RHOA

Summary

RHOA (ras homolog family member A, HGNC:667) is a protein-coding gene on chromosome 3p21.31, encoding Transforming protein RhoA (P61586). Small GTPase which cycles between an active GTP-bound and an inactive GDP-bound state. It is a selective cancer dependency (DepMap: 40.9% of cell lines).

This gene encodes a member of the Rho family of small GTPases, which cycle between inactive GDP-bound and active GTP-bound states and function as molecular switches in signal transduction cascades. Rho proteins promote reorganization of the actin cytoskeleton and regulate cell shape, attachment, and motility. Overexpression of this gene is associated with tumor cell proliferation and metastasis. Multiple alternatively spliced variants have been identified.

Source: NCBI Gene 387 — RefSeq curated summary.

At a glance

• Gene–disease (curated): ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies (Limited, GenCC)
• GWAS associations: 23
• Clinical variants (ClinVar): 33 total — 3 pathogenic, 1 likely-pathogenic
• Phenotypes (HPO): 32
• Druggable target: yes
• Cancer driver (intOGen): activating (oncogene-like) across 10 cancer types
• Cancer dependency (DepMap): dependent in 40.9% of screened cell lines
• MANE Select transcript: NM_001664

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:667
Approved symbol	RHOA
Name	ras homolog family member A
Location	3p21.31
Locus type	gene with protein product
Status	Approved
Aliases	Rho12, RHOH12
Ensembl gene	ENSG00000067560
Ensembl biotype	protein_coding
OMIM	165390
Entrez	387

Gene structure

Transcript identifiers

Ensembl transcripts: 32 — 29 protein_coding, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000265538, ENST00000418115, ENST00000422781, ENST00000431929, ENST00000445425, ENST00000454011, ENST00000676712, ENST00000677684, ENST00000678200, ENST00000678921, ENST00000679208, ENST00000880080, ENST00000880081, ENST00000880082, ENST00000880083, ENST00000880084, ENST00000880085, ENST00000918056, ENST00000918057, ENST00000918058, ENST00000918059, ENST00000918060, ENST00000918061, ENST00000918062, ENST00000918063, ENST00000918064, ENST00000918065, ENST00000918066, ENST00000960736, ENST00000960737, ENST00000960738, ENST00000960739

RefSeq mRNA: 7 — MANE Select: NM_001664 NM_001313941, NM_001313943, NM_001313944, NM_001313945, NM_001313946, NM_001313947, NM_001664

CCDS: CCDS2795, CCDS82774, CCDS82775, CCDS93276

Canonical transcript exons

ENST00000418115 — 5 exons

Exon	Start	End
ENSE00000861567	49368428	49368548
ENSE00001617266	49411820	49411976
ENSE00001954909	49359145	49360382
ENSE00003548163	49362496	49362626
ENSE00003765190	49375434	49375591

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.61.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 540.7121 / max 11146.3773, expressed in 1828 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
42260	529.0472	1828
42261	11.2113	1709
42259	0.4536	224

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.61	gold quality
leukocyte	CL:0000738	99.61	gold quality
mononuclear cell	CL:0000842	99.61	gold quality
adult organism	UBERON:0007023	99.58	gold quality
skin of hip	UBERON:0001554	99.57	gold quality
popliteal artery	UBERON:0002250	99.57	gold quality
tibial artery	UBERON:0007610	99.57	gold quality
right lung	UBERON:0002167	99.56	gold quality
synovial joint	UBERON:0002217	99.56	gold quality
thymus	UBERON:0002370	99.56	gold quality
upper arm skin	UBERON:0004263	99.55	gold quality
trabecular bone tissue	UBERON:0002483	99.54	gold quality
aorta	UBERON:0000947	99.53	gold quality
ileal mucosa	UBERON:0000331	99.52	gold quality
left coronary artery	UBERON:0001626	99.52	gold quality
upper leg skin	UBERON:0004262	99.52	gold quality
right coronary artery	UBERON:0001625	99.51	gold quality
smooth muscle tissue	UBERON:0001135	99.50	gold quality
granulocyte	CL:0000094	99.49	gold quality
ascending aorta	UBERON:0001496	99.49	gold quality
thoracic aorta	UBERON:0001515	99.49	gold quality
descending thoracic aorta	UBERON:0002345	99.49	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.49	gold quality
oral cavity	UBERON:0000167	99.48	gold quality
mucosa of stomach	UBERON:0001199	99.48	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	99.47	gold quality
colonic mucosa	UBERON:0000317	99.47	gold quality
tibial nerve	UBERON:0001323	99.46	gold quality
coronary artery	UBERON:0001621	99.46	gold quality
urethra	UBERON:0000057	99.44	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	57.49
E-HCAD-5	yes	35.86
E-CURD-88	yes	20.66
E-CURD-122	yes	17.29
E-MTAB-10042	yes	16.82
E-MTAB-10137	no	4.59
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AHR, AP1, ARHGAP35, DRAM2, EP300, ESR1, FOS, LRRFIP1, MYC, MYF5, NCOA3, NFKBIA, OLIG2, PBX2, PITX2, PTTG1, SKP2, SMAD2, SMAD3, SSRP1, STAT1, STAT6, TCF3, TP53, ZBTB17, ZHX2, ZMIZ1

miRNA regulators (miRDB)

111 targeting RHOA, 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-98-3P	100.00	74.08	3907
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-518D-5P	100.00	67.51	979
HSA-MIR-518F-5P	100.00	67.51	979
HSA-MIR-520C-5P	100.00	67.51	979
HSA-MIR-526A-5P	100.00	67.51	979
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-3605-5P	99.96	67.12	932
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-6768-5P	99.92	67.36	1942
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-8067	99.86	69.59	2260

