RHOC

Summary

RHOC (ras homolog family member C, HGNC:669) is a protein-coding gene on chromosome 1p13.2, encoding Rho-related GTP-binding protein RhoC (P08134). Regulates a signal transduction pathway linking plasma membrane receptors to the assembly of focal adhesions and actin stress fibers.

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. The protein encoded by this gene is prenylated at its C-terminus, and localizes to the cytoplasm and plasma membrane. It is thought to be important in cell locomotion. Overexpression of this gene is associated with tumor cell proliferation and metastasis. Multiple alternatively spliced variants, encoding the same protein, have been identified.

Source: NCBI Gene 389 — RefSeq curated summary.

At a glance

• GWAS associations: 12
• Clinical variants (ClinVar): 36 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_175744

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:669
Approved symbol	RHOC
Name	ras homolog family member C
Location	1p13.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000155366
Ensembl biotype	protein_coding
OMIM	165380
Entrez	389

Gene structure

Transcript identifiers

Ensembl transcripts: 60 — 54 protein_coding, 3 nonsense_mediated_decay, 3 retained_intron

ENST00000285735, ENST00000339083, ENST00000369632, ENST00000369633, ENST00000369636, ENST00000369637, ENST00000369638, ENST00000369642, ENST00000414971, ENST00000425265, ENST00000436685, ENST00000468093, ENST00000473074, ENST00000478447, ENST00000484054, ENST00000484280, ENST00000527563, ENST00000528831, ENST00000534717, ENST00000885204, ENST00000885205, ENST00000885206, ENST00000885207, ENST00000885208, ENST00000885209, ENST00000885210, ENST00000885211, ENST00000885212, ENST00000885213, ENST00000885214, ENST00000920742, ENST00000920743, ENST00000920744, ENST00000920745, ENST00000920746, ENST00000920747, ENST00000920748, ENST00000920749, ENST00000950172, ENST00000950173, ENST00000950174, ENST00000950175, ENST00000950176, ENST00000950177, ENST00000950178, ENST00000950179, ENST00000950180, ENST00000950181, ENST00000950182, ENST00000950183, ENST00000950184, ENST00000950185, ENST00000950186, ENST00000950187, ENST00000950188, ENST00000950189, ENST00000950190, ENST00000950191, ENST00000950192, ENST00000950193

RefSeq mRNA: 3 — MANE Select: NM_175744 NM_001042678, NM_001042679, NM_175744

CCDS: CCDS854

Canonical transcript exons

ENST00000339083 — 6 exons

Exon	Start	End
ENSE00003485150	112703644	112703806
ENSE00003514086	112702563	112702693
ENSE00003692669	112705100	112705168
ENSE00003784752	112702999	112703119
ENSE00003901803	112701131	112701713
ENSE00003904102	112707078	112707127

Expression profiles

Bgee: expression breadth ubiquitous, 158 present calls, max score 99.34.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 142.3164 / max 1178.8516, expressed in 1813 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
13875	122.0388	1803
13872	9.4577	1617
13874	6.5494	1568
13876	3.2084	1351
13873	0.9050	540
201619	0.1572	51

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
stromal cell of endometrium	CL:0002255	99.34	gold quality
mucosa of transverse colon	UBERON:0004991	99.34	gold quality
ascending aorta	UBERON:0001496	99.33	gold quality
thoracic aorta	UBERON:0001515	99.33	gold quality
apex of heart	UBERON:0002098	99.29	gold quality
descending thoracic aorta	UBERON:0002345	99.28	gold quality
metanephros cortex	UBERON:0010533	99.26	gold quality
peripheral nervous system	UBERON:0000010	99.24	gold quality
tibial nerve	UBERON:0001323	99.24	gold quality
right coronary artery	UBERON:0001625	99.21	gold quality
aorta	UBERON:0000947	99.20	gold quality
smooth muscle tissue	UBERON:0001135	99.17	gold quality
myometrium	UBERON:0001296	99.17	gold quality
left coronary artery	UBERON:0001626	99.16	gold quality
transverse colon	UBERON:0001157	99.15	gold quality
body of uterus	UBERON:0009853	99.15	gold quality
placenta	UBERON:0001987	99.14	gold quality
duodenum	UBERON:0002114	99.14	gold quality
right lung	UBERON:0002167	99.14	gold quality
left uterine tube	UBERON:0001303	99.13	gold quality
lower esophagus muscularis layer	UBERON:0035833	99.13	gold quality
lower esophagus	UBERON:0013473	99.12	gold quality
mucosa of stomach	UBERON:0001199	99.11	gold quality
artery	UBERON:0001637	99.11	gold quality
popliteal artery	UBERON:0002250	99.11	gold quality
tibial artery	UBERON:0007610	99.11	gold quality
gall bladder	UBERON:0002110	99.08	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	99.08	gold quality
upper lobe of left lung	UBERON:0008952	99.06	gold quality
islet of Langerhans	UBERON:0000006	99.04	gold quality

