# NM_145331.3(MAP3K7):c.745C>T (p.Pro249Ser)

https://sugi.bio/variant/map3k7-p-pro249ser

## Summary

**MAP3K7 p.Pro249Ser (c.745C>T)** is classified **Conflicting classifications of pathogenicity** in MAP3K7 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-04-15). AlphaMissense: likely pathogenic (0.9998); No allele count reported in gnomAD v4.1 (AN 1,607,746); Associated with Delayed skeletal maturation.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs2127974491 · 2 submitters · 1 linked condition · AlphaMissense likely pathogenic · no allele count reported in gnomAD v4.1 (AN 1,607,746)

## For patients & families {#patients}

This is a change in the MAP3K7 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to Delayed skeletal maturation.

*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.Pro249Ser |
| Coding change (HGVS c.) | c.745C>T |
| MANE Select transcript | [NM_145331](https://www.ncbi.nlm.nih.gov/nuccore/NM_145331) |
| dbSNP | [rs2127974491](https://www.ncbi.nlm.nih.gov/snp/rs2127974491/) |
| Variant type | single nucleotide variant |
| Location | chr6:90552171-90552171 (GRCh38) |
| ClinVar | [VCV1320301](https://www.ncbi.nlm.nih.gov/clinvar/variation/1320301/) |

**All HGVS expressions:** `NC_000006.11:g.91261890G>A`, `NC_000006.12:g.90552171G>A`, `NG_011966.2:g.40018C>T`, `NM_003188.4:c.745C>T`, `NM_145331.2:c.745C>T`, `NM_145331.3:c.745C>T`, `NM_145332.3:c.745C>T`, `NM_145333.3:c.745C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely pathogenic** (0.9998)
- REVEL 0.633 (indeterminate)
- SaProt LLR -12.233 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL is indeterminate
- Conservation: phyloP 11.816, GERP 2.93, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 8%** most-pathogenic-predicted substitutions in MAP3K7 (of 3,552 modeled).
- CADD: **PHRED 32.0**. 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.*
- Regional missense constraint: **o/e 0.36** across the covering region of the MANE Select transcript (90,552,165–90,586,780), spanning 34,615 bp — the region is depleted of missense variation. Chi-square p 4.4e-26. 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: **no allele count reported in gnomAD v4.1 (AN 1,607,746)** — 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}

Residue **249** lies in the protein kinase domain; the 'interaction with mapk8ip1' region; an α-helix.

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. p.Pro249Ser falls in the protein kinase domain. 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2024-04-15.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Uncertain significance).

**Submission history:** 2 submissions (2019–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2019-12-30 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-04-15 |

## Associated conditions {#conditions}

[Delayed skeletal maturation](https://sugi.bio/atlas/disease/delayed-skeletal-maturation/).

**Reported phenotype names (ClinVar):** Delayed skeletal maturation, not provided, none provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, Delayed bone age.

## 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 1320301). 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.*