RAC1

Summary

RAC1 (Rac family small GTPase 1, HGNC:9801) is a protein-coding gene on chromosome 7p22.1, encoding Ras-related C3 botulinum toxin substrate 1 (P63000). Plasma membrane-associated small GTPase which cycles between active GTP-bound and inactive GDP-bound states.

The protein encoded by this gene is a GTPase which belongs to the RAS superfamily of small GTP-binding proteins. Members of this superfamily appear to regulate a diverse array of cellular events, including the control of cell growth, cytoskeletal reorganization, and the activation of protein kinases. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 5879 — RefSeq curated summary.

At a glance

• Gene–disease (curated): syndromic intellectual disability (Definitive, ClinGen) — +1 more curated relationship
• Clinical variants (ClinVar): 102 total — 9 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 68
• Druggable target: yes — 3 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_006908

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9801
Approved symbol	RAC1
Name	Rac family small GTPase 1
Location	7p22.1
Locus type	gene with protein product
Status	Approved
Aliases	TC-25, p21-Rac1, Rac-1
Ensembl gene	ENSG00000136238
Ensembl biotype	protein_coding
OMIM	602048
Entrez	5879

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 11 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000348035, ENST00000356142, ENST00000473564, ENST00000488373, ENST00000495499, ENST00000497741, ENST00000696666, ENST00000704002, ENST00000704003, ENST00000887274, ENST00000887275, ENST00000887276, ENST00000887277, ENST00000887278, ENST00000925119, ENST00000966157, ENST00000966158

RefSeq mRNA: 2 — MANE Select: NM_006908 NM_006908, NM_018890

CCDS: CCDS5348, CCDS5349

Canonical transcript exons

ENST00000348035 — 6 exons

Exon	Start	End
ENSE00001551063	6402316	6403967
ENSE00001876788	6374527	6374770
ENSE00003482088	6401868	6402027
ENSE00003519520	6391924	6392041
ENSE00003544591	6400126	6400188
ENSE00003694234	6387212	6387283

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.88.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 164.1335 / max 1966.4452, expressed in 1828 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
77141	161.4138	1828
77142	2.2698	1014
77143	0.4452	200
77148	0.0047	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
esophagus squamous epithelium	UBERON:0006920	99.88	gold quality
epithelium of esophagus	UBERON:0001976	99.82	gold quality
visceral pleura	UBERON:0002401	99.80	gold quality
middle temporal gyrus	UBERON:0002771	99.80	gold quality
postcentral gyrus	UBERON:0002581	99.78	gold quality
palpebral conjunctiva	UBERON:0001812	99.77	gold quality
gingival epithelium	UBERON:0001949	99.76	gold quality
parietal pleura	UBERON:0002400	99.75	gold quality
pleura	UBERON:0000977	99.74	gold quality
parietal lobe	UBERON:0001872	99.73	gold quality
squamous epithelium	UBERON:0006914	99.73	gold quality
Brodmann (1909) area 23	UBERON:0013554	99.72	gold quality
gingiva	UBERON:0001828	99.71	gold quality
entorhinal cortex	UBERON:0002728	99.71	gold quality
Brodmann (1909) area 46	UBERON:0006483	99.68	gold quality
CA1 field of hippocampus	UBERON:0003881	99.67	gold quality
renal glomerulus	UBERON:0000074	99.65	gold quality
inferior vagus X ganglion	UBERON:0005363	99.65	gold quality
germinal epithelium of ovary	UBERON:0001304	99.64	gold quality
subthalamic nucleus	UBERON:0001906	99.64	gold quality
metanephric glomerulus	UBERON:0004736	99.63	gold quality
superior frontal gyrus	UBERON:0002661	99.62	gold quality
tibia	UBERON:0000979	99.61	gold quality
adult organism	UBERON:0007023	99.61	gold quality
medulla oblongata	UBERON:0001896	99.58	gold quality
mucosa of sigmoid colon	UBERON:0004993	99.58	gold quality
epithelium of nasopharynx	UBERON:0001951	99.57	gold quality
superior vestibular nucleus	UBERON:0007227	99.57	gold quality
dorsal plus ventral thalamus	UBERON:0001897	99.56	gold quality
colonic mucosa	UBERON:0000317	99.55	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 10.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	182.41
E-CURD-122	yes	68.10
E-MTAB-10553	yes	44.74
E-CURD-46	yes	33.50
E-MTAB-8410	yes	25.43
E-CURD-88	yes	21.50
E-MTAB-7316	yes	14.47
E-MTAB-9467	yes	13.49
E-HCAD-9	yes	12.67
E-GEOD-124472	no	664.35
E-GEOD-125970	no	16.67
E-HCAD-1	no	8.63
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AIRE, DRAM2, ESR1, HIF1A, HNF4A, JUN, NCOA3, NRXN1, PITX2, PTTG1

miRNA regulators (miRDB)

105 targeting RAC1, 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-3613-3P	100.00	76.36	7965
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515
HSA-MIR-548AS-5P	99.94	71.22	3482
HSA-MIR-548AU-5P	99.94	71.24	3488
HSA-MIR-548AY-5P	99.94	71.23	3502
HSA-MIR-548B-5P	99.94	71.23	3502
HSA-MIR-548BB-5P	99.94	71.27	3509