Single-cell (SCXA)

Detected in 29 experiment(s), a significant marker in 25.

Experiment	Marker?	Max mean expression
E-MTAB-10662	yes	1774.43
E-MTAB-8271	yes	738.86
E-MTAB-8142	yes	132.98
E-HCAD-4	yes	101.04
E-HCAD-1	yes	51.47
E-CURD-122	yes	47.92
E-HCAD-10	yes	39.29
E-MTAB-9467	yes	35.69
E-GEOD-137537	yes	34.48
E-HCAD-11	yes	29.58
E-MTAB-8410	yes	27.98
E-MTAB-5061	yes	26.78
E-MTAB-7316	yes	26.56
E-GEOD-125970	yes	24.33
E-GEOD-81547	yes	24.31

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): DRAM2, ETS1, FOXM1, JUN, NKX2-5

miRNA regulators (miRDB)

42 targeting RHOC, 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-512-3P	99.97	67.35	1049
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-2110	99.96	66.68	1930
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-106A-5P	99.90	73.94	2683
HSA-MIR-17-5P	99.89	73.83	2665
HSA-MIR-106B-5P	99.88	74.72	2795
HSA-MIR-20A-5P	99.88	74.76	2769
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-20B-5P	99.88	74.01	2621
HSA-MIR-519D-3P	99.88	73.97	2607
HSA-MIR-526B-3P	99.88	74.06	2587
HSA-MIR-93-5P	99.88	73.98	2606
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6794-5P	99.76	66.38	1048
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-4716-3P	99.69	66.73	1022
HSA-MIR-1249-5P	99.61	66.55	2049
HSA-MIR-6797-5P	99.61	66.55	2084
HSA-MIR-3609	99.52	69.89	2587
HSA-MIR-548AH-5P	99.52	69.73	2626
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-142-5P	99.48	70.92	2416

Literature-anchored findings (GeneRIF, showing 40)

