AKAP12

Summary

AKAP12 (A-kinase anchoring protein 12, HGNC:370) is a protein-coding gene on chromosome 6q25.1, encoding A-kinase anchor protein 12 (Q02952). Anchoring protein that mediates the subcellular compartmentation of protein kinase A (PKA) and protein kinase C (PKC).

The A-kinase anchor proteins (AKAPs) are a group of structurally diverse proteins, which have the common function of binding to the regulatory subunit of protein kinase A (PKA) and confining the holoenzyme to discrete locations within the cell. This gene encodes a member of the AKAP family. The encoded protein is expressed in endothelial cells, cultured fibroblasts, and osteosarcoma cells. It associates with protein kinases A and C and phosphatase, and serves as a scaffold protein in signal transduction. This protein and RII PKA colocalize at the cell periphery. This protein is a cell growth-related protein. Antibodies to this protein can be produced by patients with myasthenia gravis. Alternative splicing of this gene results in two transcript variants encoding different isoforms.

Source: NCBI Gene 9590 — RefSeq curated summary.

At a glance

• GWAS associations: 15
• Clinical variants (ClinVar): 305 total — 6 pathogenic, 1 likely-pathogenic
• Druggable target: yes
• MANE Select transcript: NM_005100

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:370
Approved symbol	AKAP12
Name	A-kinase anchoring protein 12
Location	6q25.1
Locus type	gene with protein product
Status	Approved
Aliases	AKAP250, SSeCKS
Ensembl gene	ENSG00000131016
Ensembl biotype	protein_coding
OMIM	604698
Entrez	9590

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000253332, ENST00000354675, ENST00000359755, ENST00000402676, ENST00000490177, ENST00000903473

RefSeq mRNA: 3 — MANE Select: NM_005100 NM_001370346, NM_005100, NM_144497

CCDS: CCDS5229, CCDS5230, CCDS94020

Canonical transcript exons

ENST00000402676 — 5 exons

Exon	Start	End
ENSE00001675506	151240384	151240724
ENSE00001708256	151239967	151240059
ENSE00001749317	151355727	151358559
ENSE00003891138	151348711	151353752
ENSE00003892837	151305747	151305903

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 99.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 60.8636 / max 1752.7559, expressed in 1422 samples.

FANTOM5 promoters (17 alternative TSS)

Promoter ID	TPM avg	Samples expressed
70576	28.6247	1302
70586	20.5910	1086
70575	4.6717	1137
70583	2.1108	800
70601	1.2408	579
70581	0.9166	553
70574	0.6286	333
70582	0.4785	304
70600	0.3519	170
70585	0.2807	144

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pons	UBERON:0000988	99.23	gold quality
lateral nuclear group of thalamus	UBERON:0002736	99.16	gold quality
dorsal root ganglion	UBERON:0000044	99.15	gold quality
trigeminal ganglion	UBERON:0001675	99.11	gold quality
vena cava	UBERON:0004087	98.87	gold quality
substantia nigra pars compacta	UBERON:0001965	98.46	gold quality
saphenous vein	UBERON:0007318	98.14	gold quality
superior vestibular nucleus	UBERON:0007227	98.09	gold quality
pericardium	UBERON:0002407	98.07	gold quality
colonic epithelium	UBERON:0000397	97.92	gold quality
superficial temporal artery	UBERON:0001614	97.83	gold quality
cauda epididymis	UBERON:0004360	97.75	gold quality
substantia nigra pars reticulata	UBERON:0001966	97.69	gold quality
sural nerve	UBERON:0015488	97.60	gold quality
ventricular zone	UBERON:0003053	97.52	gold quality
adult organism	UBERON:0007023	97.39	gold quality
calcaneal tendon	UBERON:0003701	96.79	gold quality
parietal pleura	UBERON:0002400	96.32	gold quality
urethra	UBERON:0000057	96.25	gold quality
adipose tissue of abdominal region	UBERON:0007808	95.91	gold quality
decidua	UBERON:0002450	95.90	gold quality
adipose tissue	UBERON:0001013	95.81	gold quality
peritoneum	UBERON:0002358	95.76	gold quality
omental fat pad	UBERON:0010414	95.76	gold quality
lower lobe of lung	UBERON:0008949	95.72	gold quality
left ovary	UBERON:0002119	95.69	gold quality
blood vessel layer	UBERON:0004797	95.69	gold quality
connective tissue	UBERON:0002384	95.42	gold quality
male germ cell	CL:0000015	95.34	gold quality
medulla oblongata	UBERON:0001896	95.23	gold quality

Single-cell (SCXA)

Detected in 41 experiment(s), a significant marker in 38.