Literature-anchored findings (GeneRIF, showing 40)

• protein interaction mapping with guanine nucleotide exchange factor, Tiam1 (PMID:11685227)
• Our findings indicate that different signal cascades resulting in the activation of Rac1 …can modulate the exocytotic process of neuroendocrine cells. (PMID:11822867)
• Rac1 is required for capillary lumen formation by vascular endothelial cells in three-dimensional extracellular matrices (PMID:11884513)
• role for the small GTPases Rac1 in the generation of skeletal muscle tumors. (PMID:11973651)
• Interaction between p21-activated protein kinase and Rac during differentiation of HL-60 human promyelocytic leukemia cell (PMID:12027902)
• Rac1 generates reactive oxygen species through beta-amyloid signaling (PMID:12038964)
• Rac1 play essential role in regulating the formation of dendritic processes by dendritic cell (PMID:12115629)
• proteasomal degradation of cytotoxic necrotizing factor 1-activated rac1 (PMID:12117911)
• These results demonstrate that Rho family small GTPases RhoA, Rac1 and Cdc42 are novel signal transducers for SP-stimulated IL-8 expression. (PMID:12169092)
• Mechanism of regulation of WAVE1-induced actin nucleation by Rac1 and Nck: we propose that Rac1 and Nck cause dissociation of the WAVE1 complex, which releases active WAVE1-HSPC300 and leads to actin nucleation. (PMID:12181570)
• Data show that arsenic trioxide induces activation of the small G-protein Rac1 and the alpha and beta isoforms of the p38 mitogen-activated protein (MAP) kinase in several leukemia cell lines. (PMID:12239215)
• Rac1 and Cdc42 are activated independent of RhoG (PMID:12376551)
• role in pathway that promotes urokinase plasminogen activator mRNA stability in invasive breast cancer cells (PMID:12377770)
• mechanism of IL-2-activated Rac1 regulation of Akt-dependent cell survival in NK cells (PMID:12393431)
• DOCK2 associates with CrkL and regulates Rac1 in human leukemia cell lines (PMID:12393632)
• Cdc42/Rac1-dependent activation of the p21-activated kinase (PAK) regulates human platelet lamellipodia spreading. (PMID:12453877)
• RAC1-controlled cascades promoting lamellar protrusion are independent of MAPK activity and partially down-regulated by p-JNK. (PMID:12499846)
• Rac/Cdc42-dependent activation of MAPK/ERK is a critical event in the immediate phagocytic response of PMNs to microbial challenge (PMID:12511425)
• Adenoviral-mediated expression of the constitutively active allele of Rac1 in human umbilical vein endothelial cells results in mitochondrial oxidative stress with induction of biochemical, molecular, and morphological features of senescence. (PMID:12524240)
• The requirement for polyamines for intestinal epithelial cell migration is mediated through this protein. (PMID:12574162)
• 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)
• Rac1 and superoxide play crucial roles in the regulation of expression of cell adhesion molecules in endothelial cells (PMID:12606638)
• TRE17 coprecipitated specifically with the active forms of Cdc42 and Rac1 in vivo. TRE17 is part of a novel effector complex for Cdc42 and Rac1, potentially contributing to their effects on actin remodeling. (PMID:12612085)
• The beta2 integrin-triggered relocalization of Rac1 to the cytoskeleton was enabled by a PI 3-kinase-induced dissociation of Rac1 from LyGDI (PMID:12676940)
• AIF-1 binds and polymerizes F actin and also regulates Rac1 activity and vascular smooth muscle migration (PMID:12714565)
• evid,ence 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)
• an enhanced activation of Rac1 in primary human schwannoma cells (PMID:12761036)
• Rac1-dependent pathways that participate in Src-induced cell transformation are regulated by Vav2 and Tiam1 (PMID:12810717)
• Rac1 has a role in thrombospondin 2 regulation of cell growth via redox-dependent signaling (PMID:12861025)
• C-terminal, hypervariable domain of Rac1 encodes two distinct binding motifs for signaling proteins and regulates intracellular targeting and differential signaling in a unique and non-redundant fashion (PMID:12874273)
• Rho protein regulates the tyrosine phosphorylation of FAK through translocation from the nucleus to the membrane (PMID:12883706)
• Rac1, but not not Rac2 has a role in the human NADPH oxidase complex (PMID:12912997)
• direct activation of Cdc42 and Rac1 by invasive Salmonella is a prerequisite of Salmonella-mediated death of U937 cells. (PMID:12960245)
• Rac1 and RhoA bind to adherens junctions and myosin light chain during formation of capillary vascular network (PMID:12972426)
• alternative splicing of Rac1 leads to a highly active Rac variant that differs in regulation and downstream signaling (PMID:14506233)
• analysis of the interaction between the small G proteins Rac1 and RhoA and protein kinase C-related kinase 1 (PMID:14514689)
• bFGF- and NGF-induced phosphorylation of p85 betaPIX mediates Rac1 activation, which in turn regulates cytoskeletal reorganization at growth cones, but not translocation of the PIX complex. (PMID:14557270)
• ROS such as superoxide and H(2)O(2) derived from Rac1-activated NADPH oxidase mediate TNF-alpha-induced MCP-1 expression in endothelial cells (PMID:14576080)
• cleavage of CD44 catalyzed by ADAM10 is augmented by the intracellular signaling elicited by engagement of CD44, through Rac1-mediated cytoskeletal rearrangement, and suggest that CD44 cleavage contributes to the migration and invasion of tumor cells (PMID:14623895)
• Alternatively spliced Rac1b is able to bind the GTPase-binding domain of PAK but not full-length PAK in a GTP-dependent manner. (PMID:14625275)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	rac1a	ENSDARG00000074849
mus_musculus	Rac1	ENSMUSG00000001847
rattus_norvegicus	Rac1	ENSRNOG00000001068
caenorhabditis_elegans		WBGENE00004287

