MAP3K21

Summary

MAP3K21 (mitogen-activated protein kinase kinase kinase 21, HGNC:29798) is a protein-coding gene on chromosome 1q42.2, encoding Mitogen-activated protein kinase kinase kinase 21 (Q5TCX8). Negative regulator of TLR4 signaling.

Predicted to enable JUN kinase kinase kinase activity and protein homodimerization activity. Predicted to be involved in protein autophosphorylation and signal transduction. Predicted to be active in cytoplasm.

Source: NCBI Gene 84451 — RefSeq curated summary.

At a glance

• GWAS associations: 7
• Clinical variants (ClinVar): 25 total
• Druggable target: yes
• MANE Select transcript: NM_032435

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29798
Approved symbol	MAP3K21
Name	mitogen-activated protein kinase kinase kinase 21
Location	1q42.2
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1804, MLK4
Ensembl gene	ENSG00000143674
Ensembl biotype	protein_coding
OMIM	614793
Entrez	84451

Gene structure

Transcript identifiers

Ensembl transcripts: 8 — 8 protein_coding

ENST00000366622, ENST00000366623, ENST00000366624, ENST00000915949, ENST00000915950, ENST00000915951, ENST00000915952, ENST00000915953

RefSeq mRNA: 1 — MANE Select: NM_032435 NM_032435

CCDS: CCDS1598

Canonical transcript exons

ENST00000366624 — 10 exons

Exon	Start	End
ENSE00000793282	233346442	233346622
ENSE00000793284	233354836	233355011
ENSE00000793285	233362053	233362293
ENSE00000961506	233376430	233376527
ENSE00000961507	233378931	233379710
ENSE00001121754	233372038	233372160
ENSE00001168217	233375916	233376066
ENSE00001442194	233382305	233385148
ENSE00001766595	233353807	233353955
ENSE00003843123	233327724	233328833

Expression profiles

Bgee: expression breadth ubiquitous, 191 present calls, max score 93.87.

FANTOM5 (CAGE): breadth broad, TPM avg 1.7673 / max 32.1078, expressed in 721 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
9076	1.2304	630
9077	0.5369	279

Top tissues by expression

245 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
kidney epithelium	UBERON:0004819	93.87	silver quality
epithelial cell of pancreas	CL:0000083	92.67	gold quality
ileal mucosa	UBERON:0000331	92.63	gold quality
jejunal mucosa	UBERON:0000399	88.91	gold quality
body of pancreas	UBERON:0001150	88.24	gold quality
mucosa of sigmoid colon	UBERON:0004993	87.94	gold quality
colonic mucosa	UBERON:0000317	86.87	gold quality
pancreas	UBERON:0001264	86.25	gold quality
duodenum	UBERON:0002114	85.70	gold quality
germinal epithelium of ovary	UBERON:0001304	84.44	gold quality
caput epididymis	UBERON:0004358	84.37	gold quality
islet of Langerhans	UBERON:0000006	83.36	gold quality
metanephros cortex	UBERON:0010533	81.74	gold quality
secondary oocyte	CL:0000655	81.09	gold quality
corpus epididymis	UBERON:0004359	80.93	gold quality
kidney	UBERON:0002113	80.77	gold quality
adult mammalian kidney	UBERON:0000082	80.59	gold quality
renal medulla	UBERON:0000362	79.75	gold quality
cerebellar hemisphere	UBERON:0002245	79.39	gold quality
cerebellar cortex	UBERON:0002129	79.28	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	78.87	gold quality
cerebellum	UBERON:0002037	78.82	gold quality
right hemisphere of cerebellum	UBERON:0014890	78.77	gold quality
esophagus squamous epithelium	UBERON:0006920	78.70	gold quality
rectum	UBERON:0001052	78.47	gold quality
pancreatic ductal cell	CL:0002079	77.75	gold quality
mucosa of transverse colon	UBERON:0004991	77.55	gold quality
metanephros	UBERON:0000081	76.52	gold quality
body of stomach	UBERON:0001161	76.46	gold quality
right uterine tube	UBERON:0001302	75.48	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.72