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 40.9% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Altogether, these results identify a mechanism by which RhoB but not RhoA antagonizes TGF-beta action through transcriptional down-regulation of AP1 in T beta R-II promoter. (PMID:11741970)
• Consequences of mevalonate depletion. Differential transcriptional, translational, and post-translational up-regulation (PMID:11788600)
• Expressed in myometrium (PMID:11818523)
• Our findings indicate that different signaling cascades resulting in the activation of RhoA… can modulate the exocytotic process of neuroendocrine cells. (PMID:11822867)
• role in sustaining integrin alphaIIbbeta3 adhesion contacts under high shear (PMID:11830597)
• inhibition of protein geranylgeranylation and RhoA pathways induce apoptosis in HUVEC and that induction of p53 or other proapoptotic proteins is required for this process (PMID:11839765)
• Data show that TGF-beta-induced rearrangements of the actin filament system required the activity of the Rho GTPases Cdc42 and RhoA, because ectopic expression of dominant negative mutant Cdc42 and RhoA abrogated the response. (PMID:11907271)
• Structural basis for the selective activation of Rho GTPases by Dbl exchange factors. (PMID:12006984)
• existence of a novel molecular mechanism by which Galpha(q) and the large family of G(q)-coupled receptors can regulate the activity of Rho and its downstream signaling pathways (PMID:12016230)
• Leukotriene D4 induces association of active RhoA with phospholipase C-gamma1 in intestinal epithelial cells. (PMID:12071848)
• RhoA play essential role in regulating the formation of dendritic processes by dendritic cell (PMID:12115629)
• cGMP-dependent protein kinase inhibits serum-response element-dependent transcription by inhibiting rho activation and functions (PMID:12119292)
• Data show that protein kinase C delta (PKC delta) is located downstream of RhoA and that active RhoA and PKCdelta are both necessary for leukotriene D(4)-induced stress-fibre formation. (PMID:12154081)
• These results demonstrate that Rho family small GTPases RhoA, Rac1 and Cdc42 are novel signal transducers for SP-stimulated IL-8 expression. (PMID:12169092)
• acted on by XPLN, a guanine nucleotide exchange factor (PMID:12221096)
• RhoA is a novel signal transducer for bacterial lipopolysaccharide-induced Toll-like receptor 4-mediated proinflammatory cytokine synthesis in monocytes. (PMID:12244193)
• These data indicate that Rho GTPases, most likely RhoA, play an important role in uterine epithelial RL95-2 cells for trophoblast binding, and suggest that RhoA may be involved in local signalling cascades during early embryo implantation in vivo. (PMID:12397214)
• Results suggest a novel mechanism of RA signaling, which involves activation of TGase and transamidation of RhoA. (PMID:12401808)
• a role for RhoA in mediating tumor metastasis independent of their affects on cell proliferation (PMID:12445208)
• basal release of NO is necessary to maintain RhoA expression and RhoA-dependent functions in vascular smooth muscle cells (PMID:12524425)
• RhoA signaling and cytoskeletal rearrangement are observed in prostate cancer cells, most likely the result of direct PAR1 and PAR2 activation by serine proteases thrombin and trypsin. (PMID:12534282)
• RhoA-mediated signaling may regulate different events in SCLC and NSCLC cells, including adhesion of SCLC cells and proliferation of NSCLC cells. (PMID:12579323)
• Data show that inhibition of endogenous RhoA, Rac1, and Cdc42 by their respective dominant negative mutants inhibits neurotensin-induced interleukin-8 protein production and promoter activity. (PMID:12584113)
• ADP-ribosylated form activates phospholipase D1 (PMID:12593858)
• RhoA activation plays an integral role in tissue factor expression in endothelial cells. (PMID:12692008)
• evidence that the small GTPases RhoA and Rac1, but not Cdc42, are directly associated with Tyk2 and PI3-K in an uPA/uPAR-dependent fashion and are necessary to mediate the uPA/uPAR-directed migration via the Tyk2/PI3-K signalling complex in human VSMC (PMID:12719789)
• Rho activation signals interaction of IP3R with TRPC1 at the plasma membrane of endothelial cells, and triggers Ca2+ entry following store depletion and the resultant increase in endothelial permeability (PMID:12766172)
• These findings show that vasodilator-stimulated phosphoprotein and diaphanous 1 function cooperatively downstream of Rho to control F-actin assembly and serum response factor activity. (PMID:12805219)
• Up-regulation of this protein is associated with tumor progression in ovarian carcinoma. (PMID:12808121)
• RhoA is involved in the control of the filamentous actin/monomeric actin balance through mDia, and this balance is critical for T cell responses. (PMID:12847276)
• RhoGAP-Rho chimeras specifically down-regulate RhoA, RhoB and RhoC activity and demonstrated that this approach may be applied to multiple human tumor cells to reverse the growth and/or invasion phenotypes associated with a distinct subtype of Rho GTPase (PMID:12939257)
• Rac1 and RhoA bind to adherens junctions and myosin light chain during formation of capillary vascular network (PMID:12972426)
• The reorganization of actins into podosomes is controlled by RHOA. (PMID:12972601)
• M-RIP can assemble a complex containing both RhoA and Myosin phosphatase myosin binding subunit, suggesting that M-RIP may play a role in myosin phosphatase regulation by RhoA (PMID:14506264)
• analysis of the interaction between the small G proteins Rac1 and RhoA and protein kinase C-related kinase 1 (PMID:14514689)
• RhoA binds to the amino terminus of (PMID:14581471)
• activation of Rho GTPases and coordinated rearrangement of F-actin within uterine epithelial cells in response to trophoblast binding are part of a generalized structural and functional reorganization of the cytoplasm. (PMID:14605490)
• actin and RhoA are involved in inhibition of tumor cell motility by antineoplastic agents (PMID:14612927)
• propose that RhoA triggers signalling pathways that, upregulating expression of a proteinase at specific membrane localizations, may confer an highly invasive phenotype to endothelial cells (PMID:14644158)
• Smurf1 links the Cdc42/Rac1-PAR6 polarity complex to degradation of RhoA in lamellipodia and filopodia to prevent RhoA signaling during dynamic membrane movements (PMID:14657501)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Rhoa	ENSMUSG00000007815
rattus_norvegicus	Rhoa	ENSRNOG00000050519
drosophila_melanogaster	Rho1	FBGN0014020

Paralogs (22): RHOBTB2 (ENSG00000008853), CDC42 (ENSG00000070831), RHOBTB1 (ENSG00000072422), RHOV (ENSG00000104140), RND2 (ENSG00000108830), RND3 (ENSG00000115963), RHOU (ENSG00000116574), RHOQ (ENSG00000119729), RHOJ (ENSG00000126785), RHOT1 (ENSG00000126858), RAC2 (ENSG00000128340), RAC1 (ENSG00000136238), RHOF (ENSG00000139725), RHOT2 (ENSG00000140983), RHOB (ENSG00000143878), RHOC (ENSG00000155366), RHOBTB3 (ENSG00000164292), RHOH (ENSG00000168421), RAC3 (ENSG00000169750), RND1 (ENSG00000172602), RHOD (ENSG00000173156), RHOG (ENSG00000177105)

Protein

Protein identifiers

Transforming protein RhoA — P61586 (reviewed: P61586)

Alternative names: Rho cDNA clone 12

All UniProt accessions (8): P61586, A0A024R324, A0A7I2V3G1, A0A7I2V5E6, A0A7I2YQV1, C9JNR4, C9JRM1, C9JX21

UniProt curated annotations — full annotation on UniProt →

Function. Small GTPase which cycles between an active GTP-bound and an inactive GDP-bound state. Mainly associated with cytoskeleton organization, in active state binds to a variety of effector proteins to regulate cellular responses such as cytoskeletal dynamics, cell migration and cell cycle. Regulates a signal transduction pathway linking plasma membrane receptors to the assembly of focal adhesions and actin stress fibers. Involved in a microtubule-dependent signal that is required for the myosin contractile ring formation during cell cycle cytokinesis. Plays an essential role in cleavage furrow formation. Required for the apical junction formation of keratinocyte cell-cell adhesion. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. The MEMO1-RHOA-DIAPH1 signaling pathway plays an important role in ERBB2-dependent stabilization of microtubules at the cell cortex. It controls the localization of APC and CLASP2 to the cell membrane, via the regulation of GSK3B activity. In turn, membrane-bound APC allows the localization of the MACF1 to the cell membrane, which is required for microtubule capture and stabilization. Involved in the reorientation of endothelial cells and their actin stress fibers in response to cellular mechantransduction-mediated activation by ARHGEF40. Regulates KCNA2 potassium channel activity by reducing its location at the cell surface in response to CHRM1 activation; promotes KCNA2 endocytosis. Acts as an allosteric activator of guanine nucleotide exchange factor ECT2 by binding in its activated GTP-bound form to the PH domain of ECT2 which stimulates the release of PH inhibition and promotes the binding of substrate RHOA to the ECT2 catalytic center. May be an activator of PLCE1. In neurons, involved in the inhibition of the initial spine growth. Upon activation by CaMKII, modulates dendritic spine structural plasticity by relaying CaMKII transient activation to synapse-specific, long-term signaling. Acts as a regulator of platelet alpha-granule release during activation and aggregation of platelets. When activated by DAAM1 may signal centrosome maturation and chromosomal segregation during cell division. May also be involved in contractile ring formation during cytokinesis. (Microbial infection) Serves as a target for the yopT cysteine peptidase from Yersinia pestis, vector of the plague.