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), RHOF (ENSG00000139725), RHOT2 (ENSG00000140983), RHOB (ENSG00000143878), RHOC (ENSG00000155366), RHOBTB3 (ENSG00000164292), RHOH (ENSG00000168421), RAC3 (ENSG00000169750), RND1 (ENSG00000172602), RHOD (ENSG00000173156), RHOG (ENSG00000177105)

Protein

Protein identifiers

Ras-related C3 botulinum toxin substrate 1 — P63000 (reviewed: P63000)

Alternative names: Cell migration-inducing gene 5 protein, Ras-like protein TC25, p21-Rac1

All UniProt accessions (5): A0A994J4S4, A0A994J6T1, A4D2P0, A4D2P1, P63000

UniProt curated annotations — full annotation on UniProt →

Function. Plasma membrane-associated small GTPase which cycles between active GTP-bound and inactive GDP-bound states. In its active state, binds to a variety of effector proteins to regulate cellular responses such as secretory processes, phagocytosis of apoptotic cells, epithelial cell polarization, neurons adhesion, migration and differentiation, and growth-factor induced formation of membrane ruffles. Rac1 p21/rho GDI heterodimer is the active component of the cytosolic factor sigma 1, which is involved in stimulation of the NADPH oxidase activity in macrophages. Essential for the SPATA13-mediated regulation of cell migration and adhesion assembly and disassembly. Stimulates PKN2 kinase activity. In concert with RAB7A, plays a role in regulating the formation of RBs (ruffled borders) in osteoclasts. In podocytes, promotes nuclear shuttling of NR3C2; this modulation is required for a proper kidney functioning. Required for atypical chemokine receptor ACKR2-induced LIMK1-PAK1-dependent phosphorylation of cofilin (CFL1) and for up-regulation of ACKR2 from endosomal compartment to cell membrane, increasing its efficiency in chemokine uptake and degradation. In neurons, is involved in dendritic spine formation and synaptic plasticity. In hippocampal neurons, involved in spine morphogenesis and synapse formation, through local activation at synapses by guanine nucleotide exchange factors (GEFs), such as ARHGEF6/ARHGEF7/PIX. In synapses, seems to mediate the regulation of F-actin cluster formation performed by SHANK3. In neurons, plays a crucial role in regulating GABA(A) receptor synaptic stability and hence GABAergic inhibitory synaptic transmission through its role in PAK1 activation and eventually F-actin stabilization. Required for DSG3 translocation to cell-cell junctions, DSG3-mediated organization of cortical F-actin bundles and anchoring of actin at cell junctions; via interaction with DSG3. Subunit of the phagocyte NADPH oxidase complex that mediates the transfer of electrons from cytosolic NADPH to O2 to produce the superoxide anion (O2(-)). Isoform B has an accelerated GEF-independent GDP/GTP exchange and an impaired GTP hydrolysis, which is restored partially by GTPase-activating proteins. It is able to bind to the GTPase-binding domain of PAK but not full-length PAK in a GTP-dependent manner, suggesting that the insertion does not completely abolish effector interaction.