Experiment	Marker?	Max mean expression
E-ENAD-20	yes	2934.83
E-GEOD-130473	yes	2769.57
E-MTAB-9543	yes	2523.59
E-CURD-7	yes	1999.63
E-GEOD-98556	yes	1784.28
E-CURD-6	yes	1747.99
E-MTAB-6308	yes	1648.68
E-CURD-112	yes	1643.14
E-GEOD-114530	yes	1383.49
E-HCAD-31	yes	1323.85
E-MTAB-9067	yes	1300.29
E-MTAB-9435	yes	926.38
E-ENAD-21	yes	828.32
E-MTAB-9154	yes	699.96
E-GEOD-81608	yes	355.12

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): GTF2I, HDAC7, SP1, SP3, SRF, STAT3, USF1

Literature-anchored findings (GeneRIF, showing 40)

• gravin provides a dynamic platform for the localization for kinases during neuronal development (PMID:12857743)
• AKAP250 acts as a scaffold that binds protein kinase A (PKA), protein kinase C and protein phosphatases, associating reversibly with the beta(2)-adrenergic receptor. (PMID:14657015)
• AKAP12A may function as an important negative regulator of the survival pathway in human gastric cancer. (PMID:15258566)
• AKAP12alpha belongs to a novel class of atypical SRF-dependent target genes (PMID:15590635)
• AKAP12 localization is regulated by a hierarchy of targeting domains and the localization of AKAP12-assembled signaling complexes may be dynamically regulated (PMID:15923193)
• Results suggest that gravin maintains a signaling complex that includes protein kinase A and phosphodiesterase 4D. (PMID:16642035)
• Membrane binding of gravin, and thus function, can be reversed by calcium/calmodulin, which binds to the membrane and causes translocation of gravin from membrane to cytoplasm. (PMID:16762919)
• We conclude that LPA-dependent increased level of cAMP in senescent human diploid fibroblasts is associated with increases in Gravin levels resulting in its increased binding with and activation of calcium-dependent PKC alpha/beta and AC4/6. (PMID:17081159)
• The Src-binding peptide-(1-51) of gravin behaves as a dominant-negative for AKAP gravin regulation of beta2-adrenergic receptor resensitization/recycling (PMID:17200117)
• Results suggest that AKAP12 may play an important role in tumor growth suppression by inducing apoptosis with the regulation of multiple molecules in the cell cycle progression. (PMID:17442483)
• AKAP12 may induce BRB formation through antiangiogenesis and barriergenesis in developing human eye and defects in this mechanism can lead to loss of tight junction proteins and contribute to development of retinal pathologies such as retinoblastoma. (PMID:17442832)
• The Gravin expression was found to be decreased in samples of acute leukaemia and was associated with an inferior overall survival. (PMID:17577780)
• Hypermethylation of the AKAP12 promoter is associated esophageal carcinoma. (PMID:18199717)
• AKAP12 in astrocytes induces barrier functions in human endothelial cells through protein kinase Czeta. (PMID:18397319)
• These findings implicate AKAP12 in the regulation of cytokinesis progression, and suggest a novel role for AKAP12 tumor suppressor. (PMID:18554502)
• Results suggest that AKAP12A may activate SREBP-2 by increasing cholesterol efflux, and is a novel regulator of cellular cholesterol metabolism. (PMID:18579430)
• AKAP12 docks to the beta2-adrenergic receptor in response to agonist stimulation, later internalizes with agonist-induced receptors, and finally dissociates from the recycled, cell membrane-bound receptor. (PMID:18950703)
• Data show that PKC activation resulted in redistribution of gravin and PKA constructs to the same subcellular site, and suggest that this response to PKC activity may mediate PKC dependent control of PKA activity. (PMID:19210988)
• Data revealed that six polymorphisms of F10, PITRM1, PCSK2, JPH3, MYO7B, and AKAP12 were related (P<0.05) to the prevalence of chronic kidney disease. (PMID:19724895)
• Findings suggest that SSeCKS suppresses metastatic motility by disengaging activated Src and then inhibiting the PKC-Raf/MEK/ERK pathways controlling matrix metalloproteinase-2 expression and podosome formation. (PMID:20018890)
• Data show that AKAP12 methylation represents a potential molecular biomarker for predicting the malignancy of colorectal cancer. (PMID:20364105)
• SERPINB5 and AKAP12 may have a role in increased metastasis in pancreatic ductal adenocarcinoma (PMID:20939879)
• In addition to genetic alterations, epigenetic mechanisms are responsible for the reduction of the tumor suppressor gene AKAP12 in human hepatocarcinogenesis. (PMID:20979053)
• AKAP12alpha promoter methylation is associated with lung cancer. (PMID:21115911)
• AKAP12 promoter methylation is a frequent event in human prostate cancer. (PMID:21310466)
• AKAP12 is involved in the regulation of endothelial cell migration through the inhibitory regulation of MMP-9 expression in tumor cells. (PMID:21461577)
• PKC-mediated remodeling of the actin cytoskeleton is likely regulated by the ability of SSeCKS to control PKC signaling and activity through a direct scaffolding function (PMID:21903576)
• The results demonstrate that AKAP12 may play an important role in tumor growth suppression and the survival of human colorectal cancer. (PMID:21918680)
• demonstrated for the first time that AKAP12 tumor/angiogenesis suppressor gene is an epigenetic target of HDAC7 (PMID:22584896)
• Data suggest a model in which SSeCKS suppresses oncogenic motility by sequestering Src to caveolin-rich lipid rafts, thereby disengaging Src from FAK-associated adhesion and signaling complexes. (PMID:22710722)
• It defines a role for Gravin as a temporal organizer of phosphorylation-dependent protein-protein interactions during mitosis. (PMID:23063527)
• Gravin gene expression is decreased in acute myeloid leukemia and correlates with poor prognosis. (PMID:23543478)
• Receptor-mediated Ca2+ and PKC signaling triggers the loss of cortical PKA compartmentalization through the redistribution of gravin. (PMID:23838009)
• AKAP12 is differentially expressed in human astrocytomas showing high expression in pilocytic but low expression in diffuse astrocytomas of all WHO-grades. further, epigenetic mechanisms are involved in silencing AKAP12 in diffuse astrocytomas (PMID:24042196)
• High AKAP12 expression is associated with colorectal cancer. (PMID:24065476)
• AKAP12 expression was positive in 82.2% of tumors in a cohort with colorectal adenocarcinoma. AKAP12 expression was unrelated to p53 or Bcl-2 expression. (PMID:24870731)
• This study showed that AKAP12,CAMK2D and a molecular pathway(cyclic amp)association to outcome of depressive during citalopram treatment. (PMID:24986638)
• PKA compartmentalization via AKAP220 and AKAP12 contributes to endothelial barrier regulation. (PMID:25188285)
• AKAP12 scaffolding protein mediates meningeal reconstruction after central nervous system injury (PMID:25229625)
• The enrichment of activated Cdc42 in SSeCKS-null leading edge filopodia correlated with recruitment of the Cdc42-specific guanine nucleotide exchange factor, Frabin. (PMID:25356636)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	akap12b	ENSDARG00000055678
danio_rerio	akap12a	ENSDARG00000091792
mus_musculus	Akap12	ENSMUSG00000038587
rattus_norvegicus	Akap12	ENSRNOG00000019549