Subunit / interactions. Interacts with ARHGEF28. Interacts (via GTP-bound form) with RIPOR1 (via N-terminus); this interaction links RHOA to STK24 and STK26 kinases. Interacts with RIPOR2 (via active GTP- or inactive GDP-bound forms) isoform 1 and isoform 2; these interactions are direct, block the loading of GTP to RHOA and decrease upon chemokine CCL19 stimulation in primary T lymphocytes. Binds PRKCL1, ROCK1 and ROCK2. Interacts with ARHGEF2, ARHGEF3, NET1 and RTKN. Interacts with PLCE1 and AKAP13. Interacts with DIAPH1. Interacts (in the constitutively activated, GTP-bound form) with DGKQ. Interacts with RACK1; enhances RHOA activation. Interacts with PKP4; the interaction is detected at the midbody. Interacts (GTP-bound form preferentially) with PKN2; the interaction stimulates autophosphorylation and phosphorylation of PKN2. Interacts with ARHGDIA; this interaction inactivates and stabilizes RHOA. Interacts with ARHGDIB. Interacts (GTP-bound form) with KCNA2 (via cytoplasmic N-terminal domain). Interacts (GTP-bound form) with ECT2; the interaction results in allosteric activation of ECT2. Interacts with RAP1GDS1; the interaction is direct and in a 1:1 stoichiometry. (Microbial infection) Interacts with yopT from Yersinia pestis. (Microbial infection) Interacts with human respiratory syncytial virus (HRSV) protein F; this interaction facilitates virus-induced syncytium formation.

Subcellular location. Cell membrane. Cytoplasm. Cytoskeleton. Cleavage furrow. Cell cortex. Midbody. Cell projection. Lamellipodium. Dendrite. Nucleus.

Post-translational modifications. (Microbial infection) Substrate for botulinum ADP-ribosyltransferase. (Microbial infection) Cleaved by yopT protease when the cell is infected by some Yersinia pathogens. This removes the lipid attachment, and leads to its displacement from plasma membrane and to subsequent cytoskeleton cleavage. (Microbial infection) AMPylation at Tyr-34 and Thr-37 are mediated by bacterial enzymes in case of infection by H.somnus and V.parahaemolyticus, respectively. AMPylation occurs in the effector region and leads to inactivation of the GTPase activity by preventing the interaction with downstream effectors, thereby inhibiting actin assembly in infected cells. It is unclear whether some human enzyme mediates AMPylation; FICD has such ability in vitro but additional experiments remain to be done to confirm results in vivo. (Microbial infection) Glycosylated at Tyr-34 by Photorhabdus asymbiotica toxin PAU_02230. Mono-O-GlcNAcylation by PAU_02230 inhibits downstream signaling by an impaired interaction with diverse regulator and effector proteins of Rho and leads to actin disassembly. (Microbial infection) Glucosylated at Thr-37 by C.difficile toxins TcdA and TcdB in the colonic epithelium. Monoglucosylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption and cell death, resulting in the loss of colonic epithelial barrier function. (Microbial infection) Glycosylated (O-GlcNAcylated) at Thr-37 by C.novyi toxin TcdA. O-GlcNAcylation completely prevents the recognition of the downstream effector, blocking the GTPases in their inactive form, leading to actin cytoskeleton disruption. (Microbial infection) Stearoylated By S.flexneri N-epsilon-fatty acyltransferase IcsB, thereby disrupting the host actin cytoskeleton. Phosphorylation by PRKG1 at Ser-188 inactivates RHOA signaling. Phosphorylation by SLK at Ser-188 in response to AGTR2 activation. Ubiquitinated by the BCR(KCTD13) and BCR(TNFAIP1) E3 ubiquitin ligase complexes, leading to its degradation by the proteasome, thereby regulating the actin cytoskeleton and synaptic transmission in neurons. Ubiquitinated at Lys-135 in a FBXL19-mediated manner; leading to proteasomal degradation. Serotonylation of Gln-63 by TGM2 during activation and aggregation of platelets leads to constitutive activation of GTPase activity.

Disease relevance. Ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies (EDFAOB) [MIM:618727] A neuroectodermal syndrome characterized by linear hypopigmentation, alopecia, apparently asymptomatic leukoencephalopathy, and facial, ocular, dental and acral anomalies. Patients show no intellectual or neurologic impairment. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Regulated by guanine nucleotide exchange factors (GEFs) which promote the exchange of bound GDP for free GTP, GTPase activating proteins (GAPs) which increase the GTP hydrolysis activity and GDP dissociation inhibitors which inhibit the dissociation of the nucleotide from the GTPase. Activated by GEFs such as ARHGEF2, ARHGEF3, ARHGEF28 and BCR. Activated by ARHGEF40 in response to mechanotransduction in endothelial cells. Inhibited by GAPs such as ARHGAP30. Inhibited by GDP dissociation inhibitors such as ARHGDIA.

Domain organisation. (Microbial infection) The basic-rich region is essential for yopT recognition and cleavage.

Similarity. Belongs to the small GTPase superfamily. Rho family.

RefSeq proteins (7): NP_001300870, NP_001300872, NP_001300873, NP_001300874, NP_001300875, NP_001300876, NP_001655* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001806	Small_GTPase	Family
IPR003578	Small_GTPase_Rho	Family
IPR005225	Small_GTP-bd	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF00071

Enzyme classification (BRENDA):

• EC 3.6.5.2 — small monomeric GTPase (BRENDA: 49 organisms, 138 substrates, 55 inhibitors, 5 Km, 1 kcat entries)

Substrate kinetics (BRENDA)

1 substrates with measured Km, best-characterized 1. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
GTP	—	0

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (60 total): strand 10, helix 10, mutagenesis site 9, modified residue 6, binding site 5, lipid moiety-binding region 4, turn 4, glycosylation site 3, sequence variant 2, chain 1, propeptide 1, region of interest 1, cross-link 1, short sequence motif 1, sequence conflict 1, site 1

Structure

Experimental structures (PDB)

131 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6V6U	X-RAY DIFFRACTION	1.16
5C4M	X-RAY DIFFRACTION	1.3
7G83	X-RAY DIFFRACTION	1.31
7G8T	X-RAY DIFFRACTION	1.39
6V6M	X-RAY DIFFRACTION	1.39
6V6V	X-RAY DIFFRACTION	1.4
8BNT	X-RAY DIFFRACTION	1.4
8FPW	X-RAY DIFFRACTION	1.4
8GI6	X-RAY DIFFRACTION	1.4
6BCB	X-RAY DIFFRACTION	1.4
7G82	X-RAY DIFFRACTION	1.41
5C2K	X-RAY DIFFRACTION	1.42
7G8B	X-RAY DIFFRACTION	1.42
7G8F	X-RAY DIFFRACTION	1.42
9VNG	X-RAY DIFFRACTION	1.43
7G8R	X-RAY DIFFRACTION	1.44
7G8V	X-RAY DIFFRACTION	1.45
6KX2	X-RAY DIFFRACTION	1.45
7G94	X-RAY DIFFRACTION	1.47
8FPX	X-RAY DIFFRACTION	1.47
7G8K	X-RAY DIFFRACTION	1.49
7G8A	X-RAY DIFFRACTION	1.5
7WZA	X-RAY DIFFRACTION	1.5
7G8Z	X-RAY DIFFRACTION	1.51
7G81	X-RAY DIFFRACTION	1.51
8GI3	X-RAY DIFFRACTION	1.52
1KMQ	X-RAY DIFFRACTION	1.55
7G95	X-RAY DIFFRACTION	1.55
7G8Q	X-RAY DIFFRACTION	1.56
7G8O	X-RAY DIFFRACTION	1.58

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P61586-F1	93.80	0.89

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): 189–190 ((microbial infection) cleavage; by yopt)

Ligand- & substrate-binding residues (5): 12–19; 30–37; 59–63; 117–120; 160–162

Post-translational modifications (11): 34, 37, 41, 63, 188, 190, 185, 186, 187, 190, 135

Glycosylation sites (3): 34, 37, 37

Mutagenesis-validated functional residues (9):

Position	Phenotype
14	increased rho protein signal transduction. constitutively active.
19	decreased rho protein signal transduction. decreased substrate adhesion-dependent cell spreading. decreased stress fiber
34	abolishes interaction with dgkq.
34	abolishes ampylation by haemophilus ibpa.
37	abolished monoglucosylation by c.difficile toxin tcda. abolished o-glcnacylation by c.novyi toxin tcda.
63	causes constitutive activation.
135	reduced fbxl19-mediated ubiquitination and subsequent degradation.
185–187	in 3kr mutant; abolished stearoylation in response to s.flexneri infection.
193	converts geranyl-geranylation to farnesylation; does not prevent the cleavage by yopt.