Subunit / interactions. Interacts with NISCH. Interacts with PIP5K1A. Interacts with the GTP-bound form of RAB7A. Interacts with SRGAP2. Interacts with CYFIP1/SRA-1. Interacts with PLXNB3. Interacts with ARHGDIA; the interaction is induced by SEMA5A, mediated through PLXNB3 and inactivates and stabilizes RAC1. Interacts (GTP-bound form preferentially) with PKN2 (via the REM repeats); the interaction stimulates autophosphorylation and phosphorylation of PKN2. Interacts with the GEF proteins PREX1, RASGRF2, FARP1, FARP2, DOCK1, DOCK2 and DOCK7, which promote the exchange between GDP and GTP, and therefore activate it. Interacts with PARD6A, PARD6B and PARD6G in a GTP-dependent manner. Part of a quaternary complex containing PARD3, some PARD6 protein (PARD6A, PARD6B or PARD6G) and some atypical PKC protein (PRKCI or PRKCZ), which plays a central role in epithelial cell polarization. Found in a trimeric complex composed of DOCK1 and ELMO1, which plays a central role in phagocytosis of apoptotic cells. Interacts with RALBP1 via its effector domain. Interacts with PLXNB1. Part of a complex with MAP2K3, MAP3K3, CCM2 and DEF6. Interacts with BAIAP2, BAIAP2L1 and DEF6. Interacts with Y.pseudotuberculosis YPKA and PLCB2. Interacts with NOXA1. Interacts with ARHGEF2. Interacts with TBC1D2. Interacts with UNKL. Interacts with USP6. Interacts with SPATA13. Interacts with ARHGEF16; mediates activation of RAC1 by EPHA2. Interacts with ITGB4. Interacts with S100A8 and calprotectin (S100A8/9). Interacts with PACSIN2. Interacts with ITGB1BP1. Interacts (when active) with PPP5C (via TPR repeats); activates PPP5C phosphatase activity and translocates PPP5C to the cell membrane. Interacts with RAPH1 (via Ras associating and PH domains). Interacts with MTSS2 (via IMD domain); this interaction may be important to potentiate PDGF-induced RAC1 activation. Interacts with PAK2. Interacts (GTP-bound form) with SH3RF1 and SH3RF3. Found in a complex with SH3RF1, MAPK8IP1/JIP1, MAP3K11/MLK3, MAP2K7/MKK7 and MAPK8/JNK1. Interacts (both active GTP- or inactive GDP-bound forms) with SH3RF2. Interacts (GTP-bound form preferentially) with CYRIB. Interacts with DOCK4 (via DOCKER domain); functions as a guanine nucleotide exchange factor (GEF) for RAC1. Interacts with GARRE1. Interacts with RAP1GDS1. Interacts with TNFAIP8L2. May interact with ARHGAP36. Interacts with CD151 and integrin beta1/ITGB1. Interacts with DSG3; the interaction is required for DSG3 translocation to cell-cell junctions, organization of cortical F-actin bundles and actin anchoring at cell-cell junctions. Component of the phagocyte NADPH oxidase complex composed of an obligatory core heterodimer formed by the membrane proteins CYBA and CYBB and the cytosolic regulatory subunits NCF1/p47-phox, NCF2/p67-phox, NCF4/p40-phox and the small GTPase RAC1 or RAC2. Interacts with NCF2.

Subcellular location. Cell membrane. Melanosome. Cytoplasm. Cell projection. Lamellipodium. Dendrite. Synapse. Nucleus.

Tissue specificity. Isoform B is predominantly identified in skin and epithelial tissues from the intestinal tract. Its expression is elevated in colorectal tumors at various stages of neoplastic progression, as compared to their respective adjacent tissues.

Post-translational modifications. GTP-bound active form is ubiquitinated at Lys-147 by HACE1, leading to its degradation by the proteasome. Phosphorylated by AKT at Ser-71. Ubiquitinated at Lys-166 in a FBXL19-mediated manner; leading to proteasomal degradation. (Microbial infection) AMPylation at Tyr-32 and Thr-35 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-32 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 Rac and leads to actin disassembly. (Microbial infection) Glucosylated at Thr-35 by C.difficile toxins TcdA and TcdB in the colonic epithelium, and by P.sordellii toxin TcsL in the vascular endothelium. 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-35 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) Palmitoylated by the N-epsilon-fatty acyltransferase F2 chain of V.cholerae toxin RtxA. Palmitoylation inhibits activation by guanine nucleotide exchange factors (GEFs), preventing Rho GTPase signaling.

Disease relevance. Intellectual developmental disorder, autosomal dominant 48 (MRD48) [MIM:617751] A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRD48 patients manifest global developmental delay and moderate to severe intellectual disability. 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. GTP hydrolysis is stimulated by ARHGAP30.

Domain organisation. The effector region mediates interaction with DEF6.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P63000-1	A, Rac1A	yes
P63000-2	B, Rac1B, Rac1ins

RefSeq proteins (2): NP_008839, NP_061485 (=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 (97 total): binding site 19, sequence variant 19, mutagenesis site 19, helix 11, strand 8, modified residue 5, lipid moiety-binding region 3, glycosylation site 3, short sequence motif 2, cross-link 2, turn 2, chain 1, propeptide 1, splice variant 1, sequence conflict 1

Structure

Experimental structures (PDB)

79 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
9RFF	X-RAY DIFFRACTION	1.25
9IFK	X-RAY DIFFRACTION	1.34
1MH1	X-RAY DIFFRACTION	1.38
9HU8	X-RAY DIFFRACTION	1.48
2WKQ	X-RAY DIFFRACTION	1.6
6X1G	X-RAY DIFFRACTION	1.6
5O33	X-RAY DIFFRACTION	1.64
9IG1	X-RAY DIFFRACTION	1.65
9I1L	X-RAY DIFFRACTION	1.68
8I5V	X-RAY DIFFRACTION	1.73
1RYF	X-RAY DIFFRACTION	1.75
1RYH	X-RAY DIFFRACTION	1.75
8S1N	X-RAY DIFFRACTION	1.8
2VRW	X-RAY DIFFRACTION	1.85
9RFB	X-RAY DIFFRACTION	1.85
2P2L	X-RAY DIFFRACTION	1.9
2WKP	X-RAY DIFFRACTION	1.9
5QQJ	X-RAY DIFFRACTION	1.9
5QQD	X-RAY DIFFRACTION	1.91
4YON	X-RAY DIFFRACTION	1.95
5QQE	X-RAY DIFFRACTION	1.95
1HE1	X-RAY DIFFRACTION	2
2NZ8	X-RAY DIFFRACTION	2
4GZL	X-RAY DIFFRACTION	2
5QU9	X-RAY DIFFRACTION	2
5QQM	X-RAY DIFFRACTION	2.02
5QQI	X-RAY DIFFRACTION	2.08
5QQH	X-RAY DIFFRACTION	2.09
3SBD	X-RAY DIFFRACTION	2.1
2FJU	X-RAY DIFFRACTION	2.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P63000-F1	93.62	0.86

