RACGAP1

Summary

RACGAP1 (Rac GTPase activating protein 1, HGNC:9804) is a protein-coding gene on chromosome 12q13.12, encoding Rac GTPase-activating protein 1 (Q9H0H5). Component of the centralspindlin complex that serves as a microtubule-dependent and Rho-mediated signaling required for the myosin contractile ring formation during the cell cycle cytokinesis. It is a common-essential gene (DepMap: required in 99.5% of cancer cell lines).

This gene encodes a GTPase-activating protein (GAP) that is a compoment of the centralspindlin complex. This protein binds activated forms of Rho GTPases and stimulates GTP hydrolysis, which results in negative regulation of Rho-mediated signals. This protein plays a regulatory role in cytokinesis, cell growth, and differentiation. Alternatively spliced transcript variants have been found for this gene. There is a pseudogene for this gene on chromosome 12.

Source: NCBI Gene 29127 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Anemia, congenital dyserythropoietic, type IIIb, autosomal recessive (Limited, GenCC)
• Clinical variants (ClinVar): 96 total — 3 pathogenic
• Phenotypes (HPO): 24
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.5% of screened cell lines (common-essential)
• MANE Select transcript: NM_001319999

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9804
Approved symbol	RACGAP1
Name	Rac GTPase activating protein 1
Location	12q13.12
Locus type	gene with protein product
Status	Approved
Aliases	MgcRacGAP, CYK4
Ensembl gene	ENSG00000161800
Ensembl biotype	protein_coding
OMIM	604980
Entrez	29127

Gene structure

Transcript identifiers

Ensembl transcripts: 50 — 46 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000312377, ENST00000427314, ENST00000454520, ENST00000546595, ENST00000546723, ENST00000546764, ENST00000546786, ENST00000547061, ENST00000547905, ENST00000548158, ENST00000548247, ENST00000548320, ENST00000548598, ENST00000548644, ENST00000548824, ENST00000548961, ENST00000549342, ENST00000549777, ENST00000550149, ENST00000550651, ENST00000551016, ENST00000551145, ENST00000551260, ENST00000551876, ENST00000552004, ENST00000552157, ENST00000552310, ENST00000552921, ENST00000883727, ENST00000883728, ENST00000883729, ENST00000883730, ENST00000883731, ENST00000883732, ENST00000883733, ENST00000883734, ENST00000883735, ENST00000883736, ENST00000883737, ENST00000883738, ENST00000921797, ENST00000921798, ENST00000921799, ENST00000921800, ENST00000921801, ENST00000921802, ENST00000921803, ENST00000921804, ENST00000921805, ENST00000951108

RefSeq mRNA: 12 — MANE Select: NM_001319999 NM_001126103, NM_001126104, NM_001319999, NM_001320000, NM_001320001, NM_001320002, NM_001320003, NM_001320004, NM_001320005, NM_001320006, NM_001320007, NM_013277

CCDS: CCDS8795

Canonical transcript exons

ENST00000312377 — 17 exons

Exon	Start	End
ENSE00001060411	49994131	49994329
ENSE00001060414	49994414	49994509
ENSE00001114502	50004235	50004304
ENSE00001162785	49990684	49990792
ENSE00001162793	49991998	49992133
ENSE00001162799	49992245	49992377
ENSE00001162806	49992550	49992655
ENSE00001162819	49997040	49997204
ENSE00001650545	49989162	49990343
ENSE00002337834	50025398	50025494
ENSE00003495076	50002247	50002300
ENSE00003512257	49999141	49999271
ENSE00003573236	49999616	49999733
ENSE00003599562	50016631	50016719
ENSE00003686952	50006434	50006636
ENSE00003783986	50005256	50005392
ENSE00003790972	50001172	50001252

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 98.46.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 18.4825 / max 864.2320, expressed in 1721 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
130896	17.4871	1719
130895	0.9954	412