• specifically expressed in invasive breast carcinomas capable of metastasizing (PMID:11839578)
• Mitogen activated protein kinase pathway is involved in RhoC GTPase induced motility, invasion and angiogenesis in inflammatory breast cancer. (PMID:12090470)
• not acted on by XPLN, a guanine nucleotide exchange factor (PMID:12221096)
• Up-regulation of this protein is associated with tumor progression in ovarian carcinoma. (PMID:12808121)
• 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)
• The RhoC gene may be related to malignant transformation and development of HCC and may play an important role in the invasion and metastasis of HCC by overexpression but not mutation. (PMID:12970882)
• elevated expression of the RHOC gene may be involved in the metastasis of gastric carcinomas and may be a good genetic marker for the prediction of a metastatic potential (PMID:14555841)
• Higher expression of RhoC is related to invasiveness in non-small cell lung carcinoma (PMID:14614010)
• prenylated proteins (at least RhoA, RhoB and/or RhoC) antagonize the ability of ERalpha and ERbeta to stimulate ERE-dependent transcriptional activity, potentially acting through both AF-1 and AF-2 transcriptional activities (PMID:15642170)
• siRNAs inhibited cell proliferation and invasion more effectively than conventional blockers of Rho cell signaling (PMID:15668138)
• caveolin 1 expression inhibits RhoC GTPase activation and subsequent activation of the p38 MAPK pathway in primary pancreatic cancer cells thus restricting migration and invasion (PMID:15969750)
• N-terminal construct of mouse mDia1 was recombinantly expressed in Escherichia coli, purified and crystallized in complex with truncated human RhoC. (PMID:16511001)
• The RhoC is a specific marker of lymph node metastases in patients form of carcinoma. RhoC levels seem to identify a subset of patients with early tumor stage primary tumors and high metastatic potential that might benefit from more aggressive therapy. (PMID:16899593)
• RhoA and RhoC are downstream of PKC epsilon & critical for PKC-epsilon-mediated cell invasion & motility. PKC epsilon coordinately regulates RhoA & RhoC activation, possibly through direct post-translational phosphorylation. (PMID:17018591)
• Findings suggest a strong correlation between the expression of autocrine motility factor receptor (AMFR) and RhoC and a correlation between overexpression of them and metastasis of hepatocellular carcinoma. (PMID:17265125)
• These results suggest that RhoC can undergo at least two conformational transitions during its conversion from a signaling-inactive to a signaling-active state, similar to what has recently been proposed for the H-Ras and M-Ras proteins. (PMID:17497936)
• RhoC may play a very important role in the metastasis of gastric carcinoma. Therapeutic strategies targeting RhoC and RhoC-mediated pathways may be a novel approach for treating metastasis of gastric cancer. (PMID:17549441)
• The expression of G3BP and RhoC protein is closely related to the lymph node metastasis and survival in esophageal squamous carcinoma (ESC) patients. G3BP and RhoC proteins can be considered as predictors of prognosis in ESC patients. (PMID:17696235)
• High expression of RHOC is associated with esophageal squamous cell carcinoma (PMID:17896152)
• The antisense RhoC gene can suppress the capacities of proliferation and invasion in a cholangiocarcinoma cell line in vitro. (PMID:17897917)
• High level of RhoC is associated with breast cancer. (PMID:18058225)
• We used suppression subtractive hybridization (SSH) to study molecular signature of melanoma progression, by showing characteristics of early neoplastic lesions including expression of KISS1, lack of alphavbeta3-integrin and low levels of RHOC. (PMID:18211678)
• RhoC may serve as an important and widely applicable target for anti-cancer immunotherapeutic strategies (PMID:18415097)
• RhoC overexpression may promote the invasive capacity of human breast cancer cells in vitro and its expression level is positively correlated with the metastatic capacity of those cells. (PMID:18478927)
• Results indicate that RhoC promotes tumor metastasis in prostate cancer by sequential activation of Pyk2, FAK, MAPK, and Akt followed by the up-regulation of MMP2 and MMP9, which results in the stimulation of invasiveness of tumor cells. (PMID:18794150)
• knockdown of the RhoC expression resulted in inhibition of metastasis of HCC in vivo for the first time. (PMID:18980974)
• RHOC is essential for angiogenesis induced by hepatocellular carcinoma cells via regulation of endothelial cell organization. (PMID:19016761)
• RhoC promotes the adhesion, invasion and migration of SiHa cells in vitro, but not proliferation and apoptosis. (PMID:19107362)
• PRL-3 up-regulates pERK and Rho expression and activity in lung cancer (PMID:19152186)
• This study illustrates that RhoC overexpression and tumor emboli are more frequent in tumors of inflammatory breast cancers relative to non-inflammatory breast cancers in the Egyptian population. (PMID:19157876)
• These results further support a role for RhoC in growth and metastasis of melanoma (PMID:19222696)
• MyoGEF cooperates with nonmuscle myosin IIA to regulate the polarity and invasion activity of breast cancer cells through activation of RhoA and RhoC. (PMID:19421144)
• The overexpression of RhoC may play an important role in the invasion and metastasis of squamous carcinoma of cervix. (PMID:19462897)
• Silencing of RhoC expression also leads to a rapid loss of E-cadherin but through proteasomal degradation rather than through reduction in transcription. (PMID:19477269)
• The significantly up-regulated RhoC expression suggest that RhoC may contribute to the initiation, development, invasion and metastasis of colorectal carcinoma in Chinese patients. (PMID:19499974)
• findings demonstrate that enhanced expression of RhoC results in a striking increase in the migration and invasion of pancreatic carcinoma cells, whereas forced expression of RhoA decreases these actions (PMID:19642867)
• LNX and RhoC might be part of a larger protein complex that would have important functions in signaling transduction about regulating the transcriptional activities of AP-1. (PMID:19701800)
• Cell motility and invasion were markedly diminished in RhoC-depleted head and neck cell lines. (PMID:19861405)
• In cervical carcinoma cell lines, RhoC contributes to wound healing, invasion & migration, anoikis resistance, colony formation, in vitro tube formation & tumour formation. RhoC is a downstream effector of Notch1. (PMID:19953094)
• WISP3 and RhoC genes expression status defines a molecular signature of inflammatory breast cancer (IBC). (PMID:20014943)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Rhoc	ENSMUSG00000002233
rattus_norvegicus	Rhoc	ENSRNOG00000012630
drosophila_melanogaster	Rho1	FBGN0014020