Antibody-complex structures (SAbDab): 1 — 8WEJ

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 (19): 18; 31; 32; 34; 35; 59; 60; 116; 118; 119; 158; 159 …

Post-translational modifications (10): 32, 35, 71, 189, 183, 184, 189, 147, 166, 71

Glycosylation sites (3): 32, 35, 35

Mutagenesis-validated functional residues (19):

Position	Phenotype
12	constitutively active. interacts with pard6 proteins. increases nuclear localization and up-regulates transcriptional ac
17	constitutively inactivated. abolishes interaction with pard6 proteins. no effect on nr3c2 transcriptional activity. no i
30	no interaction with ppp5c; when associated with l-61. translocates to the plasma membrane; also when associated with l-6
32	abolishes ampylation by haemophilus ibpa.
35	abolishes ampylation by vibrio vops.
35	no interaction with ppp5c; when associated with l-61. translocates to the plasma membrane; also when associated with l-6
37	strongly reduced interaction with plcb2.
56	strongly reduced interaction with plcb2.
61	constitutively active. interacts with pard6 proteins. interacts with ppp5c, activates its phosphatase activity and trans
67	strongly reduced interaction with plcb2.
70	strongly reduced interaction with plcb2.
71	loss of akt-mediated phosphorylation and fbxl19-induced polyubiquitination.
166	loss of fbxl19-induced polyubiquitination.
183–188	in 4ka mutant; abolished palmitoylation by the v.cholerae toxin rtxa.
183	slightly decreased palmitoylation by the v.cholerae toxin rtxa.
184	slightly decreased palmitoylation by the v.cholerae toxin rtxa.
185–187	in 2ra mutant; does not affect palmitoylation by the v.cholerae toxin rtxa.
186	decreased palmitoylation by the v.cholerae toxin rtxa.
188	decreased palmitoylation by the v.cholerae toxin rtxa.

Function

Pathways and Gene Ontology

Reactome pathways

47 pathways

ID	Pathway
R-HSA-114604	GPVI-mediated activation cascade
R-HSA-1257604	PIP3 activates AKT signaling
R-HSA-1433557	Signaling by SCF-KIT
R-HSA-1445148	Translocation of SLC2A4 (GLUT4) to the plasma membrane
R-HSA-164944	Nef and signal transduction
R-HSA-193648	NRAGE signals death through JNK
R-HSA-2029482	Regulation of actin dynamics for phagocytic cup formation
R-HSA-2219530	Constitutive Signaling by Aberrant PI3K in Cancer
R-HSA-2424491	DAP12 signaling
R-HSA-2871796	FCERI mediated MAPK activation
R-HSA-389359	CD28 dependent Vav1 pathway
R-HSA-3928662	EPHB-mediated forward signaling
R-HSA-3928664	Ephrin signaling
R-HSA-3928665	EPH-ephrin mediated repulsion of cells
R-HSA-399954	Sema3A PAK dependent Axon repulsion
R-HSA-399955	SEMA3A-Plexin repulsion signaling by inhibiting Integrin adhesion
R-HSA-4086400	PCP/CE pathway
R-HSA-416550	Sema4D mediated inhibition of cell attachment and migration
R-HSA-418885	DCC mediated attractive signaling
R-HSA-428540	Activation of RAC1
R-HSA-428543	Inactivation of CDC42 and RAC1
R-HSA-4420097	VEGFA-VEGFR2 Pathway
R-HSA-445144	Signal transduction by L1
R-HSA-5218920	VEGFR2 mediated vascular permeability
R-HSA-5625740	RHO GTPases activate PKNs
R-HSA-5625900	RHO GTPases activate CIT
R-HSA-5625970	RHO GTPases activate KTN1
R-HSA-5626467	RHO GTPases activate IQGAPs
R-HSA-5627123	RHO GTPases activate PAKs
R-HSA-5663213	RHO GTPases Activate WASPs and WAVEs

MSigDB gene sets: 0 (showing top):

GO Biological Process (103): neuron migration (GO:0001764), positive regulation of protein phosphorylation (GO:0001934), auditory receptor cell morphogenesis (GO:0002093), sphingosine-1-phosphate receptor signaling pathway (GO:0003376), epithelial cell morphogenesis (GO:0003382), inflammatory response (GO:0006954), hyperosmotic response (GO:0006972), actin filament organization (GO:0007015), cell adhesion (GO:0007155), cell-matrix adhesion (GO:0007160), establishment or maintenance of cell polarity (GO:0007163), small GTPase-mediated signal transduction (GO:0007264), motor neuron axon guidance (GO:0008045), regulation of cell shape (GO:0008360), response to wounding (GO:0009611), anatomical structure morphogenesis (GO:0009653), regulation of hydrogen peroxide metabolic process (GO:0010310), regulation of lamellipodium assembly (GO:0010591), positive regulation of lamellipodium assembly (GO:0010592), positive regulation of endothelial cell migration (GO:0010595), negative regulation of fibroblast migration (GO:0010764), regulation of neuron maturation (GO:0014041), cell migration (GO:0016477), Rac protein signal transduction (GO:0016601), quinolinate biosynthetic process (GO:0019805), cerebral cortex radially oriented cell migration (GO:0021799), embryonic olfactory bulb interneuron precursor migration (GO:0021831), cerebral cortex GABAergic interneuron development (GO:0021894), cell projection assembly (GO:0030031), lamellipodium assembly (GO:0030032), actin cytoskeleton organization (GO:0030036), actin filament polymerization (GO:0030041), regulation of cell migration (GO:0030334), positive regulation of actin filament polymerization (GO:0030838), cortical cytoskeleton organization (GO:0030865), ruffle organization (GO:0031529), response to lipopolysaccharide (GO:0032496), negative regulation of interleukin-23 production (GO:0032707), regulation of actin cytoskeleton organization (GO:0032956), substrate adhesion-dependent cell spreading (GO:0034446)