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
ventricular zone	UBERON:0003053	98.46	gold quality
ganglionic eminence	UBERON:0004023	96.12	gold quality
trabecular bone tissue	UBERON:0002483	96.01	gold quality
sperm	CL:0000019	95.40	gold quality
embryo	UBERON:0000922	93.39	gold quality
male germ cell	CL:0000015	93.35	gold quality
adult organism	UBERON:0007023	93.07	gold quality
secondary oocyte	CL:0000655	92.92	gold quality
oral cavity	UBERON:0000167	92.17	gold quality
bone marrow	UBERON:0002371	91.75	gold quality
amniotic fluid	UBERON:0000173	90.74	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	90.58	gold quality
esophagus squamous epithelium	UBERON:0006920	89.95	gold quality
right testis	UBERON:0004534	89.74	gold quality
testis	UBERON:0000473	89.68	gold quality
cartilage tissue	UBERON:0002418	89.58	gold quality
left testis	UBERON:0004533	89.53	gold quality
epithelium of esophagus	UBERON:0001976	89.40	gold quality
stromal cell of endometrium	CL:0002255	89.11	gold quality
bone marrow cell	CL:0002092	88.75	gold quality
colonic mucosa	UBERON:0000317	88.27	gold quality
squamous epithelium	UBERON:0006914	88.27	gold quality
mucosa of sigmoid colon	UBERON:0004993	88.18	gold quality
endothelial cell	CL:0000115	87.94	gold quality
gingival epithelium	UBERON:0001949	87.55	gold quality
gingiva	UBERON:0001828	87.51	gold quality
oocyte	CL:0000023	87.35	gold quality
rectum	UBERON:0001052	87.11	gold quality
cervix squamous epithelium	UBERON:0006922	86.86	gold quality
thymus	UBERON:0002370	86.81	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-MTAB-6819	yes	316.31
E-GEOD-99795	yes	192.71
E-ANND-3	yes	4.97

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CUX1, E2F1, ZHX2

miRNA regulators (miRDB)

64 targeting RACGAP1, 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-5011-5P	100.00	83.46	5820
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-512-3P	99.97	67.35	1049
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-518A-5P	99.70	69.01	2209
HSA-MIR-527	99.70	69.01	2209
HSA-MIR-519A-3P	99.67	71.67	1868
HSA-MIR-519B-3P	99.67	71.67	1868
HSA-MIR-519C-3P	99.67	71.67	1870