Protein

Protein identifiers

A-kinase anchor protein 12 — Q02952 (reviewed: Q02952)

Alternative names: A-kinase anchor protein 250 kDa, Gravin, Myasthenia gravis autoantigen

All UniProt accessions (1): Q02952

UniProt curated annotations — full annotation on UniProt →

Function. Anchoring protein that mediates the subcellular compartmentation of protein kinase A (PKA) and protein kinase C (PKC).

Subunit / interactions. Binds to dimeric RII-alpha regulatory subunit of PKC.

Subcellular location. Cytoplasm. Cell cortex. Cytoskeleton. Membrane.

Tissue specificity. Expressed in endothelial cells, cultured fibroblasts and osteosarcoma, but not in platelets, leukocytes, monocytic cell lines or peripherical blood cells.

Domain organisation. Polybasic regions located between residues 266 and 557 are involved in binding PKC.

Induction. Activated by lysophosphatidylcholine (lysoPC).

Miscellaneous. Antibodies against the C-terminal of gravin can be produced by patients with myasthenia gravis (MG).

Isoforms (3)

UniProt ID	Names	Canonical?
Q02952-1	1, Alpha	yes
Q02952-2	2, Beta
Q02952-3	3, Gamma

RefSeq proteins (3): NP_001357275, NP_005091, NP_653080 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001573	AKAP_WSK	Domain
IPR018459	RII-bd_1	Domain
IPR028540	AKAP12	Family

Pfam: PF03832, PF10522

UniProt features (114 total): modified residue 43, compositionally biased region 29, region of interest 11, sequence variant 10, sequence conflict 10, splice variant 4, short sequence motif 3, initiator methionine 1, chain 1, lipid moiety-binding region 1, cross-link 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q02952-F1	40.98	0.02