Function

Pathways and Gene Ontology

Reactome pathways

26 pathways

ID	Pathway
R-HSA-114604	GPVI-mediated activation cascade
R-HSA-193634	Axonal growth inhibition (RHOA activation)
R-HSA-198203	PI3K/AKT activation
R-HSA-209563	Axonal growth stimulation
R-HSA-2173791	TGF-beta receptor signaling in EMT (epithelial to mesenchymal transition)
R-HSA-392451	G beta:gamma signalling through PI3Kgamma
R-HSA-3928662	EPHB-mediated forward signaling
R-HSA-3928663	EPHA-mediated growth cone collapse
R-HSA-4086400	PCP/CE pathway
R-HSA-416482	G alpha (12/13) signalling events
R-HSA-416550	Sema4D mediated inhibition of cell attachment and migration
R-HSA-416572	Sema4D induced cell migration and growth-cone collapse
R-HSA-4420097	VEGFA-VEGFR2 Pathway
R-HSA-5625740	RHO GTPases activate PKNs
R-HSA-5625900	RHO GTPases activate CIT
R-HSA-5625970	RHO GTPases activate KTN1
R-HSA-5627117	RHO GTPases Activate ROCKs
R-HSA-5663220	RHO GTPases Activate Formins
R-HSA-5666185	RHO GTPases Activate Rhotekin and Rhophilins
R-HSA-5689896	Ovarian tumor domain proteases
R-HSA-6785631	ERBB2 Regulates Cell Motility
R-HSA-6798695	Neutrophil degranulation
R-HSA-8849471	PTK6 Regulates RHO GTPases, RAS GTPase and MAP kinases
R-HSA-8980692	RHOA GTPase cycle
R-HSA-8985586	SLIT2:ROBO1 increases RHOA activity
R-HSA-9013106	RHOC GTPase cycle

MSigDB gene sets: 975 (showing top): PID_SHP2_PATHWAY, BIOCARTA_RHO_PATHWAY, GOBP_MITOTIC_CYTOKINESIS, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_CHROMOSOME_ORGANIZATION, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_EPITHELIUM_DEVELOPMENT, PID_S1P_S1P1_PATHWAY, GOBP_CYTOPLASMIC_MICROTUBULE_ORGANIZATION, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_MONOPOLAR_CELL_POLARITY, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_BONE_TRABECULA_MORPHOGENESIS, GOBP_MUSCLE_TISSUE_DEVELOPMENT

GO Biological Process (78): cell morphogenesis (GO:0000902), neuron migration (GO:0001764), kidney development (GO:0001822), angiotensin-mediated vasoconstriction involved in regulation of systemic arterial blood pressure (GO:0001998), alpha-beta T cell lineage commitment (GO:0002363), regulation of systemic arterial blood pressure by endothelin (GO:0003100), aortic valve formation (GO:0003189), regulation of transcription by RNA polymerase II (GO:0006357), cell-matrix adhesion (GO:0007160), Rho protein signal transduction (GO:0007266), skeletal muscle tissue development (GO:0007519), negative regulation of cell-substrate adhesion (GO:0010812), regulation of neuron projection development (GO:0010975), cell migration (GO:0016477), substantia nigra development (GO:0021762), cerebral cortex cell migration (GO:0021795), forebrain radial glial cell differentiation (GO:0021861), actin cytoskeleton organization (GO:0030036), regulation of cell migration (GO:0030334), androgen receptor signaling pathway (GO:0030521), cytoplasmic microtubule organization (GO:0031122), positive regulation of cytokinesis (GO:0032467), regulation of actin cytoskeleton organization (GO:0032956), negative regulation of intracellular steroid hormone receptor signaling pathway (GO:0033144), regulation of osteoblast proliferation (GO:0033688), cell junction assembly (GO:0034329), substrate adhesion-dependent cell spreading (GO:0034446), Roundabout signaling pathway (GO:0035385), cleavage furrow formation (GO:0036089), apolipoprotein A-I-mediated signaling pathway (GO:0038027), odontogenesis (GO:0042476), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), stress fiber assembly (GO:0043149), apical junction assembly (GO:0043297), beta selection (GO:0043366), endothelial cell migration (GO:0043542), ossification involved in bone maturation (GO:0043931), wound healing, spreading of cells (GO:0044319), establishment of epithelial cell apical/basal polarity (GO:0045198), positive regulation of neuron differentiation (GO:0045666)

GO Molecular Function (8): GTPase activity (GO:0003924), G protein activity (GO:0003925), GTP binding (GO:0005525), myosin binding (GO:0017022), protein kinase binding (GO:0019901), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (27): nucleus (GO:0005634), endosome (GO:0005768), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), focal adhesion (GO:0005925), cell cortex (GO:0005938), cytoplasmic side of plasma membrane (GO:0009898), lamellipodium (GO:0030027), cell junction (GO:0030054), midbody (GO:0030496), secretory granule membrane (GO:0030667), vesicle (GO:0031982), cleavage furrow (GO:0032154), ruffle membrane (GO:0032587), dendritic spine (GO:0043197), apical junction complex (GO:0043296), extracellular exosome (GO:0070062), cell periphery (GO:0071944), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), ficolin-1-rich granule membrane (GO:0101003), cytoplasm (GO:0005737), membrane (GO:0016020), dendrite (GO:0030425), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-12 pathways:

Category	Pathways
RHO GTPase Effectors	6
p75NTR regulates axonogenesis	2
EPH-Ephrin signaling	2
Sema4D in semaphorin signaling	2
Platelet activation, signaling and aggregation	1
Signaling by NTRK1 (TRKA)	1
Signaling by TGF-beta Receptor Complex	1
G-protein beta:gamma signalling	1
Beta-catenin independent WNT signaling	1
GPCR downstream signalling	1
Signaling by VEGF	1
Deubiquitination	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cell migration	2
cell-substrate adhesion	2
cytoplasm	2
cell periphery	2
anatomical structure morphogenesis	1
generation of neurons	1
animal organ development	1
renal system development	1
maintenance of blood vessel diameter homeostasis by renin-angiotensin	1
positive regulation of systemic arterial blood pressure	1
vasoconstriction	1
T cell lineage commitment	1
alpha-beta T cell differentiation	1
regulation of systemic arterial blood pressure by hormone	1
aortic valve morphogenesis	1
heart valve formation	1
regulation of DNA-templated transcription	1
transcription by RNA polymerase II	1
small GTPase-mediated signal transduction	1
striated muscle tissue development	1
skeletal muscle organ development	1
negative regulation of cell adhesion	1
regulation of cell-substrate adhesion	1
neuron projection development	1
regulation of plasma membrane bounded cell projection organization	1
cell motility	1
midbrain development	1
neural nucleus development	1
cerebral cortex development	1
telencephalon cell migration	1
forebrain generation of neurons	1
radial glial cell differentiation	1
cytoskeleton organization	1
actin filament-based process	1
regulation of cell motility	1
nuclear receptor-mediated steroid hormone signaling pathway	1
ribonucleoside triphosphate phosphatase activity	1
GTPase activity	1
molecular function regulator activity	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

309 interactions, top by confidence:

A	B	Type	Score
RTKN	RHOA	psi-mi:“MI:0915”(physical association)	0.910
RHOA	RTKN	psi-mi:“MI:0915”(physical association)	0.910
RHOA	ARHGEF11	psi-mi:“MI:0407”(direct interaction)	0.900
ARHGEF11	RHOA	psi-mi:“MI:0407”(direct interaction)	0.900
RHOA	ARHGEF11	psi-mi:“MI:0914”(association)	0.900
RHOA	ARHGEF11	psi-mi:“MI:0915”(physical association)	0.900
RHOA	ARHGDIA	psi-mi:“MI:0915”(physical association)	0.860
ARHGDIA	RHOA	psi-mi:“MI:0407”(direct interaction)	0.860
ARHGDIA	RHOA	psi-mi:“MI:0915”(physical association)	0.860
MED20	MED19	psi-mi:“MI:0914”(association)	0.840
Rtkn	RHOA	psi-mi:“MI:0915”(physical association)	0.780
RHOA	Rtkn	psi-mi:“MI:0915”(physical association)	0.780
ARHGEF12	RHOA	psi-mi:“MI:0407”(direct interaction)	0.770
sseJ	RHOA	psi-mi:“MI:0407”(direct interaction)	0.740
RHOA	sseJ	psi-mi:“MI:0403”(colocalization)	0.740
sseJ	RHOA	psi-mi:“MI:1355”(lipid cleavage)	0.740
RHOA	ARHGEF2	psi-mi:“MI:0915”(physical association)	0.740
RHOC	RAP1GDS1	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
RHOA	ARHGAP1	psi-mi:“MI:0407”(direct interaction)	0.690
RHOA	ARHGAP1	psi-mi:“MI:0915”(physical association)	0.690
RHOA	RIPOR2	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (1866): RHOA (Affinity Capture-Western), RHOA (Affinity Capture-Western), KCTD13 (Reconstituted Complex), TNFAIP1 (Reconstituted Complex), RHOA (Biochemical Activity), RHOA (Biochemical Activity), ARHGDIA (Two-hybrid), TRIP6 (Two-hybrid), FAM65B (Two-hybrid), IKZF3 (Two-hybrid), RHOA (Affinity Capture-Western), RHOA (Reconstituted Complex), RHOA (Affinity Capture-Western), RHOA (Reconstituted Complex), RHOA (Affinity Capture-Western)

ESM2 similar proteins: A0A286QZ36, C4YDI6, O88931, P08134, P0CY33, P15153, P19073, P24406, P34144, P34145, P34146, P40792, P40793, P48148, P48554, P60763, P60764, P60766, P60952, P60953, P61585, P61586, P61589, P62998, P62999, P63000, P63001, Q007T2, Q03206, Q05062, Q05144, Q16YG0, Q17031, Q1RMJ6, Q22038, Q29HY3, Q2KJ93, Q4R4R6, Q5RCK9, Q5REY6

Diamond homologs: A0A286QZ36, A5D7J5, C4YDI6, O04369, O76321, O82480, O82481, O88931, O94103, O96390, P01122, P08134, P0CY33, P15153, P17081, P19073, P24406, P34144, P34145, P34146, P34147, P34148, P34149, P34150, P40792, P40793, P48148, P48554, P60763, P60764, P60766, P60952, P60953, P61585, P61586, P61589, P62998, P62999, P63000, P63001

SIGNOR signaling

96 interactions.

A	Effect	B	Mechanism
RHOA	up-regulates	FHL2	relocalization
GNAQ	up-regulates	RHOA	binding
FZD3	“up-regulates activity”	RHOA	binding
RAP1GDS1	up-regulates	RHOA	binding
DAAM1	“up-regulates activity”	RHOA	binding
GNA12	up-regulates	RHOA	binding
GNA13	up-regulates	RHOA	binding
RHOA	up-regulates	F-actin_assembly
RHOA	“up-regulates activity”	ROCK1	binding
PARD6/SMURF1	down-regulates	RHOA	ubiquitination
TGFBR1	“up-regulates activity”	RHOA
RHOA	“up-regulates activity”	DIAPH1
RHOA	“up-regulates activity”	PFN1
DVL1	“up-regulates activity”	RHOA	binding
RHOA	“up-regulates activity”	MAPK8	binding
DRAM2	“up-regulates quantity by expression”	RHOA	“transcriptional regulation”
ARAP2	“down-regulates activity”	RHOA	“gtpase-activating protein”
ARHGAP1	“down-regulates activity”	RHOA	“gtpase-activating protein”
ARHGAP5	“down-regulates activity”	RHOA	“gtpase-activating protein”
ARHGAP6	“down-regulates activity”	RHOA	“gtpase-activating protein”
ARHGAP8	“down-regulates activity”	RHOA	“gtpase-activating protein”
ARHGAP10	“down-regulates activity”	RHOA	“gtpase-activating protein”
ARHGAP11A	“down-regulates activity”	RHOA	“gtpase-activating protein”
ARHGAP11B	“down-regulates activity”	RHOA	“gtpase-activating protein”
ARHGAP19	“down-regulates activity”	RHOA	“gtpase-activating protein”
ARHGAP20	“down-regulates activity”	RHOA	“gtpase-activating protein”
ARHGAP21	“down-regulates activity”	RHOA	“gtpase-activating protein”
ARHGAP22	“down-regulates activity”	RHOA	“gtpase-activating protein”
ARHGAP23	“down-regulates activity”	RHOA	“gtpase-activating protein”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 168 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
Sema4D induced cell migration and growth-cone collapse	5	26.7×	1e-04
RHOB GTPase cycle	13	18.8×	1e-10
RHOC GTPase cycle	12	16.4×	2e-09
Signaling by high-kinase activity BRAF mutants	5	14.8×	1e-03
MAP2K and MAPK activation	5	13.3×	2e-03
Signaling by RAF1 mutants	5	13.0×	2e-03
Signaling by moderate kinase activity BRAF mutants	5	11.9×	2e-03
Paradoxical activation of RAF signaling by kinase inactive BRAF	5	11.9×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
regulation of establishment of cell polarity	6	41.3×	3e-06
Rho protein signal transduction	10	18.2×	2e-07
regulation of small GTPase mediated signal transduction	10	10.6×	2e-05

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: activating (oncogene-like) across 10 cancer types — BL, BLCA, DLBCLNOS, HNSC, MLYM, NHL, PLMESO, PRAD, SKCM, STAD.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	1
Uncertain significance	7
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (4)

Variant ID	HGVS	Classification
2681515	NM_001664.4(RHOA):c.50G>T (p.Gly17Val)	Pathogenic
695069	NM_001664.4(RHOA):c.139G>A (p.Glu47Lys)	Pathogenic
801330	NM_001664.4(RHOA):c.211C>T (p.Pro71Ser)	Pathogenic
1172623	NM_001664.4(RHOA):c.208A>G (p.Arg70Gly)	Likely pathogenic

SpliceAI

1464 predictions. Top by Δscore:

Variant	Effect	Δscore
3:49360380:CTC:C	acceptor_gain	1.0000
3:49360382:CCTA:C	acceptor_loss	1.0000
3:49360383:C:CC	acceptor_gain	1.0000
3:49362478:T:A	donor_gain	1.0000
3:49362501:T:TA	donor_gain	1.0000
3:49362516:C:CA	donor_gain	1.0000
3:49362532:AT:A	donor_gain	1.0000
3:49362533:T:C	donor_gain	1.0000
3:49368423:CTCA:C	donor_loss	1.0000
3:49368424:TCA:T	donor_loss	1.0000
3:49368425:CA:C	donor_loss	1.0000
3:49368426:A:C	donor_loss	1.0000
3:49368545:CTAC:C	acceptor_gain	1.0000
3:49375432:A:AC	donor_gain	1.0000
3:49375432:AC:A	donor_gain	1.0000
3:49375432:ACCTG:A	donor_gain	1.0000
3:49375433:C:CA	donor_gain	1.0000
3:49375433:CC:C	donor_gain	1.0000
3:49375433:CCT:C	donor_gain	1.0000
3:49375433:CCTG:C	donor_gain	1.0000
3:49375433:CCTGC:C	donor_gain	1.0000
3:49375587:CAT:C	acceptor_gain	1.0000
3:49375587:CATTG:C	acceptor_gain	1.0000
3:49375588:ATTG:A	acceptor_gain	1.0000
3:49375589:TTG:T	acceptor_gain	1.0000
3:49375589:TTGCT:T	acceptor_loss	1.0000
3:49375590:TG:T	acceptor_gain	1.0000
3:49375590:TGC:T	acceptor_loss	1.0000
3:49375591:GC:G	acceptor_loss	1.0000
3:49375592:C:CC	acceptor_gain	1.0000