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.5% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• MKLP1 interacts with CYK4, a GTPase activating protein for the Rho GTPase, to form the centralspindlin complex. Centralspindlin is a key regulator of Rho function and microtubule organisation during cytokinesis, and is essential for cell division. (PMID:11782313)
• The plexin-B1/Rac interaction inhibits PAK activation and enhances Sema4D ligand binding (PMID:11937491)
• This enzyme is down-regulated by estradiol. (PMID:12493759)
• Expression of a GTPase-activating protein (GAP)-deficient mutant (R386A) of MgcRacGAP induces abnormal cortical activity during cytokinesis in U2OS cells. Multiple large blebs were observed in cells expressing MgcRacGAP R386A. (PMID:14729465)
• data reveal an important role for MgcRacGAP in STAT3 activation, and demonstrate that MgcRacGAP regulates IL-6-induced cellular differentiation in which STAT3 plays a pivotal role (PMID:15284113)
• MgcRacGAP regulates the activation and function of Cdc42 in mitosis. (PMID:15642749)
• H-Ras-specific activation of Rac-MKK3/6-p38 pathway has a role in invasion and migration of breast epithelial cells (PMID:15677464)
• intracellular Ca2+ is mobilized by sphingosine 1 phosphate and mediates rac activation and adherens junction assembly in endothelial cells (PMID:15728185)
• beta 2 chimerin has a role in rac-GAP-dependent inhibition of breast cancer cell proliferation (PMID:15863513)
• activation of Vav1-Rac signaling pathway by CXCL12 represents an important inside-out event controlling efficient up-regulation of alpha4beta1-dependent T lymphocyte adhesion (PMID:15872091)
• Cdk1 inactivation is sufficient to activate a signaling pathway leading to cytokinesis, which emanates from mitotic spindles and is regulated by ECT2, MgcRacGAP, and RhoA (PMID:16118207)
• MgcRacGAP controls the initiation of cytokinesis by regulating ECT2, which in turn induces the assembly of the contractile ring and triggers the ingression of the cleavage furrow (PMID:16129829)
• This study defines a cellular mechanism that links centralspindlin to Cep55, which, in turn, controls the midbody structure and membrane fusion at the terminal stage of cytokinesis. (PMID:16790497)
• These findings demonstrate that HIF-1alpha function is negatively affected by its interaction with MgcRacGAP. (PMID:17982282)
• report here that (i) MgcRacGAP is phosphorylated by Aurora B and Cdk1, (ii) PP2A dephosphorylates Aurora B and Cdk1 phosphorylated sites and (iii) inhibition of PP2A abrogates MgcRacGAP/Ect2 interaction (PMID:18201571)
• Study demonstrates that FIP3 and ECT2 form mutually exclusive complexes with Cyk-4 and that dissociation of ECT2 from the mid-body at late telophase may be required for the recruitment of FIP3 and recycling endosomes to the cleavage furrow. (PMID:18511905)
• study reports that mitotic complex genes Ect2, RacGAP, and MKLP1 are coordinately induced in S phase in proliferating T lymphocytes as well as in epithelial cells, depending upon activity of the CUX1 and E2F1 transcription factors (PMID:19015243)
• the level of RACGAP1 expression is sufficient to predict the early recurrence of HCC. (PMID:21825042)
• several Rho family small GTPases activate PI3K by an indirect cooperative positive feedback that required a combination of Rac, CDC42, and RhoG small GTPase activities (PMID:22683270)
• results support the view that CYK4 is a crucial regulator of Rac1 in adherent cells and that inhibition of Rac1-dependent effector pathways in anaphase is needed for cytokinesis (PMID:22945935)
• High RACGAP1 mRNA expression (above the median) was associated with poor disease-free survival and overall survival in high risk early breast cancer (PMID:23096218)
• In untreated patients, Ki67, TOP2A, and RacGAP1 are significant and independent prognostic markers. (PMID:23135572)
• RACGAP1 and MCRS1 overexpression in nonsmall-cell lung cancer.RACGAP1 and MCRS1 may be cancer-related genes in NSCLC. (PMID:23225332)
• High expression of RACGAP1 is associated with meningiomas. (PMID:23525949)
• The crystal structure of the GAP domain of MgcRacGAP has been determined at a resolution of 1.9A; MgcRacGAP (residues 348-546) exists as a monomer in solution. (PMID:23665020)
• APC(CDH1) targets MgcRacGAP for destruction in the late M phase. (PMID:23696789)
• RacGAP1 expression at the invasive front in gastric cancer was significantly correlated with factors reflecting tumor progression and poor prognosis.RACGAP1 gene expression in diffuse type gastric cancer was elevated. (PMID:24615626)
• MgcRacGAP colocalizes with CGN and CGNL1 at TJs and forms a complex and interacts directly in vitro with CGN and CGNL1. (PMID:24807907)
• We show that some are new substrates of the anaphase-promoting complex/cyclosome and validate KIFC1 and RacGAP1/Cyk4 as two such targets involved respectively in timely mitotic spindle disassembly and cell spreading (PMID:24857844)
• HCV viral protein NS5B polymerase activity was significantly reduced by silencing RacGAP1 and, vice versa, was increased by overexpression of RacGAP1 in a cell-based reporter assay. (PMID:25305482)
• RacGAP1 mediated endothelial barrier function loss and melanoma transmigration in a focal adhesion-dependent manner.RacGAP1 activation mediates focal adhesion assembly and actin stress fiber formation. (PMID:25475728)
• central spindle assembly and 2 Plk1-dependent phosphorylations are required to establish efficient binding of the Ect2 BRCT in early cytokinesis. (PMID:25486482)
• High RacGAP1 expression was an independent predictive marker for lymph node metastasis, recurrence and poor prognosis in colorectal cancer patients. (PMID:25568185)
• RacGAP1 Is a Novel Downstream Effector of E2F7-Dependent Resistance to Doxorubicin and Is Prognostic for Overall Survival in Squamous Cell Carcinoma (PMID:26018753)
• RACGAP1 expression levels in the nucleus and cytoplasm, determined by immunohistochemical staining, predict opposite clinical outcomes and that both could be independent prognostic markers for colorectal cancer. (PMID:26508373)
• Data confirmed a strong correlation of AURKA and Wnt-modulator RACGAP1 gene expression both in the gastric tumor, the tumor-adjacent and the tumor-distant mucosa. (PMID:26778597)
• RACGAP1 promotes the metastatic phenotype in uterine carcinosarcoma via a STAT3/survivin signaling pathway. (PMID:27121792)
• High RACGAP1 expression is associated with Basal-like Breast Cancers. (PMID:27216196)
• Data show that comparing with Ki-67 and TOP2A, RacGAP1 allowed for a clearer prognostic statement. (PMID:27259241)
• This study showed that the overexpressions of Ki67, RacGAP1, and TOP2a affect the prognosis of female breast cancer patients adversely (PMID:27284123)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	racgap1	ENSDARG00000015460
mus_musculus	Racgap1	ENSMUSG00000023015
rattus_norvegicus	Racgap1	ENSRNOG00000049033
drosophila_melanogaster	RhoGAP15B	FBGN0030808
drosophila_melanogaster	RacGAP84C	FBGN0045843
drosophila_melanogaster	tum	FBGN0086356
caenorhabditis_elegans		WBGENE00000875
caenorhabditis_elegans		WBGENE00010374