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

142 targeting MAP3K21, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518E-5P	100.00	67.66	954
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-519A-5P	100.00	67.66	954
HSA-MIR-519B-5P	100.00	67.66	954
HSA-MIR-519C-5P	100.00	67.66	954
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-522-5P	100.00	67.66	954
HSA-MIR-523-5P	100.00	67.66	954
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595

Literature-anchored findings (GeneRIF, showing 7)

• MLK4 is a negative regulator of TLR4 signaling. (PMID:21602844)
• In establishing the role of MLK4 in intracellular signaling, we show it directly phosphorylates MEK1 (MAP2K1) and that MEK/ERK (MAPK1) signaling is impaired in MLK4 knockout cells (PMID:23319808)
• results uncover MLK4 as an upstream regulator of NF-kappaB signaling and a potential molecular target for the MES subtype of glioblastomas (PMID:26859459)
• These results suggest that in the early response to stressful stimuli, MLK4beta-MLK3 binding is important for regulating MLK3 activity and MAPK signalling, and after prolonged periods of stress exposure, MLK4beta and MLK3 proteins decline via CHIP-dependent degradation. (PMID:28757353)
• High expression of MLK4 promotes migratory and invasive phenotype. (PMID:30552384)
• MLK4 was over-expressed in tumor samples of Hepatocellular carcinoma patients. (PMID:31071576)
• MLK4 as an immune marker and its correlation with immune infiltration in Cervical squamous cell carcinoma and endocervical adenocarcinoma(CESC). (PMID:37594950)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	map3k21	ENSDARG00000079473
mus_musculus	Map3k21	ENSMUSG00000031853
rattus_norvegicus	Map3k21	ENSRNOG00000019931

Paralogs (23): MAP3K9 (ENSG00000006432), TESK2 (ENSG00000070759), MAP3K13 (ENSG00000073803), ARAF (ENSG00000078061), MAP3K20 (ENSG00000091436), RIPK2 (ENSG00000104312), LIMK1 (ENSG00000106683), TESK1 (ENSG00000107140), TNNI3K (ENSG00000116783), RIPK3 (ENSG00000129465), MAP3K10 (ENSG00000130758), RAF1 (ENSG00000132155), RIPK1 (ENSG00000137275), MAP3K12 (ENSG00000139625), KSR1 (ENSG00000141068), BRAF (ENSG00000157764), ILK (ENSG00000166333), MLKL (ENSG00000168404), KSR2 (ENSG00000171435), MOS (ENSG00000172680), MAP3K11 (ENSG00000173327), LIMK2 (ENSG00000182541), LRRK2 (ENSG00000188906)

Protein

Protein identifiers

Mitogen-activated protein kinase kinase kinase 21 — Q5TCX8 (reviewed: Q5TCX8)

Alternative names: Mitogen-activated protein kinase kinase kinase MLK4, Mixed lineage kinase 4

All UniProt accessions (1): Q5TCX8

UniProt curated annotations — full annotation on UniProt →

Function. Negative regulator of TLR4 signaling. Does not activate JNK1/MAPK8 pathway, p38/MAPK14, nor ERK2/MAPK1 pathways.

Subunit / interactions. Homodimer. Interacts with TLR4.

Post-translational modifications. Autophosphorylation on serine and threonine residues within the activation loop plays a role in enzyme activation.

Activity regulation. Homodimerization via the leucine zipper domains is required for autophosphorylation and subsequent activation.

Similarity. Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. MAP kinase kinase kinase subfamily.