GO Molecular Function (12): GTPase activity (GO:0003924), G protein activity (GO:0003925), GTP binding (GO:0005525), enzyme binding (GO:0019899), protein kinase binding (GO:0019901), GTP-dependent protein binding (GO:0030742), thioesterase binding (GO:0031996), protein-containing complex binding (GO:0044877), Rho GDP-dissociation inhibitor binding (GO:0051022), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (33): pericentriolar material (GO:0000242), phagocytic cup (GO:0001891), nucleus (GO:0005634), cytoplasm (GO:0005737), endoplasmic reticulum membrane (GO:0005789), trans-Golgi network (GO:0005802), cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), focal adhesion (GO:0005925), cell cortex (GO:0005938), membrane (GO:0016020), lamellipodium (GO:0030027), dendrite (GO:0030425), secretory granule membrane (GO:0030667), synaptic vesicle membrane (GO:0030672), cytoplasmic vesicle (GO:0031410), early endosome membrane (GO:0031901), ruffle membrane (GO:0032587), cytoplasmic ribonucleoprotein granule (GO:0036464), melanosome (GO:0042470), presynaptic membrane (GO:0042734), cell projection (GO:0042995), NADPH oxidase complex (GO:0043020), postsynaptic membrane (GO:0045211), recycling endosome membrane (GO:0055038), kinocilium (GO:0060091), extracellular exosome (GO:0070062), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), ficolin-1-rich granule membrane (GO:0101003), actin filament (GO:0005884), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-17 pathways:

Category	Pathways
EPH-Ephrin signaling	3
Semaphorin interactions	2
Platelet activation, signaling and aggregation	1
Intracellular signaling by second messengers	1
Signaling by Receptor Tyrosine Kinases	1
Membrane Trafficking	1
The role of Nef in HIV-1 replication and disease pathogenesis	1
Cell death signalling via NRAGE, NRIF and NADE	1
Fcgamma receptor (FCGR) dependent phagocytosis	1
PI3K/AKT Signaling in Cancer	1
DAP12 interactions	1
Fc epsilon receptor (FCERI) signaling	1
Co-stimulation by CD28	1
Beta-catenin independent WNT signaling	1
Sema4D in semaphorin signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cytoplasm	4
cellular process	2
lamellipodium assembly	2
protein binding	2
binding	2
cell periphery	2
cell migration	1
generation of neurons	1
regulation of protein phosphorylation	1
protein phosphorylation	1
positive regulation of protein modification process	1
positive regulation of phosphorylation	1
inner ear morphogenesis	1
embryonic morphogenesis	1
cell morphogenesis involved in neuron differentiation	1
auditory receptor cell development	1
G protein-coupled receptor signaling pathway	1
sphingolipid mediated signaling pathway	1
cell morphogenesis	1
epithelial cell development	1
defense response	1
response to osmotic stress	1
actin cytoskeleton organization	1
supramolecular fiber organization	1
cell-substrate adhesion	1
intracellular signaling cassette	1
axon guidance	1
regulation of cell morphogenesis	1
regulation of biological quality	1
response to stress	1
developmental process	1
anatomical structure development	1
hydrogen peroxide metabolic process	1
regulation of reactive oxygen species metabolic process	1
regulation of plasma membrane bounded cell projection assembly	1
regulation of lamellipodium organization	1
regulation of lamellipodium assembly	1
positive regulation of plasma membrane bounded cell projection assembly	1
positive regulation of lamellipodium organization	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

444 interactions, top by confidence:

A	B	Type	Score
PAK1	RAC1	psi-mi:“MI:0914”(association)	0.980
PAK1	RAC1	psi-mi:“MI:0915”(physical association)	0.980
RAC1	PAK1	psi-mi:“MI:0915”(physical association)	0.980
IQGAP1	CDC42	psi-mi:“MI:0914”(association)	0.960
PAK1	CDC42	psi-mi:“MI:0914”(association)	0.950
RAC1	ARHGDIA	psi-mi:“MI:0407”(direct interaction)	0.930
RAC1	IQGAP1	psi-mi:“MI:0915”(physical association)	0.920
RAC1	IQGAP1	psi-mi:“MI:0403”(colocalization)	0.920
RAC1	ARFIP2	psi-mi:“MI:0407”(direct interaction)	0.910
RAC1	ARFIP2	psi-mi:“MI:2364”(proximity)	0.910
RAC1	ARFIP2	psi-mi:“MI:0915”(physical association)	0.910
PIK3R1	CDC42	psi-mi:“MI:0914”(association)	0.790
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
RAC1	JUN	psi-mi:“MI:0915”(physical association)	0.670
NCF2	RAC1	psi-mi:“MI:0915”(physical association)	0.660
CAV1	RAC1	psi-mi:“MI:0915”(physical association)	0.640
RAC1	COX6C	psi-mi:“MI:0914”(association)	0.640

