# NM_005921.2(MAP3K1):c.2111C>G (p.Ser704Ter)

https://sugi.bio/variant/map3k1-p-ser704ter

## Summary

**MAP3K1 p.Ser704Ter (c.2111C>G)** is classified **Pathogenic** in MAP3K1 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2018-12-01). Absent from gnomAD v4.1; Associated with ovarian neoplasm.

**At a glance:** Pathogenic · review: No assertion criteria · rsID rs1561198459 · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the MAP3K1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to ovarian neoplasm.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 346 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MAP3K1](https://sugi.bio/atlas/gene/MAP3K1/) |
| Protein change (HGVS p.) | p.Ser704Ter |
| Coding change (HGVS c.) | c.2111C>G |
| MANE Select transcript | [NM_005921](https://www.ncbi.nlm.nih.gov/nuccore/NM_005921) |
| dbSNP | [rs1561198459](https://www.ncbi.nlm.nih.gov/snp/rs1561198459/) |
| Variant type | single nucleotide variant |
| Location | chr5:56880734-56880734 (GRCh38) |
| ClinVar | [VCV634720](https://www.ncbi.nlm.nih.gov/clinvar/variation/634720/) |

**All HGVS expressions:** `NC_000005.10:g.56880734C>G`, `NC_000005.9:g.56176561C>G`, `NG_031884.1:g.70662C>G`, `NM_005921.2:c.2111C>G`

## Computational & population evidence {#evidence}

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

- **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 7.696, GERP 2.74, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. the gene is **loss-of-function-intolerant** (LOEUF 0.355, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 12 of 20**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 38.0**. 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: **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}

**MAP3K1** population constraint: LOEUF 0.355, pLI 1, missense-Z 1.4665; ClinGen dosage — haploinsufficiency 0, triplosensitivity 0 (0–3 scale). *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 **704** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 59.80, 18% of residues very-high.

**1 experimental structure(s)** (PDB): [6WHB](https://www.rcsb.org/structure/6WHB).

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

*Describes the biological roles of MAP3K1 (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:** MAP3K1's established molecular role includes protein kinase activity.


### Pathways affected {#pathways}

MAP3K1 participates in **5 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [MyD88 cascade initiated on plasma membrane](https://reactome.org/content/detail/R-HSA-975871) | curated |
| [MyD88:MAL(TIRAP) cascade initiated on plasma membrane](https://reactome.org/content/detail/R-HSA-166058) | curated |
| [TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation](https://reactome.org/content/detail/R-HSA-975138) | curated |
| [FCERI mediated MAPK activation](https://reactome.org/content/detail/R-HSA-2871796) | electronic |
| [TRAF6 mediated NF-kB activation](https://reactome.org/content/detail/R-HSA-933542) | electronic |

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

**Molecular function:** protein kinase activity, protein serine/threonine kinase activity, protein kinase binding.

**Biological process:** cellular response to mechanical stimulus.

## Clinical significance {#significance}

**Pathogenic** — review status No assertion criteria *(no assertion criteria provided)*, last evaluated 2018-12-01.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Pathogenic | no assertion criteria provided | research | 2018-12-01 |

## Associated conditions {#conditions}

[ovarian neoplasm](https://sugi.bio/atlas/disease/ovarian-neoplasm/).

**Reported phenotype names (ClinVar):** Ovarian neoplasm, Neoplasm of ovary, Ovarian tumor, Ovarian Neoplasms.

## Similar variants {#similar}

Related MAP3K1 variant pages (same residue, condition, or type): [MAP3K1 p.His1457fs](/variant/map3k1-p-his1457fs), [MAP3K1 p.His470fs](/variant/map3k1-p-his470fs), [MAP3K1 p.Leu838_Leu841del](/variant/map3k1-p-leu838-leu841del), [MAP3K1 p.Thr876fs](/variant/map3k1-p-thr876fs), [MAP3K1 p.Arg186Gly](/variant/map3k1-p-arg186gly), [MAP3K1 p.Ala594Ser](/variant/map3k1-p-ala594ser), [MAP3K1 p.Arg204Lys](/variant/map3k1-p-arg204lys), [MAP3K1 p.Gln548Glu](/variant/map3k1-p-gln548glu).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 634720). 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.*