Isoforms (3)

UniProt ID	Names	Canonical?
Q5TCX8-1	1, MLK4beta	yes
Q5TCX8-2	2, MLK4alpha
Q5TCX8-3	3

RefSeq proteins (1): NP_115811* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000719	Prot_kinase_dom	Domain
IPR001245	Ser-Thr/Tyr_kinase_cat_dom	Domain
IPR001452	SH3_domain	Domain
IPR008271	Ser/Thr_kinase_AS	Active_site
IPR011009	Kinase-like_dom_sf	Homologous_superfamily
IPR016231	MLK1-4	Family
IPR017441	Protein_kinase_ATP_BS	Binding_site
IPR036028	SH3-like_dom_sf	Homologous_superfamily
IPR051681	Ser/Thr_Kinases-Pseudokinases	Family

Pfam: PF07714, PF14604

Enzyme classification (BRENDA):

• EC 2.7.11.25 — mitogen-activated protein kinase kinase kinase (BRENDA: 30 organisms, 191 substrates, 74 inhibitors, 12 Km, 12 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
MEK	0.0002–0.0004	6
ATP	0.02–0.394	5

Catalyzed reactions (Rhea), 2 shown:

• L-seryl-[protein] + ATP = O-phospho-L-seryl-[protein] + ADP + H(+) (RHEA:17989)
• L-threonyl-[protein] + ATP = O-phospho-L-threonyl-[protein] + ADP + H(+) (RHEA:46608)

UniProt features (65 total): helix 11, sequence variant 10, sequence conflict 10, strand 8, modified residue 7, region of interest 6, splice variant 4, domain 2, compositionally biased region 2, binding site 2, chain 1, active site 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4UYA	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5TCX8-F1	59.52	0.26

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 263 (proton acceptor)

Ligand- & substrate-binding residues (2): 130–138; 151

Post-translational modifications (7): 299, 303, 528, 543, 547, 592, 614

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 105 (showing top): BILD_E2F3_ONCOGENIC_SIGNATURE, SCHAEFFER_PROSTATE_DEVELOPMENT_48HR_UP, PYEON_CANCER_HEAD_AND_NECK_VS_CERVICAL_UP, DOUGLAS_BMI1_TARGETS_UP, GOBP_PROTEIN_AUTOPHOSPHORYLATION, CUI_TCF21_TARGETS_2_UP, GOMF_PROTEIN_DIMERIZATION_ACTIVITY, GOMF_PROTEIN_KINASE_ACTIVITY, GOMF_PROTEIN_HOMODIMERIZATION_ACTIVITY, GOMF_KINASE_ACTIVITY, GOMF_MAP_KINASE_KINASE_KINASE_ACTIVITY, GOMF_PROTEIN_SERINE_THREONINE_KINASE_ACTIVITY, GOMF_ADENYL_NUCLEOTIDE_BINDING, GOMF_TRANSFERASE_ACTIVITY_TRANSFERRING_PHOSPHORUS_CONTAINING_GROUPS, MEISSNER_BRAIN_HCP_WITH_H3K4ME3_AND_H3K27ME3

GO Biological Process (4): protein phosphorylation (GO:0006468), signal transduction (GO:0007165), protein autophosphorylation (GO:0046777), MAPK cascade (GO:0000165)

GO Molecular Function (11): protein kinase activity (GO:0004672), JUN kinase kinase kinase activity (GO:0004706), ATP binding (GO:0005524), protein homodimerization activity (GO:0042803), protein serine kinase activity (GO:0106310), nucleotide binding (GO:0000166), protein serine/threonine kinase activity (GO:0004674), MAP kinase kinase kinase activity (GO:0004709), protein binding (GO:0005515), kinase activity (GO:0016301), transferase activity (GO:0016740)

GO Cellular Component (1): cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein kinase activity	2
phosphorylation	1
protein modification process	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
protein phosphorylation	1
intracellular signaling cassette	1
kinase activity	1
phosphotransferase activity, alcohol group as acceptor	1
catalytic activity, acting on a protein	1
MAP kinase kinase kinase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
identical protein binding	1
protein dimerization activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
MAPK cascade	1
protein serine/threonine kinase activity	1
binding	1
transferase activity, transferring phosphorus-containing groups	1
catalytic activity	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1198 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MAP3K21	PTPRK	Q15262	733
MAP3K21	GUCY2F	P51841	562
MAP3K21	RSPO2	Q6UXX9	558
MAP3K21	PDIK1L	Q8N165	534
MAP3K21	MYLK2	Q9H1R3	525
MAP3K21	KRT71	Q3SY84	508
MAP3K21	GORAB	Q5T7V8	507
MAP3K21	YEATS4	O95619	488
MAP3K21	CDC42	P21181	478
MAP3K21	FGF5	P12034	454
MAP3K21	CDC7	O00311	452
MAP3K21	CHUK	O15111	436
MAP3K21	NRAS	P01111	420
MAP3K21	WNT3A	P56704	417
MAP3K21	SLC26A3	P40879	411