BioGRID (1738): RAC1 (Affinity Capture-Western), RAC1 (Affinity Capture-Western), RAC1 (Affinity Capture-Western), RAC1 (Affinity Capture-Western), RAC1 (Affinity Capture-Western), RAC1 (Affinity Capture-Western), RAC1 (Affinity Capture-Luminescence), RAC1 (Affinity Capture-Luminescence), RAC1 (Affinity Capture-Luminescence), RAC1 (Affinity Capture-Luminescence), RAC1 (Affinity Capture-Luminescence), CDC23 (Two-hybrid), USH1C (Two-hybrid), LZTS2 (Two-hybrid), KRT40 (Two-hybrid)

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

115 interactions.

A	Effect	B	Mechanism
MTSS1	up-regulates	RAC1	binding
RAC1	up-regulates	MAPK8	binding
ARHGEF7	up-regulates	RAC1
PLCG1	up-regulates	RAC1
SRC	up-regulates	RAC1	phosphorylation
TIAM1	up-regulates	RAC1
RAP1GDS1	up-regulates	RAC1	binding
RAC1	up-regulates	MAPK14
PIK3CA	up-regulates	RAC1
RAC1	up-regulates	MAPK9	binding
“phosphatidic acid”	up-regulates	RAC1	“chemical activation”
DVL1	“up-regulates activity”	RAC1	binding
RAC1	“up-regulates activity”	MAPK8	binding
CTNND1	up-regulates	RAC1	binding
DAAM1	“up-regulates activity”	RAC1
DVL1	“up-regulates activity”	RAC1
PARD6A	up-regulates	RAC1
RAC1	“up-regulates activity”	MAPK8
TGFBR1	“up-regulates activity”	RAC1
AKT	“down-regulates activity”	RAC1	phosphorylation
AKT1	“down-regulates activity”	RAC1	phosphorylation
PI3K	up-regulates	RAC1
HACE1	“down-regulates quantity by destabilization”	RAC1	ubiquitination
SDC4	“up-regulates activity”	RAC1	binding
RAC1	“up-regulates activity”	ROCK1	binding
RAC1	up-regulates	Proliferation
DRAM2	“up-regulates quantity by expression”	RAC1	“transcriptional regulation”
PREX2	“up-regulates activity”	RAC1	“catalytic activity”
ARAP1	“down-regulates activity”	RAC1	“gtpase-activating protein”
ARAP2	“down-regulates activity”	RAC1	“gtpase-activating protein”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 110 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
RHO GTPases activate PAKs	5	34.4×	1e-05
RHOV GTPase cycle	9	32.5×	1e-09
FCERI mediated MAPK activation	7	30.7×	3e-07
VEGFR2 mediated vascular permeability	5	25.8×	4e-05
RHOH GTPase cycle	6	23.4×	1e-05
RHO GTPases activate IQGAPs	5	21.9×	8e-05
RHOU GTPase cycle	6	21.1×	2e-05
RHOQ GTPase cycle	9	20.6×	6e-08

GO biological processes:

GO term	Partners	Fold	FDR
Fc-epsilon receptor signaling pathway	5	38.2×	9e-05
JNK cascade	6	17.0×	4e-04
endocytosis	9	8.9×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	14
Uncertain significance	45
Likely benign	11
Benign	4

Top pathogenic / likely-pathogenic (23)

Variant ID	HGVS	Classification
1727258	NM_006908.5(RAC1):c.475G>A (p.Ala159Thr)	Pathogenic
1727259	NM_006908.5(RAC1):c.184G>A (p.Glu62Lys)	Pathogenic
2446363	NM_006908.5(RAC1):c.181C>G (p.Gln61Glu)	Pathogenic
2446365	NM_006908.5(RAC1):c.202C>A (p.Arg68Ser)	Pathogenic
2446366	NM_006908.5(RAC1):c.202C>G (p.Arg68Gly)	Pathogenic
3377146	NM_006908.5(RAC1):c.94T>C (p.Tyr32His)	Pathogenic
445280	NM_006908.5(RAC1):c.53G>A (p.Cys18Tyr)	Pathogenic
625787	GRCh37/hg19 7p22.1(chr7:6385256-6431775)	Pathogenic
986286	NM_006908.5(RAC1):c.77A>G (p.Asn26Ser)	Pathogenic
1027690	NM_006908.5(RAC1):c.168G>C (p.Trp56Cys)	Likely pathogenic
1176531	NM_006908.5(RAC1):c.493C>G (p.Leu165Val)	Likely pathogenic
1333690	NM_006908.5(RAC1):c.191A>G (p.Tyr64Cys)	Likely pathogenic
2431922	NM_006908.5(RAC1):c.190T>C (p.Tyr64His)	Likely pathogenic
2503252	NM_006908.5(RAC1):c.394A>G (p.Lys132Glu)	Likely pathogenic
2577934	NM_006908.5(RAC1):c.122_123delinsAC (p.Ser41Tyr)	Likely pathogenic
3235757	NM_006908.5(RAC1):c.129T>A (p.Asn43Lys)	Likely pathogenic
4072487	NM_006908.5(RAC1):c.103A>G (p.Thr35Ala)	Likely pathogenic
4082372	NM_006908.5(RAC1):c.178G>A (p.Gly60Arg)	Likely pathogenic
445282	NM_006908.5(RAC1):c.470G>A (p.Cys157Tyr)	Likely pathogenic
445285	NM_006908.5(RAC1):c.151G>C (p.Val51Leu)	Likely pathogenic
4532075	NM_006908.5(RAC1):c.171T>G (p.Asp57Glu)	Likely pathogenic
4539929	NM_006908.5(RAC1):c.348A>C (p.Lys116Asn)	Likely pathogenic
4823705	NM_006908.5(RAC1):c.479T>C (p.Leu160Pro)	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

