# NM_145331.3(MAP3K7):c.1524G>A (p.Gln508=)

https://sugi.bio/variant/map3k7-p-gln508

## Summary

**MAP3K7 p.Gln508= (c.1524G>A)** is classified **Uncertain significance** in MAP3K7 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-16). No allele count reported in gnomAD v4.1 (AN 1,586,250).

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · no allele count reported in gnomAD v4.1 (AN 1,586,250)

## For patients & families {#patients}

This is a change in the MAP3K7 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | [MAP3K7](https://sugi.bio/atlas/gene/MAP3K7/) |
| Protein change (HGVS p.) | p.Gln508= |
| Coding change (HGVS c.) | c.1524G>A |
| MANE Select transcript | [NM_145331](https://www.ncbi.nlm.nih.gov/nuccore/NM_145331) |
| Variant type | single nucleotide variant |
| Location | chr6:90519258-90519258 (GRCh38) |
| ClinVar | [VCV3664551](https://www.ncbi.nlm.nih.gov/clinvar/variation/3664551/) |

**All HGVS expressions:** `NC_000006.11:g.91228977C>T`, `NC_000006.12:g.90519258C>T`, `NG_011966.2:g.72931G>A`, `NM_003188.4:c.1443G>A`, `NM_145331.3:c.1524G>A`, `NM_145332.3:c.1524G>A`, `NM_145333.3:c.1443G>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 7.64, GERP 1.91, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 21.6**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.63 donor loss), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Pangolin: Δ**0.75** (loss), gain 0.01 / loss 0.75. SpliceAI below 0.2. 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: **no allele count reported in gnomAD v4.1 (AN 1,586,250)** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**MAP3K7** population constraint: LOEUF 0.397, pLI 0.99991, missense-Z 2.8775. *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 70.27, 41% of residues very-high.

**25 experimental structure(s)** (PDB): [2EVA](https://www.rcsb.org/structure/2EVA), [2YIY](https://www.rcsb.org/structure/2YIY), [4GS6](https://www.rcsb.org/structure/4GS6), [4L3P](https://www.rcsb.org/structure/4L3P), [4L52](https://www.rcsb.org/structure/4L52), [4L53](https://www.rcsb.org/structure/4L53).

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

*Describes the biological roles of MAP3K7 (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:** MAP3K7's established molecular role includes protein serine/threonine kinase activity. In Reactome, MAP3K7 is annotated in disease pathway(s) including **SARS-CoV-2 activates/modulates innate and adaptive immune responses**.

**Disease mechanism (Reactome):** MAP3K7 loss or alteration is curated in [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671).

### Pathways affected {#pathways}

MAP3K7 participates in **18 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [SARS-CoV-2 activates/modulates innate and adaptive immune responses](https://reactome.org/content/detail/R-HSA-9705671) | curated |
| [Alpha-protein kinase 1 signaling pathway](https://reactome.org/content/detail/R-HSA-9645460) | curated |
| [CLEC7A (Dectin-1) signaling](https://reactome.org/content/detail/R-HSA-5607764) | curated |
| [Ca2+ pathway](https://reactome.org/content/detail/R-HSA-4086398) | curated |
| [Downstream TCR signaling](https://reactome.org/content/detail/R-HSA-202424) | curated |
| [FCERI mediated NF-kB activation](https://reactome.org/content/detail/R-HSA-2871837) | curated |
| [IRAK2 mediated activation of TAK1 complex](https://reactome.org/content/detail/R-HSA-937042) | curated |
| [IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation](https://reactome.org/content/detail/R-HSA-975163) | curated |
| [Interleukin-1 signaling](https://reactome.org/content/detail/R-HSA-9020702) | curated |
| [JNK (c-Jun kinases) phosphorylation and  activation mediated by activated human TAK1](https://reactome.org/content/detail/R-HSA-450321) | curated |
| [NOD1/2 Signaling Pathway](https://reactome.org/content/detail/R-HSA-168638) | curated |
| [TAK1-dependent IKK and NF-kappa-B activation  ](https://reactome.org/content/detail/R-HSA-445989) | curated |
| [TICAM1,TRAF6-dependent induction of TAK1 complex](https://reactome.org/content/detail/R-HSA-9014325) | curated |
| [TNFR1-induced NF-kappa-B signaling pathway](https://reactome.org/content/detail/R-HSA-5357956) | curated |
| [TRAF6-mediated induction of TAK1 complex within TLR4 complex](https://reactome.org/content/detail/R-HSA-937072) | curated |
| [Ub-specific processing proteases](https://reactome.org/content/detail/R-HSA-5689880) | curated |
| [activated TAK1 mediates p38 MAPK activation](https://reactome.org/content/detail/R-HSA-450302) | curated |
| [Activation of NF-kappaB in B cells](https://reactome.org/content/detail/R-HSA-1169091) | electronic |

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

**Molecular function:** protein serine/threonine kinase activity, MAP kinase activity, MAP kinase kinase kinase activity, kinase activity, receptor tyrosine kinase binding, identical protein binding.

**Biological process:** MAPK cascade, positive regulation of T cell cytokine production, inflammatory response, canonical NF-kappaB signal transduction, I-kappaB phosphorylation, JNK cascade.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-10-16.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-16 |

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

## Similar variants {#similar}

Related MAP3K7 variant pages (same residue, condition, or type): [MAP3K7 p.Arg274Cys](/variant/map3k7-p-arg274cys), [MAP3K7 p.Gly110Ser](/variant/map3k7-p-gly110ser), [MAP3K7 p.Pro512Leu](/variant/map3k7-p-pro512leu), [MAP3K7 p.Ala313Thr](/variant/map3k7-p-ala313thr), [MAP3K7 p.Ala400Thr](/variant/map3k7-p-ala400thr), [MAP3K7 p.Ala6Thr](/variant/map3k7-p-ala6thr), [MAP3K7 p.Arg289Gln](/variant/map3k7-p-arg289gln), [MAP3K7 p.Arg347His](/variant/map3k7-p-arg347his).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 3664551). 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.*