Protein

Protein identifiers

Rac GTPase-activating protein 1 — Q9H0H5 (reviewed: Q9H0H5)

Alternative names: Male germ cell RacGap, Protein CYK4 homolog

All UniProt accessions (22): Q9H0H5, F8VQF5, F8VQZ5, F8VRD2, F8VRL2, F8VS54, F8VUW9, F8VV37, F8VV39, F8VV47, F8VVE5, F8VVY0, F8VWX0, F8VWY4, F8VXH1, F8VYH6, F8VZ41, F8VZ66, F8W0L1, F8W1E5, F8W1T4, H0YIK5

UniProt curated annotations — full annotation on UniProt →

Function. Component of the centralspindlin complex that serves as a microtubule-dependent and Rho-mediated signaling required for the myosin contractile ring formation during the cell cycle cytokinesis. Required for proper attachment of the midbody to the cell membrane during cytokinesis. Sequentially binds to ECT2 and RAB11FIP3 which regulates cleavage furrow ingression and abscission during cytokinesis. Plays key roles in controlling cell growth and differentiation of hematopoietic cells through mechanisms other than regulating Rac GTPase activity. Has a critical role in erythropoiesis. Also involved in the regulation of growth-related processes in adipocytes and myoblasts. May be involved in regulating spermatogenesis and in the RACGAP1 pathway in neuronal proliferation. Shows strong GAP (GTPase activation) activity towards CDC42 and RAC1 and less towards RHOA. Essential for the early stages of embryogenesis. May play a role in regulating cortical activity through RHOA during cytokinesis. May participate in the regulation of sulfate transport in male germ cells.

Subunit / interactions. Heterotetramer of two molecules each of RACGAP1 and KIF23. Found in the centralspindlin complex. Associates with alpha-, beta- and gamma-tubulin and microtubules. Interacts via its Rho-GAP domain with RND2. Associates with AURKB during M phase. Interacts via its Rho-GAP domain and basic region with PRC1. The interaction with PRC1 inhibits its GAP activity towards CDC42 in vitro, which may be required for maintaining normal spindle morphology. Interacts with SLC26A8 via its N-terminus. Interacts with ECT2; the interaction is direct, occurs at anaphase and during cytokinesis in a microtubule-dependent manner, is enhanced by phosphorylation by PLK1 and phosphorylation at Ser-164 plays a major role in mediating binding. Interacts with RAB11FIP3; the interaction occurs at late telophase. Interacts with KIF23; the interaction is direct.

Subcellular location. Nucleus. Cytoplasm. Cytoskeleton. Spindle. Cytoplasmic vesicle. Secretory vesicle. Acrosome. Cleavage furrow. Midbody. Midbody ring. Cell membrane.

Tissue specificity. Highly expressed in testis, thymus and placenta. Expressed at lower levels in spleen and peripheral blood lymphocytes. In testis, expression is restricted to germ cells with the highest levels of expression found in spermatocytes. Expression is regulated in a cell cycle-dependent manner and peaks during G2/M phase.

Post-translational modifications. Phosphorylated at multiple sites in the midbody during cytokinesis. Phosphorylation by AURKB on Ser-387 at the midbody is, at least in part, responsible for exerting its latent GAP activity towards RhoA. Phosphorylation on multiple serine residues by PLK1 enhances its association with ECT2 and is critical for cleavage furrow formation. Phosphorylation on Ser-164 plays a major role in mediating interaction with ECT2. Phosphorylation on Ser-157 does not appear to contribute to binding to ECT2.

Disease relevance. Anemia, congenital dyserythropoietic, 3B, autosomal recessive (CDAN3B) [MIM:619789] An autosomal recessive blood disorder characterized by marked dyserythropoiesis, hemolytic anemia, macrocytosis in the peripheral blood, and giant multinucleated erythroblasts in the bone marrow. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The coiled coil region is indispensible for localization to the midbody during cytokinesis. The phorbol-ester/DAG-type zinc finger domain mediates interaction with membranes enriched in phosphatidylinositol 3,4,5-trisphosphate and is required during mitotic cytokinesis for normal attachment of the midbody to the cell membrane.

Induction. Expression is down-regulated during macrophage differention of HL-60 cells.