IntAct

121 interactions, top by confidence:

A	B	Type	Score
HIF1AN	APBA3	psi-mi:“MI:0914”(association)	0.850
HIF1AN	GMDS	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
YWHAB	BLTP3B	psi-mi:“MI:0914”(association)	0.610
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
HAVCR2	TCAF2	psi-mi:“MI:0914”(association)	0.530
SLX1A	BACH1	psi-mi:“MI:0914”(association)	0.530
YWHAQ	IGLC7	psi-mi:“MI:0914”(association)	0.530
YWHAB	SHTN1	psi-mi:“MI:0914”(association)	0.530
YWHAE	SHTN1	psi-mi:“MI:0914”(association)	0.530
YWHAZ	SHTN1	psi-mi:“MI:0914”(association)	0.530
YWHAZ	BLTP3B	psi-mi:“MI:0914”(association)	0.530
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
NCALD	TPP2	psi-mi:“MI:0914”(association)	0.530
MAP3K21	CHUK	psi-mi:“MI:0915”(physical association)	0.520
MAP3K21	IKBKB	psi-mi:“MI:0915”(physical association)	0.400
MAP3K21	H1-2	psi-mi:“MI:0915”(physical association)	0.400
TACC3	DHRS2	psi-mi:“MI:0914”(association)	0.350
Tubg1	RTL8C	psi-mi:“MI:0914”(association)	0.350
Snf8	ACTBL2	psi-mi:“MI:0914”(association)	0.350
EXOSC9	MPHOSPH6	psi-mi:“MI:0914”(association)	0.350
Amot	SART1	psi-mi:“MI:0914”(association)	0.350
HIF1AN	CNOT1	psi-mi:“MI:0914”(association)	0.350

BioGRID (160): KIAA1804 (Biochemical Activity), KIAA1804 (Affinity Capture-MS), KIAA1804 (Affinity Capture-MS), KIAA1804 (Affinity Capture-MS), KIAA1804 (Affinity Capture-MS), KIAA1804 (Affinity Capture-MS), KIAA1804 (Affinity Capture-MS), KIAA1804 (Affinity Capture-MS), KIAA1804 (Affinity Capture-MS), KCTD3 (Affinity Capture-MS), KIF13B (Affinity Capture-MS), ZBTB21 (Affinity Capture-MS), KIAA1804 (Affinity Capture-MS), GIGYF1 (Affinity Capture-MS), LRFN1 (Affinity Capture-MS)

ESM2 similar proteins: A2AB59, B1AK53, B2DD29, D3YZU1, D3ZG83, O09039, O14976, O54967, O75427, P80192, P98171, Q02779, Q17R13, Q3TBD2, Q3U1V8, Q3UHC7, Q4ACU6, Q4LDD4, Q5DU25, Q5JU85, Q5RB40, Q5RJI5, Q5TCX8, Q5U2X5, Q5VWQ8, Q61097, Q61210, Q66HA1, Q66L42, Q6TLK4, Q6ZUM4, Q80XI6, Q86VW2, Q8IVT5, Q8R0S2, Q8R5F8, Q8R5G7, Q8TDC3, Q8TE68, Q8WWN8

Diamond homologs: A0A0K3AV08, A7J1T0, A7J1T2, A7MBB4, A8X775, D3ZG83, G5EE56, H2KZW3, O01700, O19064, O22558, O43283, O54967, O60674, P00529, P00533, P00534, P00535, P03949, P04412, P06239, P06240, P08069, P08922, P08941, P09760, P09769, P11273, P11362, P13388, P14234, P14616, P14617, P16092, P16591, P18461, P21802, P21803, P21804, P22607