Functional residue map

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

Post-translational modifications (45): 11, 19, 28, 75, 96, 154, 219, 248, 258, 280, 283, 286, 347, 371, 374, 381, 392, 483, 505, 554 …

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-9013405	RHOD GTPase cycle
R-HSA-9035034	RHOF GTPase cycle
R-HSA-162582	Signal Transduction
R-HSA-194315	Signaling by Rho GTPases
R-HSA-9012999	RHO GTPase cycle
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 429 (showing top): RNGTGGGC_UNKNOWN, MODULE_52, CHIARADONNA_NEOPLASTIC_TRANSFORMATION_KRAS_DN, GOBP_RESPONSE_TO_ELECTRICAL_STIMULUS, GOBP_CIRCULATORY_SYSTEM_PROCESS, GOBP_RESPONSE_TO_PEPTIDE, MODULE_64, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_POSITIVE_REGULATION_OF_MAPK_CASCADE, GOBP_REGULATION_OF_FIBROBLAST_MIGRATION, KYNG_DNA_DAMAGE_DN, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_POSITIVE_REGULATION_OF_FIBROBLAST_MIGRATION, TOMLINS_PROSTATE_CANCER_DN

GO Biological Process (17): signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193), obsolete regulation of protein kinase A signaling (GO:0010738), obsolete positive regulation of protein kinase A signaling (GO:0010739), response to lipopolysaccharide (GO:0032496), positive regulation of tumor necrosis factor production (GO:0032760), hepatic stellate cell activation (GO:0035733), negative regulation of vascular permeability (GO:0043116), modulation of chemical synaptic transmission (GO:0050804), response to electrical stimulus (GO:0051602), positive regulation of hepatic stellate cell migration (GO:0061870), positive regulation of ERK1 and ERK2 cascade (GO:0070374), cellular response to interleukin-1 (GO:0071347), cellular response to tumor necrosis factor (GO:0071356), regulation of protein kinase C signaling (GO:0090036), positive regulation of oligodendrocyte apoptotic process (GO:1900143)

GO Molecular Function (4): calmodulin binding (GO:0005516), adenylate cyclase binding (GO:0008179), protein kinase A binding (GO:0051018), protein binding (GO:0005515)

GO Cellular Component (9): cytoplasm (GO:0005737), cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), focal adhesion (GO:0005925), cell cortex (GO:0005938), neuronal cell body (GO:0043025), Schaffer collateral - CA1 synapse (GO:0098685), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
RHO GTPase cycle	2
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Signaling by Rho GTPases	1
Signal Transduction	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
cellular response to cytokine stimulus	2
protein binding	2
cytoplasm	2
cell periphery	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
G protein-coupled receptor activity	1
signal transduction	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase inhibitor activity	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	1
tumor necrosis factor production	1
regulation of tumor necrosis factor production	1
positive regulation of tumor necrosis factor superfamily cytokine production	1
fibroblast activation	1
regulation of vascular permeability	1
chemical synaptic transmission	1
regulation of trans-synaptic signaling	1
response to abiotic stimulus	1
positive regulation of fibroblast migration	1
hepatic stellate cell migration	1
regulation of hepatic stellate cell migration	1
positive regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
response to interleukin-1	1
response to tumor necrosis factor	1
protein kinase C signaling	1
regulation of intracellular signal transduction	1
positive regulation of glial cell apoptotic process	1
oligodendrocyte apoptotic process	1
regulation of oligodendrocyte apoptotic process	1
enzyme binding	1
binding	1

Protein interactions and networks

STRING

1482 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AKAP12	PRKACA	P17612	989
AKAP12	PRKACB	P22694	989
AKAP12	PRKACG	P22612	989
AKAP12	ADRB2	P07550	967
AKAP12	CALML3	P27482	937
AKAP12	CALM1	P02593	936
AKAP12	CALML6	Q8TD86	936
AKAP12	CALML5	Q9NZT1	936
AKAP12	CALML4	Q96GE6	936
AKAP12	AKAP1	Q92667	915
AKAP12	CCNL2	Q96S94	876
AKAP12	AKAP5	P24588	845
AKAP12	AKAP13	Q12802	768
AKAP12	PDE4D	Q08499	764
AKAP12	ANGPT1	Q15389	732

IntAct

106 interactions, top by confidence:

A	B	Type	Score
PSMD10	PSMD11	psi-mi:“MI:0914”(association)	0.800
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
AKAP12	FHL1	psi-mi:“MI:0915”(physical association)	0.670
SH3KBP1	USP27X	psi-mi:“MI:0914”(association)	0.640
UNC119	UNC119B	psi-mi:“MI:0914”(association)	0.640
SLC39A5	FAM171A2	psi-mi:“MI:0914”(association)	0.640
EGFR	AKAP12	psi-mi:“MI:0915”(physical association)	0.630
AKAP12	EGFR	psi-mi:“MI:0915”(physical association)	0.630
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
AKAP12	PRKAR2A	psi-mi:“MI:0915”(physical association)	0.560
GRB2	ARHGEF35	psi-mi:“MI:0914”(association)	0.530
AKAP12	HSPA12A	psi-mi:“MI:0914”(association)	0.530
HSPA12B	EEF2K	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
SCLT1	CCDC22	psi-mi:“MI:0914”(association)	0.420
Akap12		psi-mi:“MI:0915”(physical association)	0.400
AKAP12	PDE4D	psi-mi:“MI:0915”(physical association)	0.400
ERBB2	AKAP12	psi-mi:“MI:0915”(physical association)	0.370
CEP290	SUPT5H	psi-mi:“MI:0914”(association)	0.350
OFD1	SUPT5H	psi-mi:“MI:0914”(association)	0.350
	PGRMC1	psi-mi:“MI:0914”(association)	0.350
RIPK4	VWA8	psi-mi:“MI:0914”(association)	0.350
	ZNF316	psi-mi:“MI:0914”(association)	0.350

BioGRID (222): AKAP12 (Affinity Capture-MS), AKAP12 (Reconstituted Complex), AKAP12 (Affinity Capture-MS), AKAP12 (Affinity Capture-MS), AKAP12 (Affinity Capture-MS), AKAP12 (Affinity Capture-MS), AKAP12 (Affinity Capture-MS), AKAP12 (Affinity Capture-MS), AKAP12 (Affinity Capture-MS), AKAP12 (Affinity Capture-MS), AKAP12 (Affinity Capture-MS), AKAP12 (Affinity Capture-MS), AKAP12 (Affinity Capture-MS), AKAP12 (Affinity Capture-MS), AKAP12 (Affinity Capture-MS)

ESM2 similar proteins: A2TJV2, A6QLZ1, O15231, O75363, O75952, P19332, P20810, P24275, P24588, P27123, P27546, P27816, P36225, P49342, P51125, P62025, Q02952, Q16799, Q3T0A6, Q3ZB98, Q4R3X7, Q571C7, Q5FVI4, Q5IS59, Q5M7W5, Q5QD51, Q62394, Q64548, Q6FW26, Q6RJR6, Q710D7, Q7TT18, Q80YN3, Q811Q2, Q8BHB9, Q8C4A5, Q8GUP3, Q8K0T0, Q8N111, Q8TDB4

Diamond homologs: Q02952, Q5QD51, Q9WTQ5

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
CDK1	“up-regulates activity”	AKAP12	phosphorylation
CyclinB/CDK1	“up-regulates activity”	AKAP12	phosphorylation
ATR	“up-regulates activity”	AKAP12	phosphorylation
AKAP12	“up-regulates activity”	PRKACA	relocalization
AKAP12	“up-regulates activity”	PRKCA	relocalization
AKAP12	“up-regulates activity”	PKA	relocalization
AKAP12	“up-regulates activity”	PKC	relocalization
PRKACA	“up-regulates activity”	AKAP12	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 129 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
Signaling by ERBB2 ECD mutants	7	48.0×	1e-08
VEGFR2 mediated cell proliferation	8	46.6×	1e-09
SHC1 events in ERBB2 signaling	9	43.7×	2e-10
SHC1 events in EGFR signaling	6	43.7×	2e-07
Constitutive Signaling by EGFRvIII	6	43.7×	2e-07
GRB2 events in ERBB2 signaling	6	38.8×	4e-07
GRB2 events in EGFR signaling	5	38.8×	5e-06
Erythropoietin activates RAS	5	38.8×	5e-06

GO biological processes:

GO term	Partners	Fold	FDR
zinc ion transmembrane transport	5	30.3×	3e-04
epidermal growth factor receptor signaling pathway	8	17.1×	3e-05
positive regulation of insulin secretion	6	13.2×	1e-03
cellular response to cAMP	5	12.5×	4e-03
positive regulation of protein localization to plasma membrane	5	11.7×	5e-03
insulin receptor signaling pathway	5	9.6×	8e-03
MAPK cascade	7	9.2×	2e-03
protein autophosphorylation	6	7.5×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	1
Uncertain significance	248
Likely benign	22
Benign	12