RefSeq proteins (12): NP_001119575, NP_001119576, NP_001306928, NP_001306929, NP_001306930, NP_001306931, NP_001306932, NP_001306933, NP_001306934, NP_001306935, NP_001306936, NP_037409 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000198	RhoGAP_dom	Domain
IPR002219	PKC_DAG/PE	Domain
IPR008936	Rho_GTPase_activation_prot	Homologous_superfamily
IPR046349	C1-like_sf	Homologous_superfamily

Pfam: PF00130, PF00620

UniProt features (78 total): modified residue 23, helix 13, mutagenesis site 12, turn 6, strand 5, compositionally biased region 4, region of interest 4, cross-link 2, sequence variant 2, sequence conflict 2, chain 1, domain 1, site 1, zinc finger region 1, coiled-coil region 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
5C2K	X-RAY DIFFRACTION	1.42
2OVJ	X-RAY DIFFRACTION	1.49
3WPQ	X-RAY DIFFRACTION	1.84
3W6R	X-RAY DIFFRACTION	1.9
4B6D	X-RAY DIFFRACTION	2.2
5C2J	X-RAY DIFFRACTION	2.5
3WPS	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H0H5-F1	70.66	0.36

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): 385 (arginine finger; crucial for gtp hydrolysis by stabilizing the transition state)

Post-translational modifications (25): 1, 149, 154, 157, 161, 164, 170, 203, 206, 214, 249, 257, 260, 342, 387, 410, 567, 580, 588, 600 …

Mutagenesis-validated functional residues (12):

Position	Phenotype
149	does not inhibit interaction with ect2. strongly reduces phosphorylation, inhibits interaction with ect2 and cleavage fu
157	does not inhibit interaction with ect2. strongly reduces phosphorylation, inhibits interaction with ect2 and cleavage fu
164	does not inhibit interaction with ect2. strongly reduces phosphorylation, inhibits interaction with ect2 and cleavage fu
167	more than 20-fold reduction in binding to ect2.
170	does not inhibit interaction with ect2. strongly reduces phosphorylation, inhibits interaction with ect2 and cleavage fu
214	strongly reduces phosphorylation by plk1, inhibits interaction with ect2 and cleavage furrow formation; when associated
289	cytokinesis failure.
292	cytokinesis failure. abolishes localization at the cell membrane.
306	cytokinesis failure. abolishes localization at the cell membrane.
309	cytokinesis failure. abolishes localization at the cell membrane.
316	cytokinesis failure.
385	abolishes gap activity towards rac1. abolishes gap activity towards cdc42 in prometaphase. abolishes gap activity toward

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-2132295	MHC class II antigen presentation
R-HSA-6811434	COPI-dependent Golgi-to-ER retrograde traffic
R-HSA-8980692	RHOA GTPase cycle
R-HSA-9013026	RHOB GTPase cycle
R-HSA-9013106	RHOC GTPase cycle
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-9013149	RAC1 GTPase cycle
R-HSA-9013404	RAC2 GTPase cycle
R-HSA-9013405	RHOD GTPase cycle
R-HSA-9013423	RAC3 GTPase cycle
R-HSA-983189	Kinesins

MSigDB gene sets: 515 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_MITOTIC_CYTOKINESIS, GOBP_CHROMOSOME_ORGANIZATION, WU_APOPTOSIS_BY_CDKN1A_VIA_TP53, GOBP_ATTACHMENT_OF_SPINDLE_MICROTUBULES_TO_KINETOCHORE, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, HORIUCHI_WTAP_TARGETS_DN, GOBP_MYELOID_CELL_HOMEOSTASIS, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, PAL_PRMT5_TARGETS_UP, GOCC_SECRETORY_GRANULE, OHASHI_AURKB_TARGETS, GOBP_CHROMOSOME_LOCALIZATION, WANG_RECURRENT_LIVER_CANCER_UP

GO Biological Process (16): mitotic cytokinesis (GO:0000281), actomyosin contractile ring assembly (GO:0000915), monoatomic ion transport (GO:0006811), Rho protein signal transduction (GO:0007266), spermatogenesis (GO:0007283), neuroblast proliferation (GO:0007405), erythrocyte differentiation (GO:0030218), positive regulation of cytokinesis (GO:0032467), regulation of embryonic development (GO:0045995), regulation of small GTPase mediated signal transduction (GO:0051056), mitotic spindle midzone assembly (GO:0051256), regulation of attachment of spindle microtubules to kinetochore (GO:0051988), sulfate transmembrane transport (GO:1902358), signal transduction (GO:0007165), cell differentiation (GO:0030154), cell division (GO:0051301)

