | [VCV708695](https://www.ncbi.nlm.nih.gov/clinvar/variation/708695/) |

**All HGVS expressions:** `NC_000015.10:g.67692480C>T`, `NC_000015.9:g.67984818C>T`, `NG_029143.1:g.154798C>T`, `NM_001206804.2:c.741C>T`, `NM_002757.4:c.849C>T`, `NM_145160.3:c.849C>T`

## 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 0.31, GERP -3.76, phastCons 0.997 — weakly conserved position
- CADD: **PHRED 5.927**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.20 acceptor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **1.3%** (nfe) · FAF95 1.28% · FAF99 1.28% · 15,326/1,178,702 in the highest group · 17,083/1,612,470 alleles overall — low-frequency (popmax 1.3%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 1.3% | 77 |
| Amish (not grpmax-eligible) | 1.21% | 83 |
| Remaining individuals (not grpmax-eligible) | 0.735% | 136 |
| Finnish (not grpmax-eligible) | 0.719% | 139 |
| Admixed American | 0.507% | 197 |
| South Asian | 0.379% | 264 |
| African / African-American | 0.175% | 572 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.135% | 739 |
| Middle Eastern | 0.0661% | 1,513 |
| East Asian | 0.00669% | 14,947 |

*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}

**MAP2K5** population constraint: LOEUF 1.201, pLI 7.4834e-07, missense-Z 0.77293. *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 **283** lies in the protein kinase domain; an active site.

AlphaFold model confidence (whole protein): pLDDT 79.20, 41% of residues very-high.

**3 experimental structure(s)** (PDB): [2NPT](https://www.rcsb.org/structure/2NPT), [2O2V](https://www.rcsb.org/structure/2O2V), [4IC7](https://www.rcsb.org/structure/4IC7).

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

*Describes the biological roles of MAP2K5 (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.*


### Pathways affected {#pathways}

MAP2K5 participates in **1 Reactome pathway** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Signalling to ERK5](https://reactome.org/content/detail/R-HSA-198765) | electronic |

## Clinical significance {#significance}

**Benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-07-31.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2018-07-31 |

**Reported phenotype names (ClinVar):** not provided, none provided.

## Similar variants {#similar}

Related MAP2K5 variant pages (same residue, condition, or type): [MAP2K5 c.586-8A>G](/variant/map2k5-c-586-minus-8a-g), [MAP2K5 c.1074+1G>A](/variant/map2k5-c-1074-plus-1g-a), [MAP2K5 p.Ala150Ser](/variant/map2k5-p-ala150ser), [MAP2K5 p.Ala157Thr](/variant/map2k5-p-ala157thr), [MAP2K5 p.Ala266Val](/variant/map2k5-p-ala266val), [MAP2K5 p.Ala437Ser](/variant/map2k5-p-ala437ser), [MAP2K5 p.Arg125Gln](/variant/map2k5-p-arg125gln), [MAP2K5 p.Arg125Trp](/variant/map2k5-p-arg125trp).

### 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 708695). 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.*