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
150766	GRCh38/hg38 6q25.1-25.3(chr6:150381239-159553952)x1	Pathogenic
2663766	NC_000006.12:g.(?150381239)(159553952_?)del	Pathogenic
3391891	GRCh37/hg19 6q24.3-25.1(chr6:147992673-152474066)x1	Pathogenic
4075855	GRCh37/hg19 6q24.3-25.1(chr6:147868275-151680357)x1	Pathogenic
685788	GRCh37/hg19 6q24.3-25.3(chr6:148195086-160127254)x3	Pathogenic
814879	GRCh37/hg19 6q25.1-25.2(chr6:149431322-154120064)x1	Pathogenic
979577	GRCh37/hg19 6q25.1-25.2(chr6:151472860-154839846)x3	Likely pathogenic

SpliceAI

1434 predictions. Top by Δscore:

Variant	Effect	Δscore
6:151305743:A:AG	acceptor_gain	1.0000
6:151305744:T:G	acceptor_gain	1.0000
6:151305745:A:AG	acceptor_gain	1.0000
6:151305745:AGC:A	acceptor_loss	1.0000
6:151305746:G:GG	acceptor_gain	1.0000
6:151305746:GC:G	acceptor_gain	1.0000
6:151305746:GCT:G	acceptor_gain	1.0000
6:151305746:GCTC:G	acceptor_gain	1.0000
6:151305746:GCTCC:G	acceptor_gain	1.0000
6:151305900:GAGG:G	donor_gain	1.0000
6:151305902:GG:G	donor_gain	1.0000
6:151305903:GG:G	donor_gain	1.0000
6:151348709:A:AG	acceptor_gain	1.0000
6:151348709:AGTT:A	acceptor_gain	1.0000
6:151348710:G:GA	acceptor_gain	1.0000
6:151348710:GTTG:G	acceptor_gain	1.0000
6:151355725:A:AG	acceptor_gain	1.0000
6:151355726:G:GG	acceptor_gain	1.0000
6:151240721:CAAGG:C	donor_loss	0.9900
6:151240723:AGGTA:A	donor_loss	0.9900
6:151240724:GGTA:G	donor_loss	0.9900
6:151240725:G:A	donor_loss	0.9900
6:151240726:T:G	donor_loss	0.9900
6:151305879:G:GT	donor_gain	0.9900
6:151305885:G:GT	donor_gain	0.9900
6:151305901:AGGGT:A	donor_loss	0.9900
6:151305902:GGGTA:G	donor_loss	0.9900
6:151305904:G:GA	donor_loss	0.9900
6:151305905:TAAGC:T	donor_loss	0.9900
6:151348709:AGTTG:A	acceptor_gain	0.9900

AlphaMissense

11645 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:151350219:T:A	W610R	1.000
6:151350219:T:C	W610R	1.000
6:151350233:A:C	K614N	1.000
6:151350233:A:T	K614N	1.000
6:151350426:T:A	W679R	1.000
6:151350426:T:C	W679R	1.000
6:151348939:T:C	F183S	0.999
6:151350221:G:C	W610C	0.999
6:151350221:G:T	W610C	0.999
6:151350229:T:C	F613S	0.999
6:151350428:G:C	W679C	0.999
6:151350428:G:T	W679C	0.999
6:151350666:T:A	W759R	0.999
6:151350666:T:C	W759R	0.999
6:151350668:G:C	W759C	0.999
6:151350668:G:T	W759C	0.999
6:151350676:T:C	F762S	0.999
6:151350680:A:C	K763N	0.999
6:151350680:A:T	K763N	0.999
6:151350688:T:A	V766D	0.999
6:151348910:G:C	K173N	0.998
6:151348910:G:T	K173N	0.998
6:151350229:T:G	F613C	0.998
6:151350231:A:G	K614E	0.998
6:151350232:A:T	K614I	0.998
6:151350931:T:A	V847D	0.998
6:151348918:T:C	F176S	0.997
6:151348938:T:C	F183L	0.997
6:151348940:C:A	F183L	0.997
6:151348940:C:G	F183L	0.997

dbSNP variants (sampled 300 via entrez): RS1000004896 (6:151265344 C>T), RS1000057558 (6:151281855 A>G), RS1000071738 (6:151264022 G>A,C), RS1000077795 (6:151275985 G>A), RS1000085268 (6:151304401 A>G), RS1000209854 (6:151281385 A>G), RS1000224169 (6:151298650 G>A), RS1000225183 (6:151287164 C>G), RS1000235401 (6:151323789 G>A), RS1000246548 (6:151329359 A>C), RS1000255521 (6:151298983 G>A), RS1000266084 (6:151255778 T>C), RS1000313627 (6:151242669 C>T), RS1000325249 (6:151281536 A>G), RS1000328435 (6:151299438 C>T)