Paralogs (22): RHOBTB2 (ENSG00000008853), RHOA (ENSG00000067560), 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), RHOBTB3 (ENSG00000164292), RHOH (ENSG00000168421), RAC3 (ENSG00000169750), RND1 (ENSG00000172602), RHOD (ENSG00000173156), RHOG (ENSG00000177105)

Protein

Protein identifiers

Rho-related GTP-binding protein RhoC — P08134 (reviewed: P08134)

Alternative names: Rho cDNA clone 9

All UniProt accessions (9): P08134, A0A024R0C8, E9PLA2, E9PN11, E9PQH6, Q5JR05, Q5JR06, Q5JR07, Q5JR08

UniProt curated annotations — full annotation on UniProt →

Function. Regulates a signal transduction pathway linking plasma membrane receptors to the assembly of focal adhesions and actin stress fibers. Serves as a microtubule-dependent signal that is required for the myosin contractile ring formation during cell cycle cytokinesis. Regulates apical junction formation in bronchial epithelial cells.

Subunit / interactions. Interacts with RTKN. Interacts with AKAP13. Interacts with DIAPH1. Interacts with PKN2. Interacts with ROCK1 and ROCK2. Interacts with ARHGDIA. Interacts with RIPOR1.

Subcellular location. Cell membrane. Cleavage furrow.

Post-translational modifications. (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.

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

RefSeq proteins (3): NP_001036143, NP_001036144, NP_786886* (*=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

UniProt features (30 total): helix 9, strand 6, turn 3, binding site 3, glycosylation site 2, modified residue 2, chain 1, propeptide 1, sequence variant 1, short sequence motif 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
2GCO	X-RAY DIFFRACTION	1.4
2GCN	X-RAY DIFFRACTION	1.85
2GCP	X-RAY DIFFRACTION	2.15
1Z2C	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P08134-F1	93.36	0.88

Functional residue map

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

Ligand- & substrate-binding residues (3): 12–19; 59–63; 117–120

Post-translational modifications (3): 41, 190, 190

Glycosylation sites (2): 37, 34

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-416482	G alpha (12/13) signalling events
R-HSA-416572	Sema4D induced cell migration and growth-cone collapse
R-HSA-5625740	RHO GTPases activate PKNs
R-HSA-5625900	RHO GTPases activate CIT
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-9013106	RHOC GTPase cycle

MSigDB gene sets: 342 (showing top): GOBP_MITOTIC_CYTOKINESIS, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, PID_PRL_SIGNALING_EVENTS_PATHWAY, GOBP_APICAL_JUNCTION_ASSEMBLY, GOBP_POSITIVE_REGULATION_OF_ORGANELLE_ORGANIZATION, CACCAGC_MIR138, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, HUMMERICH_SKIN_CANCER_PROGRESSION_UP, PATIL_LIVER_CANCER, GOBP_REGULATION_OF_ACTIN_FILAMENT_BASED_PROCESS, GOBP_WOUND_HEALING, BORLAK_LIVER_CANCER_EGF_UP

