# NM_005921.2(MAP3K1):c.1926C>A (p.Val642=)

https://sugi.bio/variant/map3k1-p-val642

## Summary

**MAP3K1 p.Val642= (c.1926C>A)** is classified **Likely benign** in MAP3K1 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-09-22). Ultra-rare (popmax 0.0497%, mid); Associated with 46,XY sex reversal 6.

**At a glance:** Likely benign · review: Single submitter · rsID rs867527029 · 1 submitter · 1 linked condition · ultra-rare (popmax 0.0497%, mid)

## For patients & families {#patients}

This is a change in the MAP3K1 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter, and is linked to 46,XY sex reversal 6.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015703/index) · [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.Val642= |
| Coding change (HGVS c.) | c.1926C>A |
| MANE Select transcript | [NM_005921](https://www.ncbi.nlm.nih.gov/nuccore/NM_005921) |
| dbSNP | [rs867527029](https://www.ncbi.nlm.nih.gov/snp/rs867527029/) |
| Variant type | single nucleotide variant |
| Location | chr5:56875271-56875271 (GRCh38) |
| ClinVar | [VCV1545388](https://www.ncbi.nlm.nih.gov/clinvar/variation/1545388/) |

**All HGVS expressions:** `NC_000005.10:g.56875271C>A`, `NC_000005.9:g.56171098C>A`, `NG_031884.1:g.65199C>A`, `NM_005921.2:c.1926C>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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor gain** (Δ 0.88) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 1.826, GERP 2.42, phastCons 1 — weakly conserved position
- CADD: **PHRED 21.1**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.32**, acceptor gain **0.00**, donor gain **0.88**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.88**.
- Pangolin: Δ**0.69** (gain), gain 0.69 / loss 0.51. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0497%** (mid) · FAF95 0.0134% · FAF99 0.00721% · 3/6,040 in the highest group · 3/1,614,138 alleles overall — ultra-rare (popmax 0.0497%, mid).

*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 0/3, triplosensitivity 0/3. *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 **642** 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}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2021-09-22.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2021-09-22 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related MAP3K1 variant pages (same residue, condition, or type): [MAP3K1 p.Val642Ile](/variant/map3k1-p-val642ile), [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), [MAP3K1 c.1687-46C>G](/variant/map3k1-c-1687-minus-46c-g), [MAP3K1 c.2179+16T>G](/variant/map3k1-c-2179-plus-16t-g).

### 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 2026-10-14); 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 1545388). 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.*