Disease associations

OMIM: gene MIM:604698 | disease phenotypes: MIM:189800, MIM:612863

GenCC curated gene-disease

Mondo (2): preeclampsia (MONDO:0005081), chromosome 6q24-q25 deletion syndrome (MONDO:0013025)

Orphanet (2): Preeclampsia (Orphanet:275555), 6q25.2q25.3 microdeletion syndrome (Orphanet:251056)

HPO phenotypes

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

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST001063_1	Chronic myeloid leukemia	2.000000e-06
GCST002806_8	Type 2 diabetes	2.000000e-07
GCST005194_140	Coronary artery disease	2.000000e-06
GCST005851_23	Delirium	3.000000e-06
GCST006136_6	Alzheimer’s disease progression score	4.000000e-06
GCST006979_701	Heel bone mineral density	2.000000e-09
GCST006988_124	Blond vs. brown/black hair color	5.000000e-13
GCST006989_31	Brown vs. black hair color	1.000000e-09
GCST010002_338	Refractive error	5.000000e-20
GCST010302_36	Cutaneous melanoma or hair colour	2.000000e-42
GCST010303_49	Nevus count or cutaneous melanoma	8.000000e-10
GCST010304_48	Cutaneous malignant melanoma	8.000000e-08
GCST011011_48	Youthful appearance (self-reported)	4.000000e-10
GCST011011_66	Youthful appearance (self-reported)	2.000000e-20
GCST012490_184	Femur bone mineral density x serum urate levels interaction	3.000000e-08

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0006514	Alzheimer’s disease biomarker measurement
EFO:0009270	heel bone mineral density
EFO:0003924	hair color
EFO:0004632	nevus count
EFO:0004531	urate measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D011225	Pre-Eclampsia	C12.050.703.395.249

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295800 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

