# NM_145109.3(MAP2K3):c.118C>A (p.Pro40Thr)

https://sugi.bio/variant/map2k3-p-pro40thr

## Summary

**MAP2K3 p.Pro40Thr (c.118C>A)** is classified **Benign** in MAP2K3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-06-04). AlphaMissense: ambiguous (0.3718); Common (popmax 50%, mid) — too common for a highly-penetrant pathogenic allele.

**At a glance:** Benign · review: Multiple submitters · rsID rs33911218 · 2 submitters · AlphaMissense ambiguous · common (popmax 50%, mid) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the MAP2K3 gene that is classified as benign — not considered disease-causing, submitted by 2 submitters.

*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 | [MAP2K3](https://sugi.bio/atlas/gene/MAP2K3/) |
| Protein change (HGVS p.) | p.Pro40Thr |
| Coding change (HGVS c.) | c.118C>A |
| MANE Select transcript | [NM_145109](https://www.ncbi.nlm.nih.gov/nuccore/NM_145109) |
| dbSNP | [rs33911218](https://www.ncbi.nlm.nih.gov/snp/rs33911218/) |
| Variant type | single nucleotide variant |
| Location | chr17:21298879-21298879 (GRCh38) |
| ClinVar | [VCV768842](https://www.ncbi.nlm.nih.gov/clinvar/variation/768842/) |

**All HGVS expressions:** `NC_000017.10:g.21202191C>A`, `NC_000017.11:g.21298879C>A`, `NG_028256.2:g.19224C>A`, `NM_001316332.2:c.31C>A`, `NM_002756.4:c.31C>A`, `NM_145109.3:c.118C>A`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 50%, mid) — too common for a highly-penetrant pathogenic allele.

- AlphaMissense **ambiguous** (0.3718) — no call either way
- REVEL 0.357 (indeterminate)
- SaProt LLR -6.535 (tolerated)
- Conservation: phyloP 3.987, GERP 0.19, phastCons 0.999 — highly conserved
- CADD: **PHRED 24.8**. 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 1.07** across the covering region of the MANE Select transcript (21,284,921–21,304,464), spanning 19,543 bp. Chi-square p 0.26. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 MAP2K3 (892 scored positions, the nearest 2 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 **50%** (mid) · FAF95 49.9% · FAF99 49.8% · 3,030/6,060 in the highest group · 805,424/1,611,164 alleles overall — common (popmax 50%, mid) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian | 50% | 2 |
| Finnish (not grpmax-eligible) | 50% | 2 |
| Amish (not grpmax-eligible) | 50% | 2 |
| Middle Eastern (grpmax) | 50% | 2 |
| Remaining individuals (not grpmax-eligible) | 50% | 2 |
| Admixed American | 50% | 2 |
| African / African-American | 50% | 2 |
| South Asian | 50% | 2 |
| Ashkenazi Jewish (not grpmax-eligible) | 50% | 2 |
| European (non-Finnish) | 50% | 2 |

*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}

**MAP2K3** population constraint: LOEUF 0.993, pLI 3.7073e-08, missense-Z 0.93376. *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 **40** lies in a UniProt-annotated variant site (in); the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 81.13, 51% of residues very-high.

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

*Describes the biological roles of MAP2K3 (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:** MAP2K3's established molecular role includes MAP kinase kinase activity. p.Pro40Thr falls in the disordered region. In Reactome, MAP2K3 is annotated in disease pathway(s) including **Uptake and function of anthrax toxins**.

**Disease mechanism (Reactome):** MAP2K3 loss or alteration is curated in [Uptake and function of anthrax toxins](https://reactome.org/content/detail/R-HSA-5210891).

### Pathways affected {#pathways}

MAP2K3 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Uptake and function of anthrax toxins](https://reactome.org/content/detail/R-HSA-5210891) | other |
| [Oxidative Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559580) | curated |
| [activated TAK1 mediates p38 MAPK activation](https://reactome.org/content/detail/R-HSA-450302) | curated |

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

**Molecular function:** MAP kinase kinase activity, protein kinase binding.

**Biological process:** stress-activated protein kinase signaling cascade, negative regulation of hippo signaling, cellular response to vascular endothelial growth factor stimulus, p38MAPK cascade, positive regulation of blood vessel endothelial cell migration, positive regulation of protein kinase activity.

## Clinical significance {#significance}

**Benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2018-06-04.

**Submitter consensus:** unanimous (2/2 Benign).

**Submission history:** 2 submissions (2018); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2018-06-04 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |

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

## Similar variants {#similar}

Related MAP2K3 variant pages (same residue, condition, or type): [MAP2K3 p.Leu215Trp](/variant/map2k3-p-leu215trp), [MAP2K3 c.568+10C>T](/variant/map2k3-c-568-plus-10c-t), [MAP2K3 p.Ala220=](/variant/map2k3-p-ala220), [MAP2K3 p.Ala225=](/variant/map2k3-p-ala225), [MAP2K3 p.Leu25=](/variant/map2k3-p-leu25), [MAP2K3 p.Leu319=](/variant/map2k3-p-leu319), [MAP2K3 p.Ser286=](/variant/map2k3-p-ser286), [MAP2K3 p.Thr39Ile](/variant/map2k3-p-thr39ile).

### 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 768842). 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.*