GO Biological Process (14): mitotic cytokinesis (GO:0000281), actin filament organization (GO:0007015), signal transduction (GO:0007165), small GTPase-mediated signal transduction (GO:0007264), cell migration (GO:0016477), positive regulation of cell migration (GO:0030335), positive regulation of protein-containing complex assembly (GO:0031334), regulation of actin cytoskeleton organization (GO:0032956), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), apical junction assembly (GO:0043297), wound healing, spreading of cells (GO:0044319), positive regulation of stress fiber assembly (GO:0051496), positive regulation of lipase activity (GO:0060193), skeletal muscle satellite cell migration (GO:1902766)

GO Molecular Function (5): GTPase activity (GO:0003924), GTP binding (GO:0005525), protein kinase binding (GO:0019901), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (8): nucleus (GO:0005634), endoplasmic reticulum membrane (GO:0005789), cytosol (GO:0005829), plasma membrane (GO:0005886), cleavage furrow (GO:0032154), stereocilium (GO:0032420), extracellular exosome (GO:0070062), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-4 pathways:

Category	Pathways
RHO GTPase Effectors	5
GPCR downstream signalling	1
Sema4D in semaphorin signaling	1
RHO GTPase cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cell migration	3
actin cytoskeleton organization	2
cellular anatomical structure	2
mitotic cell cycle	1
cytoskeleton-dependent cytokinesis	1
mitotic cell cycle process	1
supramolecular fiber organization	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
intracellular signaling cassette	1
cell motility	1
regulation of cell migration	1
positive regulation of cell motility	1
regulation of protein-containing complex assembly	1
positive regulation of cellular component biogenesis	1
positive regulation of cellular component organization	1
protein-containing complex assembly	1
regulation of actin filament-based process	1
regulation of cytoskeleton organization	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
positive regulation of intracellular signal transduction	1
cell-cell junction assembly	1
epiboly involved in wound healing	1
positive regulation of actin filament bundle assembly	1
stress fiber assembly	1
regulation of stress fiber assembly	1
lipase activity	1
positive regulation of hydrolase activity	1
ribonucleoside triphosphate phosphatase activity	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
kinase binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

4061 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RHOC	FMNL2	Q96PY5	898
RHOC	RTKN	Q9BST9	858
RHOC	DIAPH1	O60610	845
RHOC	PCSK9	Q8NBP7	823
RHOC	ROCK1	Q13464	821
RHOC	HOXD10	P28358	819
RHOC	ARHGDIA	P52565	812
RHOC	ARHGEF3	Q9NR81	804
RHOC	ARHGDIG	Q99819	801
RHOC	ARHGEF2	Q92974	797
RHOC	CFL1	P23528	777
RHOC	CFL2	Q9Y281	776
RHOC	PKN3	Q6P5Z2	750
RHOC	RIPOR1	Q6ZS17	731
RHOC	ARHGAP35	Q9NRY4	731

IntAct

53 interactions, top by confidence:

A	B	Type	Score
RHOC	RAP1GDS1	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
DAAM1	RHOC	psi-mi:“MI:0407”(direct interaction)	0.690
RAP1GDS1	DIRAS1	psi-mi:“MI:0914”(association)	0.640
RHOC	DIAPH1	psi-mi:“MI:0407”(direct interaction)	0.590
ARHGAP1	RHOC	psi-mi:“MI:0915”(physical association)	0.570
RHOC	ARHGAP1	psi-mi:“MI:0915”(physical association)	0.570
RHOC	RIPOR2	psi-mi:“MI:0915”(physical association)	0.560
RIPOR2	RHOC	psi-mi:“MI:0915”(physical association)	0.560
RHOC	RIPOR3	psi-mi:“MI:0915”(physical association)	0.560
RHOC	ARHGEF11	psi-mi:“MI:0914”(association)	0.530
env	PGRMC1	psi-mi:“MI:0914”(association)	0.460
	AP3D1	psi-mi:“MI:0914”(association)	0.460
	MYL12B	psi-mi:“MI:0914”(association)	0.460
RHOC	Diaph1	psi-mi:“MI:0407”(direct interaction)	0.440
RHOC	sseJ	psi-mi:“MI:0407”(direct interaction)	0.440
TUBA1A	TUBAL3	psi-mi:“MI:2364”(proximity)	0.420
sseJ	RHOC	psi-mi:“MI:0914”(association)	0.350
PTPN12	PRPSAP2	psi-mi:“MI:0914”(association)	0.350
RHOA	ERLIN1	psi-mi:“MI:0914”(association)	0.350
RHOA	PPP6C	psi-mi:“MI:0914”(association)	0.350

