# NM_145185.4(MAP2K7):c.1212G>A (p.Pro404=)

https://sugi.bio/variant/map2k7-p-pro404

## Summary

**MAP2K7 p.Pro404= (c.1212G>A)** is classified **Likely benign** in MAP2K7 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-02). Ultra-rare (popmax 0.0121%, sas).

**At a glance:** Likely benign · review: Single submitter · 1 submitter · ultra-rare (popmax 0.0121%, sas)

## For patients & families {#patients}

This is a change in the MAP2K7 gene that is classified as likely 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 | [MAP2K7](https://sugi.bio/atlas/gene/MAP2K7/) |
| Protein change (HGVS p.) | p.Pro404= |
| Coding change (HGVS c.) | c.1212G>A |
| MANE Select transcript | [NM_145185](https://www.ncbi.nlm.nih.gov/nuccore/NM_145185) |
| Variant type | single nucleotide variant |
| Location | chr19:7912383-7912383 (GRCh38) |
| ClinVar | [VCV3542724](https://www.ncbi.nlm.nih.gov/clinvar/variation/3542724/) |

**All HGVS expressions:** `NC_000019.10:g.7912383G>A`, `NC_000019.9:g.7977268G>A`, `NG_029438.2:g.13504G>A`, `NM_001297555.2:c.1260G>A`, `NM_001297556.2:c.1233G>A`, `NM_145185.4:c.1212G>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 0.295, GERP 1.04, phastCons 0.911 — weakly conserved position
- CADD: **PHRED 11.61**. 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: **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 (gnomAD v4.1): grpmax **0.0121%** (sas) · FAF95 0.00676% · FAF99 0.00522% · 11/91,094 in the highest group · 68/1,612,886 alleles overall — ultra-rare (popmax 0.0121%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0128% | 7,809 |
| South Asian (grpmax) | 0.0121% | 8,281 |
| European (non-Finnish) | 0.0039% | 25,652 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,600 |
| Admixed American | 0.00167% | 59,988 |
| African / African-American | 0.00133% | 74,942 |

Remaining individuals shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**MAP2K7** population constraint: LOEUF 0.454, pLI 0.99747, missense-Z 2.388. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 77.94, 45% of residues very-high.

**37 experimental structure(s)** (PDB): [2DYL](https://www.rcsb.org/structure/2DYL), [3WZU](https://www.rcsb.org/structure/3WZU), [4UX9](https://www.rcsb.org/structure/4UX9), [5B2K](https://www.rcsb.org/structure/5B2K), [5B2L](https://www.rcsb.org/structure/5B2L), [5B2M](https://www.rcsb.org/structure/5B2M) — incl. mutant structure 2DYL.

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

*Describes the biological roles of MAP2K7 (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:** MAP2K7's established molecular role includes magnesium ion binding. In Reactome, MAP2K7 is annotated in disease pathway(s) including **Uptake and function of anthrax toxins**.

**Disease mechanism (Reactome):** MAP2K7 loss or alteration is curated in [Uptake and function of anthrax toxins](https://reactome.org/content/detail/R-HSA-5210891).

### Pathways affected {#pathways}

MAP2K7 participates in **4 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Uptake and function of anthrax toxins](https://reactome.org/content/detail/R-HSA-5210891) | curated |
| [FCERI mediated MAPK activation](https://reactome.org/content/detail/R-HSA-2871796) | curated |
| [JNK (c-Jun kinases) phosphorylation and  activation mediated by activated human TAK1](https://reactome.org/content/detail/R-HSA-450321) | curated |
| [Oxidative Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559580) | curated |

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

**Molecular function:** magnesium ion binding, MAP kinase kinase activity, enzyme binding, protein kinase binding, molecular function activator activity.

**Biological process:** response to osmotic stress, response to heat, response to UV, positive regulation of telomere maintenance, response to tumor necrosis factor, positive regulation of DNA-templated transcription.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-12-02.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-12-02 |

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

## Similar variants {#similar}

Related MAP2K7 variant pages (same residue, condition, or type): [MAP2K7 p.Pro404Gln](/variant/map2k7-p-pro404gln), [MAP2K7 c.855+10G>C](/variant/map2k7-c-855-plus-10g-c), [MAP2K7 c.856-19T>C](/variant/map2k7-c-856-minus-19t-c), [MAP2K7 c.856-8C>G](/variant/map2k7-c-856-minus-8c-g), [MAP2K7 p.Cys131=](/variant/map2k7-p-cys131), [MAP2K7 p.Pro215=](/variant/map2k7-p-pro215), [MAP2K7 p.Ser277=](/variant/map2k7-p-ser277), [MAP2K7 p.Ala391Val](/variant/map2k7-p-ala391val).

### 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 3542724). 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.*