# NM_005921.2(MAP3K1):c.566T>C (p.Leu189Pro)

https://sugi.bio/variant/map3k1-p-leu189pro

## Summary

**MAP3K1 p.Leu189Pro (c.566T>C)** is classified **Pathogenic** in MAP3K1 (ClinVar, Single submitter, 2 submitters; last evaluated 2023-05-30). AlphaMissense: likely pathogenic (0.9915); Absent from gnomAD v4.1; Associated with MAP3K1-related disorder.

**At a glance:** Pathogenic · review: Single submitter · rsID rs387906788 · 2 submitters · 2 linked conditions · AlphaMissense likely pathogenic · 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 2 submitters, and is linked to MAP3K1-related disorder.

*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 | [MAP3K1](https://sugi.bio/atlas/gene/MAP3K1/) |
| Protein change (HGVS p.) | p.Leu189Pro |
| Coding change (HGVS c.) | c.566T>C |
| MANE Select transcript | [NM_005921](https://www.ncbi.nlm.nih.gov/nuccore/NM_005921) |
| dbSNP | [rs387906788](https://www.ncbi.nlm.nih.gov/snp/rs387906788/) |
| Variant type | single nucleotide variant |
| Location | chr5:56856683-56856683 (GRCh38) |
| ClinVar | [VCV30146](https://www.ncbi.nlm.nih.gov/clinvar/variation/30146/) |

**All HGVS expressions:** `NC_000005.10:g.56856683T>C`, `NC_000005.9:g.56152510T>C`, `NG_031884.1:g.46611T>C`, `NM_005921.1:c.566T>C`, `NM_005921.2:c.566T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.9915) — concordant with the pathogenic call
- REVEL 0.524 (indeterminate)
- SaProt LLR -6.162 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- Conservation: phyloP 7.822, GERP 2.73, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 8%** most-pathogenic-predicted substitutions in MAP3K1 (of 8,799 modeled).
- CADD: **PHRED 27.7**. 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 0.84** across the covering region of the MANE Select transcript (56,856,646–56,864,838), spanning 8,192 bp. Chi-square p 0.028. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **189** lies in a UniProt-annotated variant site (in srxy6; increases phosphorylation of the downstream target mapk3/mapk1 compared to wild-type and enhances binding of rhoa to the mutant map3k1 complex); a UniProt-annotated variant site (in srxy6; increases phosphorylation of the downstream targets mapk14 and mapk3/mapk1 compared to wild-type and enhances binding of rhoa to the mutant map3k1 complex).

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 Single submitter *(criteria provided, single submitter)*, last evaluated 2023-05-30.

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

**Submission history:** 2 submissions (2010–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Pathogenic | criteria provided, single submitter | clinical testing | 2023-05-30 |
| OMIM | Pathogenic | no assertion criteria provided | literature only | 2010-12-10 |

## Associated conditions {#conditions}

[MAP3K1-related disorder](https://sugi.bio/atlas/disease/map3k1-related-disorder/), [46,XY sex reversal 6](https://sugi.bio/atlas/disease/46-xy-sex-reversal-6/).

**Reported phenotype names (ClinVar):** MAP3K1-related disorder, 46,XY sex reversal 6, MAP3K1-related condition, 46,XY GONADAL DYSGENESIS, PARTIAL OR COMPLETE, MAP3K1-RELATED, 46,XY SEX REVERSAL, PARTIAL OR COMPLETE, MAP3K1-RELATED.

## Same-residue context {#hotspot}

Residue **189** carries **3 other pathogenic ClinVar variants** — a recurrently-mutated position: [MAP3K1 p.Leu189Arg](/variant/map3k1-p-leu189arg), [MAP3K1 p.Leu189Val](/variant/map3k1-p-leu189val), [MAP3K1 p.Leu189Gln](/variant/map3k1-p-leu189gln). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MAP3K1 variant pages (same residue, condition, or type): [MAP3K1 p.Leu189Gln](/variant/map3k1-p-leu189gln), [MAP3K1 p.Leu189Val](/variant/map3k1-p-leu189val), [MAP3K1 p.Leu189Arg](/variant/map3k1-p-leu189arg), [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), [MAP3K1 c.1035+12C>T](/variant/map3k1-c-1035-plus-12c-t).

### 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 30146). 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.*