AlphaMissense

1276 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:49362542:A:G	L121P	1.000
3:49362550:C:A	K118N	1.000
3:49362550:C:G	K118N	1.000
3:49362557:C:T	G116E	1.000
3:49362558:C:A	G116W	1.000
3:49362586:G:C	F106L	1.000
3:49362586:G:T	F106L	1.000
3:49362588:A:G	F106L	1.000
3:49362607:C:A	W99C	1.000
3:49362607:C:G	W99C	1.000
3:49362608:C:G	W99S	1.000
3:49362609:A:G	W99R	1.000
3:49362609:A:T	W99R	1.000
3:49368456:A:C	C83W	1.000
3:49368458:A:G	C83R	1.000
3:49368466:A:T	I80K	1.000
3:49368485:A:G	Y74H	1.000
3:49368490:A:T	L72H	1.000
3:49368495:C:A	R70S	1.000
3:49368495:C:G	R70S	1.000
3:49368496:C:A	R70M	1.000
3:49368496:C:G	R70T	1.000
3:49368499:A:G	L69P	1.000
3:49368499:A:T	L69Q	1.000
3:49368520:C:A	G62V	1.000
3:49368520:C:T	G62E	1.000
3:49368521:C:A	G62W	1.000
3:49368521:C:G	G62R	1.000
3:49368521:C:T	G62R	1.000
3:49368523:G:T	A61D	1.000

dbSNP variants (sampled 300 via entrez): RS1000024406 (3:49396419 C>CA), RS1000124313 (3:49365109 G>A), RS1000143378 (3:49393539 C>G), RS1000151172 (3:49378012 G>A), RS1000155692 (3:49364863 T>C), RS1000170655 (3:49365027 C>T), RS1000203507 (3:49412305 C>G,T), RS1000291791 (3:49411270 T>A), RS1000319458 (3:49399484 T>C), RS1000322619 (3:49411534 C>T), RS1000391562 (3:49400980 A>C), RS1000396742 (3:49371310 G>A), RS1000449756 (3:49371111 C>A), RS1000488910 (3:49363902 C>G), RS1000626912 (3:49395103 C>A,T)

Disease associations

OMIM: gene MIM:165390 | disease phenotypes: MIM:618727

GenCC curated gene-disease

Disease	Classification	Inheritance
ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies	Limited	Unknown

Mondo (1): ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies (MONDO:0032884)

Orphanet (0):

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000272	Malar flattening
HP:0000324	Facial asymmetry
HP:0000431	Wide nasal bridge
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000501	Glaucoma
HP:0000518	Cataract
HP:0000545	Myopia
HP:0000568	Microphthalmia
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000677	Oligodontia
HP:0000689	Dental malocclusion
HP:0000691	Microdontia
HP:0000698	Conical tooth
HP:0001156	Brachydactyly
HP:0001249	Intellectual disability
HP:0001263	Global developmental delay
HP:0001442	Typified by somatic mosaicism
HP:0001852	Sandal gap
HP:0003577	Congenital onset
HP:0004552	Scarring alopecia of scalp
HP:0006297	Enamel hypoplasia
HP:0006335	Persistence of primary teeth
HP:0007663	Reduced visual acuity
HP:0007946	Unilateral narrow palpebral fissure
HP:0009779	3-4 toe syndactyly
HP:0009918	Ectopia pupillae
HP:0009928	Thick nasal alae
HP:0010055	Broad hallux

GWAS associations

23 associations (top):

Study	Trait	p-value
GCST002774_6	Cognitive function	8.000000e-06
GCST003854_53	Gut microbiota (functional units)	4.000000e-06
GCST004131_23	Inflammatory bowel disease	1.000000e-33
GCST004132_17	Crohn’s disease	3.000000e-23
GCST004133_11	Ulcerative colitis	8.000000e-20
GCST004787_29	Coronary artery disease (myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass grafting, angina or chromic ischemic heart disease)	4.000000e-10
GCST005196_105	Coronary artery disease	1.000000e-08
GCST006269_761	General cognitive ability	5.000000e-09
GCST006922_9	Regular attendance at a religious group	3.000000e-08
GCST007044_11	Extremely high intelligence	4.000000e-08
GCST007559_24	Sleep duration (short sleep)	3.000000e-08
GCST007565_89	Morning person	1.000000e-17
GCST007990_8	Coronary artery disease	2.000000e-08
GCST008357_20	Mood instability	4.000000e-11
GCST009524_65	Household income (MTAG)	1.000000e-10
GCST010002_422	Refractive error	4.000000e-14
GCST010698_80	Subcortical volume (min-P)	3.000000e-24
GCST010699_110	Brain morphology (min-P)	4.000000e-08
GCST010701_52	Cortical surface area (MOSTest)	1.000000e-16
GCST010702_36	Subcortical volume (MOSTest)	1.000000e-10
GCST010703_262	Brain morphology (MOSTest)	2.000000e-13
GCST011011_2	Youthful appearance (self-reported)	2.000000e-09
GCST90000047_41	Age at first sexual intercourse	7.000000e-21

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004337	intelligence
EFO:0007874	gut microbiome measurement
EFO:0009592	social interaction measurement
EFO:0008328	chronotype measurement
EFO:0008475	mood instability measurement
EFO:0009695	household income
EFO:0004346	neuroimaging measurement
EFO:0009749	age at first sexual intercourse measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (11): CHEMBL3883318 (PROTEIN FAMILY), CHEMBL4523642 (PROTEIN COMPLEX), CHEMBL4523643 (PROTEIN COMPLEX), CHEMBL4523644 (PROTEIN COMPLEX), CHEMBL4523645 (PROTEIN COMPLEX), CHEMBL4523646 (PROTEIN COMPLEX), CHEMBL4523647 (PROTEIN COMPLEX), CHEMBL4523648 (PROTEIN COMPLEX), CHEMBL4523649 (PROTEIN COMPLEX), CHEMBL4523650 (PROTEIN COMPLEX)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs11716445	Efficacy	3	pravastatin;simvastatin	Hypercholesterolemia

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs11716445	RHOA	3	2.50	1	pravastatin;simvastatin

ChEMBL bioactivities

41 potent at pChembl≥5 of 74 total, top 40 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.91	IC50	1240	nM	CHEMBL1802838
5.82	IC50	1500	nM	CHEMBL2398697
5.82	IC50	1500	nM	CHEMBL595382
5.82	IC50	1510	nM	CHEMBL1802763
5.80	IC50	1600	nM	CHEMBL2398698
5.78	IC50	1680	nM	CHEMBL1802837
5.77	IC50	1700	nM	CHEMBL591786
5.69	IC50	2050	nM	CHEMBL1802766
5.68	IC50	2090	nM	CHEMBL1802534
5.64	IC50	2300	nM	CHEMBL2398699
5.59	IC50	2580	nM	CHEMBL1802525
5.58	IC50	2620	nM	CHEMBL1802767
5.53	IC50	2940	nM	CHEMBL2153773
5.52	IC50	3000	nM	CHEMBL1802764
5.48	IC50	3280	nM	CHEMBL1802522
5.39	IC50	4100	nM	CHEMBL606913
5.38	IC50	4200	nM	CHEMBL589372
5.35	Kd	4470	nM	CHEMBL1802524
5.33	IC50	4700	nM	CHEMBL2398669
5.33	IC50	4700	nM	CHEMBL594911
5.29	IC50	5100	nM	CHEMBL590596
5.29	Kd	5180	nM	CHEMBL1802522
5.28	IC50	5300	nM	CHEMBL2398678
5.25	IC50	5600	nM	CHEMBL2398700
5.23	IC50	5900	nM	CHEMBL591077
5.21	IC50	6100	nM	CHEMBL2398701
5.19	IC50	6400	nM	CHEMBL2398678
5.13	IC50	7400	nM	CHEMBL2398672
5.09	IC50	8100	nM	CHEMBL2398702
5.09	IC50	8100	nM	CHEMBL591549
5.07	IC50	8600	nM	CHEMBL591080
5.05	IC50	8900	nM	CHEMBL592022
5.04	IC50	9200	nM	CHEMBL2398670
5.04	IC50	9100	nM	CHEMBL591550
5.02	IC50	9500	nM	CHEMBL591081
5.01	IC50	9800	nM	CHEMBL603141
5.00	IC50	1e+04	nM	CHEMBL2398674
5.00	IC50	1e+04	nM	CHEMBL2398673
5.00	IC50	9900	nM	CHEMBL2398679
5.00	IC50	1e+04	nM	CHEMBL589131