GO Molecular Function (12): GTPase activator activity (GO:0005096), phosphatidylinositol-3,4,5-trisphosphate binding (GO:0005547), microtubule binding (GO:0008017), zinc ion binding (GO:0008270), protein kinase binding (GO:0019901), protein-macromolecule adaptor activity (GO:0030674), alpha-tubulin binding (GO:0043014), gamma-tubulin binding (GO:0043015), beta-tubulin binding (GO:0048487), protein binding (GO:0005515), lipid binding (GO:0008289), metal ion binding (GO:0046872)

GO Cellular Component (20): acrosomal vesicle (GO:0001669), nucleus (GO:0005634), nucleoplasm (GO:0005654), mitochondrion (GO:0005739), spindle (GO:0005819), cytosol (GO:0005829), microtubule (GO:0005874), cytoplasmic side of plasma membrane (GO:0009898), midbody (GO:0030496), cleavage furrow (GO:0032154), spindle midzone (GO:0051233), extracellular exosome (GO:0070062), mitotic spindle (GO:0072686), Flemming body (GO:0090543), centralspindlin complex (GO:0097149), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
RHO GTPase cycle	8
Adaptive Immune System	1
Golgi-to-ER retrograde transport	1
Factors involved in megakaryocyte development and platelet production	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
tubulin binding	4
cytoplasm	3
mitotic cell cycle process	2
small GTPase-mediated signal transduction	2
cellular process	2
binding	2
intracellular membrane-bounded organelle	2
microtubule cytoskeleton	2
intracellular membraneless organelle	2
spindle	2
mitotic cell cycle	1
cytoskeleton-dependent cytokinesis	1
assembly of actomyosin apparatus involved in cytokinesis	1
actomyosin contractile ring organization	1
transport	1
developmental process involved in reproduction	1
male gamete generation	1
generation of neurons	1
neural precursor cell proliferation	1
myeloid cell differentiation	1
erythrocyte homeostasis	1
cytokinesis	1
regulation of cytokinesis	1
positive regulation of cell division	1
positive regulation of cell cycle process	1
embryo development	1
regulation of multicellular organismal development	1
regulation of intracellular signal transduction	1
mitotic spindle elongation	1
spindle midzone assembly	1
mitotic spindle assembly	1
mitotic nuclear division	1
attachment of spindle microtubules to kinetochore	1
regulation of cell cycle process	1
inorganic anion transport	1
transmembrane transport	1
sulfur compound transport	1
cell communication	1
signaling	1

Protein interactions and networks

STRING

2318 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RACGAP1	KIF23	Q02241	999
RACGAP1	ECT2	Q9H8V3	999
RACGAP1	ANLN	Q9NQW6	990
RACGAP1	IQGAP1	P46940	937
RACGAP1	SLC26A8	Q96RN1	932
RACGAP1	CGN	Q9P2M7	919
RACGAP1	AURKB	Q96GD4	873
RACGAP1	CGNL1	Q0VF96	839
RACGAP1	RHOA	P06749	837
RACGAP1	CDK1	P06493	833
RACGAP1	MIS18BP1	Q6P0N0	809
RACGAP1	CEP55	Q53EZ4	804
RACGAP1	RASA1	P20936	763
RACGAP1	PLK1	P53350	761
RACGAP1	CCNB1	P14635	757

IntAct

175 interactions, top by confidence:

A	B	Type	Score
GRB2	EGFR	psi-mi:“MI:0914”(association)	0.980
RACGAP1	KIF23	psi-mi:“MI:0914”(association)	0.920
KIF23	RACGAP1	psi-mi:“MI:0915”(physical association)	0.920
RACGAP1	KIF23	psi-mi:“MI:0915”(physical association)	0.920
RACGAP1	KIF23	psi-mi:“MI:0403”(colocalization)	0.920
KIF23	RACGAP1	psi-mi:“MI:0403”(colocalization)	0.920
YWHAG	RACGAP1	psi-mi:“MI:0915”(physical association)	0.900
ECT2	RACGAP1	psi-mi:“MI:0407”(direct interaction)	0.880
ECT2	RACGAP1	psi-mi:“MI:0915”(physical association)	0.880
RACGAP1	ECT2	psi-mi:“MI:0915”(physical association)	0.880
YWHAQ	WDR62	psi-mi:“MI:0914”(association)	0.830
YWHAB	RACGAP1	psi-mi:“MI:0915”(physical association)	0.810
PLK1	RACGAP1	psi-mi:“MI:0217”(phosphorylation reaction)	0.710
PLK1	RACGAP1	psi-mi:“MI:0407”(direct interaction)	0.710