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
MAP3K21	“up-regulates activity”	MAP2K1	phosphorylation
MAP3K21	“down-regulates activity”	CHUK	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 117 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	8	71.7×	2e-11
Activation of BAD and translocation to mitochondria	7	71.1×	4e-10
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	62.7×	8e-10
Activation of BH3-only proteins	7	46.3×	6e-09
RHO GTPases activate PKNs	8	33.8×	5e-09
Intrinsic Pathway for Apoptosis	7	27.3×	2e-07
FOXO-mediated transcription	5	22.4×	5e-05
SARS-CoV-1-host interactions	7	16.4×	6e-06

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	6	21.6×	2e-04
substantia nigra development	5	18.0×	2e-03
intracellular protein localization	9	9.2×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

25 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	8
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

1627 predictions. Top by Δscore:

Variant	Effect	Δscore
1:233328831:ACA:A	donor_gain	1.0000
1:233328831:ACAGT:A	donor_loss	1.0000
1:233328832:CAG:C	donor_loss	1.0000
1:233328833:AGT:A	donor_loss	1.0000
1:233328834:G:GG	donor_gain	1.0000
1:233328834:G:T	donor_loss	1.0000
1:233328835:T:G	donor_loss	1.0000
1:233346440:A:AG	acceptor_gain	1.0000
1:233346441:G:GG	acceptor_gain	1.0000
1:233354829:A:AG	acceptor_gain	1.0000
1:233354831:TTTA:T	acceptor_loss	1.0000
1:233354833:TAGA:T	acceptor_loss	1.0000
1:233354834:A:AG	acceptor_gain	1.0000
1:233354834:A:C	acceptor_loss	1.0000
1:233354834:AGAAT:A	acceptor_gain	1.0000
1:233354835:G:GC	acceptor_gain	1.0000
1:233354835:GA:G	acceptor_gain	1.0000
1:233354835:GAA:G	acceptor_gain	1.0000
1:233354835:GAAT:G	acceptor_gain	1.0000
1:233354835:GAATG:G	acceptor_gain	1.0000
1:233355007:AAAAG:A	donor_loss	1.0000
1:233355010:AGGTG:A	donor_loss	1.0000
1:233355011:GGTG:G	donor_loss	1.0000
1:233355012:G:A	donor_loss	1.0000
1:233355013:T:G	donor_loss	1.0000
1:233362289:TTCAG:T	donor_loss	1.0000
1:233362290:TCAG:T	donor_loss	1.0000
1:233362291:CAG:C	donor_loss	1.0000
1:233362292:AG:A	donor_loss	1.0000
1:233362293:GGTAT:G	donor_loss	1.0000

AlphaMissense

6689 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:233362150:G:C	R470P	1.000
1:233362171:G:C	R477P	1.000
1:233362177:T:C	L479P	1.000
1:233372040:T:C	F519L	1.000
1:233372041:T:C	F519S	1.000
1:233372041:T:G	F519C	1.000
1:233372042:C:A	F519L	1.000
1:233372042:C:G	F519L	1.000
1:233328303:T:C	F92S	0.999
1:233328431:T:C	F135L	0.999
1:233328433:C:A	F135L	0.999
1:233328433:C:G	F135L	0.999
1:233328481:G:C	K151N	0.999
1:233328481:G:T	K151N	0.999
1:233328816:A:C	D263A	0.999
1:233346502:A:C	D289A	0.999
1:233346502:A:T	D289V	0.999
1:233346503:T:A	D289E	0.999
1:233346503:T:G	D289E	0.999
1:233346564:T:A	W310R	0.999
1:233346564:T:C	W310R	0.999
1:233353823:T:A	W335R	0.999
1:233353823:T:C	W335R	0.999
1:233354961:T:A	W421R	0.999
1:233354961:T:C	W421R	0.999
1:233362120:T:C	L460P	0.999
1:233362129:G:C	R463P	0.999
1:233362141:T:C	L467P	0.999
1:233362165:T:C	L475P	0.999
1:233362229:G:C	R496S	0.999