120 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases methylation, increases expression	9
bisphenol A	affects expression, decreases expression, affects cotreatment	5
trichostatin A	decreases expression, increases expression, affects cotreatment, affects expression, affects methylation	5
Valproic Acid	affects expression, increases expression, increases methylation	4
Cyclosporine	increases expression	4
Aflatoxin B1	affects expression, decreases methylation, increases expression	4
Cadmium Chloride	increases expression, decreases expression, increases abundance	4
bisphenol F	increases expression, decreases expression, affects cotreatment, increases methylation	3
sodium arsenite	decreases expression, increases expression	3
Air Pollutants	decreases expression, increases expression, affects expression, increases abundance	3
Cisplatin	decreases expression, affects cotreatment, affects response to substance, affects reaction	3
Doxorubicin	affects response to substance, increases expression	3
Estradiol	affects cotreatment, decreases expression, increases expression	3
Particulate Matter	decreases expression, increases abundance, affects cotreatment, increases expression	3
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment	2
Decitabine	affects methylation, affects cotreatment, affects expression	2
Arsenic Trioxide	increases expression	2
Panobinostat	affects cotreatment, decreases expression	2
Calcitriol	affects cotreatment, increases expression	2
Folic Acid	decreases expression	2
Progesterone	affects cotreatment, decreases expression, increases expression	2
Silicon Dioxide	increases expression	2
Testosterone	affects cotreatment, decreases expression, increases expression	2
Tretinoin	increases expression	2
Asbestos, Serpentine	increases expression	2
FR900359	affects phosphorylation	1
methylmercuric chloride	decreases expression, increases expression	1
methyleugenol	increases expression	1
triphenyl phosphate	affects expression	1
glycidyl methacrylate	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118556	Binding	Binding affinity to AKAP12 in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00117546	PHASE4	UNKNOWN	Cardiovascular and Autonomic Reactivity in Women With a History of Pre-eclampsia
NCT00567957	PHASE4	UNKNOWN	Remifentanil for General Anesthesia in Preeclamptics
NCT01030627	PHASE4	COMPLETED	Treatment Approaches to Preeclampsia
NCT01352234	PHASE4	COMPLETED	Comparison of Doses of Acetylsalicylic Acid in Women With Previous History of Preeclampsia
NCT01361425	PHASE4	UNKNOWN	Anti-Hypertensive Treatment In Stable Pregnant Women With Severe Pre-Eclampsia (Metildopape)
NCT01729468	PHASE4	COMPLETED	Prevention of Pre-eclampsia and SGA by Low-Dose Aspirin in Nulliparous Women With Abnormal First-trimester Uterine Artery Dopplers
NCT01761916	PHASE4	COMPLETED	Clonidine Versus Captopril for Treatment of Postpartum Very High Blood Pressure
NCT01912677	PHASE4	COMPLETED	Oral Antihypertensive Regimens for Management of Hypertension in Pregnancy
NCT02025426	PHASE4	TERMINATED	Phenylephrine Versus Ephedrine in Pre-eclampsia
NCT02091401	PHASE4	COMPLETED	A Trial Comparing Treatment With the Springfusor Infusion Pump to the IV Magnesium Sulfate Regimen
NCT02163655	PHASE4	COMPLETED	Diuretics for Postpartum High Blood Pressure in Preeclampsia
NCT02338687	PHASE4	COMPLETED	Low Dose Calcium to Prevent Preeclampsia
NCT02396030	PHASE4	TERMINATED	Different Schemes of Magnesium Sulfate for Preeclampsia
NCT02531490	PHASE4	UNKNOWN	Early Vascular Adjustments During Hypertensive Pregnancy
NCT02699827	PHASE4	COMPLETED	Adding MgSO4 to Epidural Levobupivacaine in CS for Patients With Preeclampsia
NCT02835339	PHASE4	COMPLETED	Magnesium Sulfate in Obese Preeclamptics
NCT02891174	PHASE4	COMPLETED	The Effect of Ibuprofen on Post-partum Blood Pressure in Women With Hypertensive Disorders of Pregnancy
NCT02911701	PHASE4	COMPLETED	Effect of Acetaminophen on Postpartum Blood Pressure Control in Preeclampsia With Severe Features
NCT03171480	PHASE4	COMPLETED	Use of Nitrous Oxide Donor for Labor Induction in Women With PreEclampsia
NCT03233880	PHASE4	UNKNOWN	Impact of Antichlamydial Treatment on the Rate of Preeclampsia
NCT03237000	PHASE4	UNKNOWN	Effect of Administering Intravenous Magnesium Sulfate on Fetal Cardiotocography and Neonatal Outcome in Preeclamptic Patients
NCT03506724	PHASE4	COMPLETED	Response to Anti-hypertensives in Pregnant and Postpartum Patients
NCT03674606	PHASE4	COMPLETED	Trial of Early Screening Test for Pre-eclampsia and Growth Restriction
NCT03735433	PHASE4	TERMINATED	The Effect of Two Aspirin Dosing Strategies for Obese Women at High Risk for Preeclampsia
NCT03824119	PHASE4	UNKNOWN	Postpartum NSAIDS and Maternal Hypertension
NCT04051567	PHASE4	UNKNOWN	Low-dose Aspirin for Prevention of Adverse Pregnancy Outcomes in Twin Pregnancies
NCT04077853	PHASE4	COMPLETED	Progesterone in Expectantly Managed Early-onset Preeclampsia
NCT04158830	PHASE4	WITHDRAWN	Aspirin (ASA) Therapy and Preeclampsia Prevention
NCT04424693	PHASE4	UNKNOWN	Comparing the Incidence of Preeclampsia Between Pregnant Women Receiving Tdap Vaccinations at Week 28 or at Week 36
NCT04631627	PHASE4	UNKNOWN	Early Prediction and Randomised Prevention of Preeclampsia With Low Dose Aspirin in Chinese Cohort
NCT04656665	PHASE4	UNKNOWN	The Effectiveness of Aspirin on Preventing Pre-eclampsia
NCT04797949	PHASE4	WITHDRAWN	Adherence to Universal Aspirin Compared to Screening Indicated Aspirin for Prevention of Preeclampsia
NCT04908982	PHASE4	UNKNOWN	Aspirin for the Prevention of Preeclampsia in Women With Stage 1 Hypertension
NCT05221164	PHASE4	UNKNOWN	162 mg of Aspirin for Prevention of Preeclampsia
NCT05294952	PHASE4	UNKNOWN	co Ihibtory Receptor in Preeclampsia
NCT05514847	PHASE4	ACTIVE_NOT_RECRUITING	Low Dose Aspirin for Preterm Preeclampsia Preventionmg/day Dose in High-risk Patients
NCT05586373	PHASE4	COMPLETED	Ibuprofen vs Dipyrone After C-section in Preeclampsia
NCT06069102	PHASE4	COMPLETED	Optimal Blood Pressure Treatment Thresholds Postpartum
NCT06107335	PHASE4	NOT_YET_RECRUITING	Effect of Albumin Versus Routine Care on Hemodynamic Response and Stability in Patients With Preeclampsia Guided by a Non-invasive Hemodynamic Monitoring System During Cesarean Delivery With Spinal Anesthesia
NCT06281665	PHASE4	RECRUITING	Treatment With Aspirin After Preeclampsia: TAP Trial