PubChem BioAssay actives

41 with measured affinity, of 320 total; 38 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
(E)-3-[3-(quinolin-2-ylamino)phenyl]prop-2-enoic acid	606271: Inhibition of rhoA expressed in Escherichia coli BL21 after 1 hr by G-LISA activation based chemiluminescence assay	ic50	1.2400	uM
N-[1-(4-chloroanilino)-1-hydroxypropan-2-yl]oxy-3,5-bis(trifluoromethyl)benzamide	453429: Inhibition of RhoA/C-mediated transcriptional response in human PC3 cells by serum response factor-luciferase reporter gene assay	ic50	1.5000	uM
1-[3,5-bis(trifluoromethyl)benzoyl]-N-(3-phenoxyphenyl)piperidine-3-carboxamide	755578: Inhibition of RhoC-mediated pathway in human PC3 cells assessed as inhibition of SRE-regulated gene transcription by luciferase reporter gene assay	ic50	1.5000	uM
(E)-3-[3-(quinoxalin-2-ylamino)phenyl]prop-2-enoic acid	606271: Inhibition of rhoA expressed in Escherichia coli BL21 after 1 hr by G-LISA activation based chemiluminescence assay	ic50	1.5100	uM
N-(3-benzylphenyl)-1-[3,5-bis(trifluoromethyl)benzoyl]piperidine-3-carboxamide	755578: Inhibition of RhoC-mediated pathway in human PC3 cells assessed as inhibition of SRE-regulated gene transcription by luciferase reporter gene assay	ic50	1.6000	uM
(E)-3-[3-(quinoxalin-2-ylamino)phenyl]prop-2-en-1-ol	606271: Inhibition of rhoA expressed in Escherichia coli BL21 after 1 hr by G-LISA activation based chemiluminescence assay	ic50	1.6800	uM
N-[3-[(4-chlorophenyl)carbamoyl]phenyl]-3,5-bis(trifluoromethyl)benzamide	453429: Inhibition of RhoA/C-mediated transcriptional response in human PC3 cells by serum response factor-luciferase reporter gene assay	ic50	1.7000	uM
3-[3-(quinoxalin-2-ylamino)phenyl]propanoic acid	606271: Inhibition of rhoA expressed in Escherichia coli BL21 after 1 hr by G-LISA activation based chemiluminescence assay	ic50	2.0500	uM
1-[3-(4-carboxypiperidin-1-yl)-6-nitroquinoxalin-2-yl]piperidine-4-carboxylic acid	606271: Inhibition of rhoA expressed in Escherichia coli BL21 after 1 hr by G-LISA activation based chemiluminescence assay	ic50	2.0900	uM
1-[3,5-bis(trifluoromethyl)benzoyl]-N-[3-(2-pyridin-2-ylethoxy)phenyl]piperidine-3-carboxamide	755578: Inhibition of RhoC-mediated pathway in human PC3 cells assessed as inhibition of SRE-regulated gene transcription by luciferase reporter gene assay	ic50	2.3000	uM
(E)-3-[4-[[3-[4-[(E)-2-carboxyethenyl]anilino]-6-nitroquinoxalin-2-yl]amino]phenyl]prop-2-enoic acid	606271: Inhibition of rhoA expressed in Escherichia coli BL21 after 1 hr by G-LISA activation based chemiluminescence assay	ic50	2.5800	uM
(E)-3-(3-quinoxalin-2-yloxyphenyl)prop-2-enoic acid	606271: Inhibition of rhoA expressed in Escherichia coli BL21 after 1 hr by G-LISA activation based chemiluminescence assay	ic50	2.6200	uM
prop-2-enyl 1,1-dioxo-1-benzothiophene-3-carboxylate	1974821: Inhibition of N-terminal 6His-tagged human RHoA (1 to 181 residues) expressed Escherichia coli BL21 (DE3) cells assessed as GDP/GTP exchange rate incubated for 1hr by fluorescence based assay	ic50	2.9400	uM
N-(2,3-dihydro-1,4-benzodioxin-6-yl)quinoxalin-2-amine	606271: Inhibition of rhoA expressed in Escherichia coli BL21 after 1 hr by G-LISA activation based chemiluminescence assay	ic50	3.0000	uM
(E)-3-[3-[[3-[3-[(E)-2-carboxyethenyl]anilino]-6-nitroquinoxalin-2-yl]amino]phenyl]prop-2-enoic acid	606271: Inhibition of rhoA expressed in Escherichia coli BL21 after 1 hr by G-LISA activation based chemiluminescence assay	ic50	3.2800	uM
N-[[2-(4-chlorophenyl)-1,3-thiazol-4-yl]methyl]-3,5-bis(trifluoromethyl)benzamide	453429: Inhibition of RhoA/C-mediated transcriptional response in human PC3 cells by serum response factor-luciferase reporter gene assay	ic50	4.1000	uM
2-[3-[3,5-bis(trifluoromethyl)phenyl]-4,5-dihydro-1,2-oxazol-5-yl]-N-(4-chlorophenyl)acetamide	453429: Inhibition of RhoA/C-mediated transcriptional response in human PC3 cells by serum response factor-luciferase reporter gene assay	ic50	4.2000	uM
3-[(4,6-dianilino-1,3,5-triazin-2-yl)amino]benzoic acid	606273: Binding affinity to rhoA by SPR assay	kd	4.4700	uM
N-[2-(4-chloroanilino)-2-oxoethoxy]-3,5-bis(trifluoromethyl)benzamide	453429: Inhibition of RhoA/C-mediated transcriptional response in human PC3 cells by serum response factor-luciferase reporter gene assay	ic50	4.7000	uM
N-(4-chlorophenyl)-1-(3-thiophen-2-ylbenzoyl)piperidine-3-carboxamide	755578: Inhibition of RhoC-mediated pathway in human PC3 cells assessed as inhibition of SRE-regulated gene transcription by luciferase reporter gene assay	ic50	4.7000	uM
N-[3-(4-chloroanilino)propyl]-3,5-bis(trifluoromethyl)benzamide	453429: Inhibition of RhoA/C-mediated transcriptional response in human PC3 cells by serum response factor-luciferase reporter gene assay	ic50	5.1000	uM
N-(4-chlorophenyl)-1-[3-(furan-2-yl)benzoyl]piperidine-3-carboxamide	755569: Inhibition of RhoC-mediated pathway in human SK-Mel-147 cells assessed as inhibition of SRE-regulated gene transcription by luciferase reporter gene assay	ic50	5.3000	uM
1-[3,5-bis(trifluoromethyl)benzoyl]-N-(3-pyrrolidin-1-ylsulfonylphenyl)piperidine-3-carboxamide	755578: Inhibition of RhoC-mediated pathway in human PC3 cells assessed as inhibition of SRE-regulated gene transcription by luciferase reporter gene assay	ic50	5.6000	uM
N-[2-(3-chloroanilino)-2-oxoethoxy]-3,5-bis(trifluoromethyl)benzamide	453429: Inhibition of RhoA/C-mediated transcriptional response in human PC3 cells by serum response factor-luciferase reporter gene assay	ic50	5.9000	uM
1-[3,5-bis(trifluoromethyl)benzoyl]-N-[3-(2-methyl-1,3-thiazol-4-yl)phenyl]piperidine-3-carboxamide	755578: Inhibition of RhoC-mediated pathway in human PC3 cells assessed as inhibition of SRE-regulated gene transcription by luciferase reporter gene assay	ic50	6.1000	uM
1-[3,5-bis(trifluoromethyl)benzoyl]-N-[3-(pyridin-2-ylmethoxy)phenyl]piperidine-3-carboxamide	755578: Inhibition of RhoC-mediated pathway in human PC3 cells assessed as inhibition of SRE-regulated gene transcription by luciferase reporter gene assay	ic50	7.4000	uM
3-[[3,5-bis(trifluoromethyl)phenyl]methylamino]-N-(4-chlorophenyl)propanamide	453429: Inhibition of RhoA/C-mediated transcriptional response in human PC3 cells by serum response factor-luciferase reporter gene assay	ic50	8.1000	uM