BioGRID (660): FAM65B (Two-hybrid), ARHGAP1 (Two-hybrid), GNB2 (Co-fractionation), RAC3 (Co-fractionation), RHOC (Co-fractionation), RHOC (Co-fractionation), RHOC (Co-fractionation), RHOA (Affinity Capture-MS), DAAM2 (Affinity Capture-MS), ARHGEF11 (Affinity Capture-MS), C1orf198 (Affinity Capture-MS), DAAM1 (Affinity Capture-MS), RTKN (Affinity Capture-MS), ARHGEF1 (Affinity Capture-MS), ARHGEF12 (Affinity Capture-MS)

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

4 interactions.

A	Effect	B	Mechanism
RAP1GDS1	up-regulates	RHOC	binding
DRAM2	“up-regulates quantity by expression”	RHOC	“transcriptional regulation”
hsa-miR-493-5p	“down-regulates quantity by repression”	RHOC	“post transcriptional regulation”
PAK6	“down-regulates activity”	RHOC	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 49 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
RHOC GTPase cycle	6	28.3×	2e-05
RHOA GTPase cycle	6	14.4×	4e-04
RHO GTPases Activate Formins	5	12.5×	2e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	17
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1297 predictions. Top by Δscore:

Variant	Effect	Δscore
1:112701709:GGCTC:G	acceptor_gain	1.0000
1:112701711:CTC:C	acceptor_gain	1.0000
1:112701712:TC:T	acceptor_gain	1.0000
1:112701713:CC:C	acceptor_gain	1.0000
1:112701714:C:CC	acceptor_gain	1.0000
1:112701714:C:T	acceptor_gain	1.0000
1:112702558:CCCA:C	donor_gain	1.0000
1:112702560:CAC:C	donor_loss	1.0000
1:112702561:A:AC	donor_gain	1.0000
1:112702562:C:CC	donor_gain	1.0000
1:112702562:CCTG:C	donor_gain	1.0000
1:112702689:GTTTT:G	acceptor_gain	1.0000
1:112702690:TTTT:T	acceptor_gain	1.0000
1:112702691:TTT:T	acceptor_gain	1.0000
1:112702692:TT:T	acceptor_gain	1.0000
1:112702693:TCTG:T	acceptor_loss	1.0000
1:112702694:C:CC	acceptor_gain	1.0000
1:112702694:CTGT:C	acceptor_loss	1.0000
1:112702696:G:C	acceptor_gain	1.0000
1:112702696:G:GC	acceptor_gain	1.0000
1:112702698:G:GC	acceptor_gain	1.0000
1:112702704:A:C	acceptor_gain	1.0000
1:112703640:TCA:T	donor_loss	1.0000
1:112703641:CAC:C	donor_loss	1.0000
1:112703642:A:AT	donor_loss	1.0000
1:112703643:C:T	donor_loss	1.0000
1:112703643:CCTG:C	donor_gain	1.0000
1:112703646:G:A	donor_gain	1.0000
1:112703650:G:A	donor_gain	1.0000
1:112703705:T:TA	donor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000114216 (1:112701137 C>G,T), RS1000726231 (1:112702707 C>T), RS1000856088 (1:112708992 T>C), RS1001048596 (1:112705054 T>G), RS1001391725 (1:112705417 C>G), RS1001438684 (1:112705301 A>G), RS1001988334 (1:112705154 G>A,C), RS1003513155 (1:112700870 C>A,T), RS1003712852 (1:112700643 C>G,T), RS1004328887 (1:112704574 C>T), RS1004389032 (1:112706868 C>A,T), RS1004454584 (1:112706539 G>C), RS1004716845 (1:112705379 C>T), RS1004790247 (1:112705138 G>A,C,T), RS1005392740 (1:112708552 C>G)