BioGRID (292): RACGAP1 (Two-hybrid), RACGAP1 (Affinity Capture-MS), PSMD1 (Co-fractionation), RACGAP1 (Co-fractionation), RACGAP1 (Co-fractionation), RACGAP1 (Co-fractionation), RACGAP1 (Co-fractionation), RACGAP1 (Co-fractionation), RACGAP1 (Co-fractionation), RACGAP1 (Affinity Capture-MS), RACGAP1 (Proximity Label-MS), RACGAP1 (Affinity Capture-MS), AKT2 (Affinity Capture-MS), ENTPD6 (Affinity Capture-MS), DLG3 (Affinity Capture-MS)

ESM2 similar proteins: A2CEA7, A4IF90, B0S6J3, D3ZGS3, D4A208, F1LYQ8, F1M386, F1MSG6, F1P065, F1PBJ0, G5EDB9, H2KZZ6, O14827, O43295, O43307, O75044, P27671, P28818, P46941, P70392, Q13972, Q15057, Q3UTH8, Q45FX5, Q53QZ3, Q58DL7, Q5DU57, Q5FVC7, Q5ZMM3, Q6AYC5, Q6IVG4, Q6ZQK5, Q7Z6B7, Q811M1, Q812A2, Q8C0D4, Q8CHG7, Q8IWW6, Q8T0G4, Q8TEU7

Diamond homologs: A0A0G2JTR4, A1A4S6, A2AB59, A2RUV4, A4IF90, A4II46, A6QNS3, A6X8Z5, A7KAX9, A7YY57, A8WRJ2, D3ZFJ3, E7EZG2, E7F3F0, F1LXF1, O14559, O94466, P11274, P15882, P30337, P34288, P38339, P46941, P52757, P55194, P81128, P97393, Q03070, Q08DP6, Q10164, Q12979, Q13017, Q15311, Q17QN0, Q20498, Q2M1Z3, Q3TBD2, Q3UIA2, Q52LW3, Q53QZ3

SIGNOR signaling

13 interactions.

A	Effect	B	Mechanism
AURKB	“up-regulates activity”	RACGAP1	phosphorylation
PPP2CA	down-regulates	RACGAP1	dephosphorylation
PLK1	up-regulates	RACGAP1	phosphorylation
RACGAP1	“down-regulates activity”	RAC1	“gtpase-activating protein”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 139 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	10	76.3×	6e-15
Activation of BAD and translocation to mitochondria	7	60.6×	2e-09
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	53.4×	4e-09
Activation of BH3-only proteins	7	39.5×	2e-08
RHO GTPases activate PKNs	8	28.8×	2e-08
Intrinsic Pathway for Apoptosis	7	23.3×	9e-07
RAF activation	5	19.1×	1e-04
FOXO-mediated transcription	5	19.1×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
regulation of cytokinesis	5	18.3×	3e-03
protein targeting	5	15.9×	4e-03
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	5	14.7×	4e-03
G2/M transition of mitotic cell cycle	5	13.6×	5e-03
intracellular protein localization	11	10.0×	1e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	60
Likely benign	2
Benign	14

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1344519	NM_001319999.2(RACGAP1):c.1187T>A (p.Leu396Gln)	Pathogenic
1344520	NM_001319999.2(RACGAP1):c.1294C>T (p.Pro432Ser)	Pathogenic
1693582	NM_001319999.2(RACGAP1):c.658A>G (p.Thr220Ala)	Pathogenic

SpliceAI

2657 predictions. Top by Δscore:

Variant	Effect	Δscore
12:49990807:C:CT	acceptor_gain	1.0000
12:49990808:A:AC	acceptor_gain	1.0000
12:49990808:A:C	acceptor_gain	1.0000
12:49990810:A:C	acceptor_gain	1.0000
12:49990811:T:C	acceptor_gain	1.0000
12:49990811:T:TC	acceptor_gain	1.0000
12:49990812:T:C	acceptor_gain	1.0000
12:49990812:T:TC	acceptor_gain	1.0000
12:49990814:T:TC	acceptor_gain	1.0000
12:49990823:G:GC	acceptor_gain	1.0000
12:49991992:CCTTA:C	donor_loss	1.0000
12:49991993:CTTA:C	donor_loss	1.0000
12:49991994:TTACC:T	donor_loss	1.0000
12:49991995:TA:T	donor_loss	1.0000
12:49991997:C:A	donor_loss	1.0000
12:49992130:CCAC:C	acceptor_gain	1.0000
12:49992131:CAC:C	acceptor_gain	1.0000
12:49992131:CACC:C	acceptor_gain	1.0000
12:49992133:CCT:C	acceptor_loss	1.0000
12:49992240:CCTA:C	donor_loss	1.0000
12:49992241:CTAC:C	donor_loss	1.0000
12:49992242:TACC:T	donor_loss	1.0000
12:49992244:C:A	donor_loss	1.0000
12:49992373:CCACT:C	acceptor_gain	1.0000
12:49992374:CACT:C	acceptor_gain	1.0000
12:49992374:CACTC:C	acceptor_gain	1.0000
12:49992375:ACTC:A	acceptor_loss	1.0000
12:49992376:CT:C	acceptor_gain	1.0000
12:49992378:C:CC	acceptor_gain	1.0000
12:49992383:C:CT	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000092464 (12:50003901 G>A), RS1000103178 (12:49991647 C>T), RS1000419559 (12:50006126 G>A), RS1000464770 (12:50004133 A>T), RS1000580857 (12:50029998 C>A), RS1000728399 (12:50019619 A>G,T), RS1000821209 (12:49990500 A>C,T), RS1000936008 (12:50011504 A>G), RS1000969016 (12:49993079 T>A), RS1001009319 (12:50018088 G>A), RS1001090765 (12:49988869 T>G), RS1001106347 (12:49993454 T>C), RS1001120777 (12:50029771 T>C), RS1001245533 (12:50005159 A>G), RS1001270408 (12:50005677 A>G)

Disease associations

OMIM: gene MIM:604980 | disease phenotypes: MIM:619789

GenCC curated gene-disease

Disease	Classification	Inheritance
Anemia, congenital dyserythropoietic, type IIIb, autosomal recessive	Limited	Autosomal recessive

Mondo (1): Anemia, congenital dyserythropoietic, type IIIb, autosomal recessive (MONDO:0030711)

Orphanet (0):

HPO phenotypes

24 total (24 of 24 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000225	Gingival bleeding
HP:0000980	Pallor
HP:0001877	Abnormal erythrocyte morphology
HP:0001903	Anemia
HP:0001972	Macrocytic anemia
HP:0002249	Melena
HP:0002315	Headache
HP:0002904	Hyperbilirubinemia
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0003452	Increased circulating iron concentration
HP:0004322	Short stature
HP:0004447	Poikilocytosis
HP:0005518	Increased mean corpuscular volume
HP:0005532	Macrocytic dyserythropoietic anemia
HP:0011273	Anisocytosis
HP:0011463	Childhood onset
HP:0011891	Post-partum hemorrhage
HP:0012130	Abnormal erythroid lineage cell morphology
HP:0012378	Fatigue
HP:0025035	Abnormal proerythroblast morphology
HP:0025196	Increased total iron binding capacity
HP:0025354	Abnormal cellular phenotype
HP:0030140	Oral cavity bleeding

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL2146306 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, affects cotreatment, increases abundance, increases expression	4
Cyclosporine	decreases expression	4
Doxorubicin	decreases expression, affects response to substance	3
Estradiol	increases expression	3
bisphenol A	decreases expression, increases expression	2
Resveratrol	affects cotreatment, increases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
Arsenic	affects cotreatment, decreases expression, increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Cadmium	decreases expression	2
Coumestrol	affects cotreatment, increases expression, affects reaction	2
Valproic Acid	affects expression, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
TAK-243	increases sumoylation	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
geraniol	decreases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, decreases reaction	1
afimoxifene	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
nickel chloride	increases expression	1
zinc chromate	decreases expression, increases abundance	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	increases expression, affects cotreatment	1
coumarin	decreases phosphorylation	1
cupric oxide	decreases expression	1
methacrylaldehyde	increases oxidation, increases abundance, affects cotreatment	1
diallyl trisulfide	decreases expression	1
M-VAC protocol	increases response to substance	1

ChEMBL screening assays

1 unique, capped per target: 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2114881	Functional	PubChem BioAssay. Discovery of small molecule inhibitors of the oncogenic and cytokinetic protein MgcRacGAP - Primary and Confirmatory Screens. (Class of assay: confirmatory)	PubChem BioAssay data set

Clinical trials (associated diseases)

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