1-[3,5-bis(trifluoromethyl)benzoyl]-N-(3-ethylphenyl)piperidine-3-carboxamide	755578: Inhibition of RhoC-mediated pathway in human PC3 cells assessed as inhibition of SRE-regulated gene transcription by luciferase reporter gene assay	ic50	8.1000	uM
N-[2-[3,5-bis(trifluoromethyl)anilino]-2-oxoethoxy]-4-chlorobenzamide	453429: Inhibition of RhoA/C-mediated transcriptional response in human PC3 cells by serum response factor-luciferase reporter gene assay	ic50	8.6000	uM
N-[3-(4-chlorophenoxy)propyl]-3,5-bis(trifluoromethyl)benzamide	453429: Inhibition of RhoA/C-mediated transcriptional response in human PC3 cells by serum response factor-luciferase reporter gene assay	ic50	8.9000	uM
N-[[3,5-bis(trifluoromethyl)phenyl]methyl]-N’-(4-chlorophenyl)propane-1,3-diamine	453429: Inhibition of RhoA/C-mediated transcriptional response in human PC3 cells by serum response factor-luciferase reporter gene assay	ic50	9.1000	uM
N-(4-chlorophenyl)-1-[4-(furan-2-yl)benzoyl]piperidine-3-carboxamide	755578: Inhibition of RhoC-mediated pathway in human PC3 cells assessed as inhibition of SRE-regulated gene transcription by luciferase reporter gene assay	ic50	9.2000	uM
2-[1-[3,5-bis(trifluoromethyl)benzoyl]piperidin-2-yl]-N-(4-chlorophenyl)acetamide	453429: Inhibition of RhoA/C-mediated transcriptional response in human PC3 cells by serum response factor-luciferase reporter gene assay	ic50	9.5000	uM
1-[3,5-bis(trifluoromethyl)benzoyl]-N-(4-chlorophenyl)piperidine-3-carboxamide	453429: Inhibition of RhoA/C-mediated transcriptional response in human PC3 cells by serum response factor-luciferase reporter gene assay	ic50	9.8000	uM
1-(3-benzoylbenzoyl)-N-(4-chlorophenyl)piperidine-3-carboxamide	755578: Inhibition of RhoC-mediated pathway in human PC3 cells assessed as inhibition of SRE-regulated gene transcription by luciferase reporter gene assay	ic50	9.9000	uM
N-[3,5-bis(trifluoromethyl)phenyl]-1-(4-chlorobenzoyl)piperidine-4-carboxamide	453429: Inhibition of RhoA/C-mediated transcriptional response in human PC3 cells by serum response factor-luciferase reporter gene assay	ic50	10.0000	uM
1-[3-(furan-2-yl)benzoyl]-N-(3-methylsulfanylphenyl)piperidine-3-carboxamide	755578: Inhibition of RhoC-mediated pathway in human PC3 cells assessed as inhibition of SRE-regulated gene transcription by luciferase reporter gene assay	ic50	10.0000	uM
1-[3,5-bis(trifluoromethyl)benzoyl]-N-(3-pyridin-2-yloxyphenyl)piperidine-3-carboxamide	755578: Inhibition of RhoC-mediated pathway in human PC3 cells assessed as inhibition of SRE-regulated gene transcription by luciferase reporter gene assay	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Simvastatin	decreases localization, affects localization, decreases geranoylation, increases activity, affects reaction (+6 more)	14
Mevalonic Acid	affects reaction, increases expression, decreases activity, increases localization, affects localization (+4 more)	7
geranylgeranyl pyrophosphate	increases activity, decreases activity, decreases reaction, increases localization, affects localization	6
Guanosine Triphosphate	increases abundance, increases expression, affects binding, decreases reaction, increases reaction (+1 more)	5
geranylgeraniol	decreases geranoylation, decreases expression, decreases reaction, increases phosphorylation, increases activity (+1 more)	4
Atorvastatin	decreases activity, decreases localization, increases localization, decreases reaction, affects cotreatment (+6 more)	3
Lipopolysaccharides	decreases activity, decreases reaction, increases activity, affects expression, affects response to substance (+2 more)	3
Oxygen	increases expression, decreases reaction, increases activity, affects cotreatment, decreases expression (+2 more)	3
Plant Extracts	decreases expression, decreases reaction, increases abundance, increases expression	3
bisphenol A	affects expression, increases expression	2
ochratoxin A	increases expression, affects binding	2
exoenzyme C3, Clostridium botulinum	decreases reaction, increases activity, decreases activity	2
cerivastatin	decreases localization, decreases prenylation, increases localization	2
Y 27632	affects cotreatment, decreases reaction, increases expression, decreases expression	2
Everolimus	affects cotreatment, decreases reaction, increases expression, decreases expression	2
Zoledronic Acid	affects binding, affects localization, decreases expression, decreases reaction, decreases geranoylation (+1 more)	2
Cannabidiol	decreases reaction, increases expression, affects cotreatment, decreases expression, increases reaction	2
Doxorubicin	decreases expression, decreases response to substance	2
Ivermectin	decreases expression, affects cotreatment, increases expression	2
Lovastatin	affects localization, decreases reaction, decreases prenylation	2
Parathion	decreases reaction, increases expression, affects cotreatment	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Aflatoxin B1	increases expression	2
Asbestos, Crocidolite	affects binding, decreases reaction, decreases activity, decreases lipidation, decreases prenylation	2
Cadmium Chloride	affects binding, increases reaction, increases activity, increases expression	2
Particulate Matter	affects expression, increases reaction, increases expression	2
bisphenol F	increases expression, affects cotreatment	1
tempol	affects binding, decreases reaction, decreases prenylation	1
4-oxoretinoic acid	decreases expression	1
allyl isothiocyanate	decreases expression	1

ChEMBL screening assays

48 unique, capped per target: 48 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1066764	Binding	Inhibition of RhoA/C-mediated LPA-induced DNA synthesis in human PC3 cells	Design, synthesis and prostate cancer cell-based studies of analogs of the Rho/MKL1 transcriptional pathway inhibitor, CCG-1423. — Bioorg Med Chem Lett

Cellosaurus cell lines

61 cell lines: 55 cancer cell line, 5 transformed cell line, 1 finite cell line

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

Cellosaurus	Name	Category	Sex
CVCL_0076	SNU-16	Cancer cell line	Female
CVCL_0139	AGS	Cancer cell line	Female
CVCL_0632	SW948	Cancer cell line	Female
CVCL_1335	KNS-62	Cancer cell line	Male
CVCL_1337	KOSC-2	Cancer cell line	Male
CVCL_1360	KYSE-50	Cancer cell line	Male
CVCL_1535	NCI-H2170	Cancer cell line	Male
CVCL_1622	OE19	Cancer cell line	Male
CVCL_2228	UPCI-SCC-116	Cancer cell line	Male
CVCL_2873	CCK-81	Cancer cell line	Female

Clinical trials (associated diseases)

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