Disease associations

OMIM: gene MIM:165380 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST003074_4	Cerebral amyloid deposition in APOEe4 non-carriers (PET imaging)	3.000000e-07
GCST004292_42	Glomerular filtration rate (creatinine)	3.000000e-08
GCST007344_9	Estimated glomerular filtration rate	2.000000e-08
GCST010225_17	Cortical surface area (visual PC2)	4.000000e-10
GCST010696_10	Cortical thickness (min-P)	6.000000e-41
GCST010697_23	Cortical surface area (min-P)	1.000000e-08
GCST010698_26	Subcortical volume (min-P)	2.000000e-08
GCST010699_12	Brain morphology (min-P)	2.000000e-10
GCST010700_13	Cortical thickness (MOSTest)	8.000000e-13
GCST010701_138	Cortical surface area (MOSTest)	9.000000e-10
GCST010702_169	Subcortical volume (MOSTest)	2.000000e-17
GCST010703_263	Brain morphology (MOSTest)	3.000000e-13

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007707	cerebral amyloid deposition measurement
EFO:0004771	visual cortical surface area measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL3883318 (PROTEIN FAMILY), CHEMBL5465545 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 68,788 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1487	ATORVASTATIN	4	68,788

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

ChEMBL bioactivities

15 potent at pChembl≥5 of 26 total, top 15 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.82	IC50	1500	nM	CHEMBL595382
5.77	IC50	1700	nM	CHEMBL591786
5.39	IC50	4100	nM	CHEMBL606913
5.38	IC50	4200	nM	CHEMBL589372
5.33	IC50	4700	nM	CHEMBL594911
5.30	IC50	5000	nM	ATORVASTATIN
5.29	IC50	5100	nM	CHEMBL590596
5.23	IC50	5900	nM	CHEMBL591077
5.09	IC50	8100	nM	CHEMBL591549
5.07	IC50	8600	nM	CHEMBL591080
5.05	IC50	8900	nM	CHEMBL592022
5.04	IC50	9100	nM	CHEMBL591550
5.02	IC50	9500	nM	CHEMBL591081
5.01	IC50	9800	nM	CHEMBL603141
5.00	IC50	1e+04	nM	CHEMBL589131

PubChem BioAssay actives

15 with measured affinity, of 141 total; 15 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
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
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
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
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
Atorvastatin	1974814: Inhibition of RhoC geranylgeranylation in human UMSCC1 cells by G-LISA assay	ic50	5.0000	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-[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
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
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
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
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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases expression	4
Aflatoxin B1	affects expression, increases expression	4
sodium arsenite	affects cotreatment, increases expression	3
bisphenol F	increases expression, affects cotreatment, decreases expression	2
bisphenol A	affects cotreatment, decreases expression	2
Air Pollutants	increases expression, affects cotreatment, increases abundance, increases oxidation	2
Cisplatin	affects expression, affects reaction	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Tretinoin	affects cotreatment, increases expression	2
Cadmium Chloride	decreases expression, increases expression	2
2,4,6-tribromophenol	decreases expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
decabromobiphenyl ether	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
beta-lapachone	decreases expression	1
geranylgeraniol	increases activity, decreases reaction	1
tetrabromobisphenol A	decreases expression	1
tanshinone	increases expression	1
benzo(k)fluoranthene	increases expression	1
ochratoxin A	affects binding	1
1,2,5,6-dibenzanthracene	increases expression	1
nickel sulfate	increases expression	1
benz(a)anthracene	increases expression	1
chrysene	increases expression	1
phenanthrene	increases expression	1
naphthalene	increases expression	1
lysophosphatidic acid	increases activity, decreases reaction	1
triadimefon	decreases expression	1

ChEMBL screening assays

11 unique, capped per target: 11 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

Clinical trials (associated diseases)

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