dbSNP variants (sampled 300 via entrez): RS1000020006 (1:233330027 G>A), RS1000034979 (1:233378147 A>G), RS1000089489 (1:233336303 G>A), RS1000141181 (1:233327798 C>A,T), RS1000189097 (1:233385354 G>A), RS1000217522 (1:233375166 A>T), RS1000365794 (1:233348770 A>C,T), RS1000421519 (1:233381512 T>A,G), RS1000449624 (1:233369397 A>G), RS1000525585 (1:233341267 C>T), RS1000558194 (1:233334312 G>A), RS1000577726 (1:233345914 C>T), RS1000605107 (1:233381841 A>G), RS1000631041 (1:233335990 C>T), RS1000636830 (1:233351963 A>C,T)

Disease associations

OMIM: gene MIM:614793 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001017_19	Diabetic retinopathy	6.000000e-06
GCST001588_1	Periodontal microbiota	3.000000e-07
GCST001588_9	Periodontal microbiota	4.000000e-06
GCST003427_89	Alzheimer disease and age of onset	7.000000e-07
GCST004068_45	Venous thromboembolism adjusted for sickle cell variant rs77121243-T	3.000000e-06
GCST009391_1102	Metabolite levels	8.000000e-06
GCST009391_963	Metabolite levels	6.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004847	age at onset
EFO:0010447	3-hydroxyanthranilic acid measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3627584 (SINGLE PROTEIN), CHEMBL6066133 (PROTEIN-PROTEIN INTERACTION)

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

3 potent at pChembl≥5 of 3 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.12	IC50	765	nM	STAUROSPORINE
5.87	IC50	1360	nM	STAUROSPORINE
5.83	IC50	1470	nM	STAUROSPORINE

PubChem BioAssay actives

3 with measured affinity, of 32 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S,3R,4R,6R)-3-methoxy-2-methyl-4-(methylamino)-29-oxa-1,7,17-triazaoctacyclo[12.12.2.12,6.07,28.08,13.015,19.020,27.021,26]nonacosa-8,10,12,14,19,21,23,25,27-nonaen-16-one	1715263: Inhibition of human MLK4 using MEK1 as substrate by [gamma-33P]-ATP assay	ic50	0.7650	uM

CTD chemical–gene interactions

27 total (human), top 27 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	increases expression, affects cotreatment	6
entinostat	increases expression, affects cotreatment	2
Benzo(a)pyrene	decreases methylation, increases expression	2
Estradiol	increases expression	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
sodium arsenate	increases abundance, increases expression	1
trichostatin A	increases expression	1
arsenite	affects binding, decreases reaction	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	increases expression	1
cupric oxide	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Arsenic	increases abundance, increases expression	1
Calcitriol	increases expression	1
Carbamazepine	affects expression	1
Catechin	affects cotreatment, increases expression	1
Vanadates	decreases expression	1
Cyclosporine	increases expression	1
Aflatoxin B1	decreases methylation	1
Okadaic Acid	increases expression	1
Copper Sulfate	increases expression	1

ChEMBL screening assays

45 unique, capped per target: 45 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3631910	Binding	Inhibition of MLK4 (unknown origin) at 10 uM after 120 mins P33 radiolabeled kinase activity assay	Crystal structures of human RIP2 kinase catalytic domain complexed with ATP-competitive inhibitors: Foundations for understanding inhibitor selectivity. — Bioorg Med Chem

Cellosaurus cell lines

4 cell lines: 4 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_SU66	HAP1 KIAA1804 (-) 1	Cancer cell line	Male
CVCL_SU67	HAP1 KIAA1804 (-) 2	Cancer cell line	Male
CVCL_SU68	HAP1 KIAA1804 (-) 3	Cancer cell line	Male
CVCL_SU69	HAP1 KIAA1804 (-) 4	Cancer cell line	Male

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.