1232 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:6374763:G:A	G10R	1.000
7:6374763:G:C	G10R	1.000
7:6374764:G:A	G10E	1.000
7:6374764:G:T	G10V	1.000
7:6374766:G:C	D11H	1.000
7:6374767:A:T	D11V	1.000
7:6387219:G:C	G15R	1.000
7:6387219:G:T	G15C	1.000
7:6387220:G:A	G15D	1.000
7:6387222:A:C	K16Q	1.000
7:6387223:A:T	K16I	1.000
7:6387224:A:C	K16N	1.000
7:6387224:A:T	K16N	1.000
7:6387226:C:T	T17I	1.000
7:6387228:T:C	C18R	1.000
7:6387232:T:C	L19P	1.000
7:6387235:T:C	L20P	1.000
7:6387258:T:C	F28L	1.000
7:6387260:T:A	F28L	1.000
7:6387260:T:G	F28L	1.000
7:6387270:T:C	Y32H	1.000
7:6387280:C:T	T35I	1.000
7:6391925:T:A	F37I	1.000
7:6391925:T:C	F37L	1.000
7:6391927:T:A	F37L	1.000
7:6391927:T:G	F37L	1.000
7:6391928:G:C	D38H	1.000
7:6391929:A:T	D38V	1.000
7:6391974:T:C	L53P	1.000
7:6391980:T:C	L55S	1.000

dbSNP variants (sampled 300 via entrez): RS1000026016 (7:6384743 A>G), RS1000032888 (7:6400024 C>A,G,T), RS1000127557 (7:6387616 T>C,G), RS1000178868 (7:6387425 A>G), RS1000307258 (7:6375236 G>T), RS1000330128 (7:6375060 C>T), RS1000437654 (7:6390871 T>C), RS1000484522 (7:6399294 G>A,C), RS1000534240 (7:6386409 G>A), RS1000550264 (7:6395415 A>C,G), RS1000677976 (7:6378581 A>G), RS1000680540 (7:6391513 G>A), RS1000691830 (7:6382907 T>A,G), RS1000817677 (7:6382257 T>C), RS1000913846 (7:6404431 A>G)

Disease associations

OMIM: gene MIM:602048 | disease phenotypes: MIM:617751, MIM:617755

GenCC curated gene-disease

Disease	Classification	Inheritance
intellectual disability, autosomal dominant 48	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
syndromic intellectual disability	Definitive	AD

Mondo (2): intellectual disability, autosomal dominant 48 (MONDO:0030913), neurodevelopmental disorder with dysmorphic facies and distal limb anomalies (MONDO:0060596)

Orphanet (2): Microcephaly-corpus callosum and cerebellar vermis hypoplasia-facial dysmorphism-intellectual disability syndrom (Orphanet:500159), BPTF-related intellectual disability-facial dysmorphism-skeletal anomalies syndrome (Orphanet:686482)

HPO phenotypes

68 total (30 of 68 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000194	Open mouth
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000363	Abnormal earlobe morphology
HP:0000369	Low-set ears
HP:0000403	Recurrent otitis media
HP:0000407	Sensorineural hearing impairment
HP:0000426	Prominent nasal bridge
HP:0000463	Anteverted nares
HP:0000637	Long palpebral fissure
HP:0000664	Synophrys
HP:0000708	Atypical behavior
HP:0000729	Autistic behavior
HP:0000733	Motor stereotypy
HP:0000752	Hyperactivity
HP:0000819	Diabetes mellitus
HP:0000964	Eczematoid dermatitis
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001263	Global developmental delay
HP:0001270	Motor delay
HP:0001320	Cerebellar vermis hypoplasia
HP:0001321	Cerebellar hypoplasia
HP:0001344	Absent speech
HP:0001357	Plagiocephaly
HP:0001382	Joint hypermobility

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL3301397 (PROTEIN-PROTEIN INTERACTION), CHEMBL4106177 (PROTEIN FAMILY), CHEMBL5482993 (PROTEIN FAMILY), CHEMBL6094 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

3 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 57,177 (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
CHEMBL469	KETOROLAC	4	53,920
CHEMBL490129	SANGUINARIUM CHLORIDE	2	3,189
CHEMBL5290216	MBQ-167	1	68

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

Binding affinities (BindingDB)

9 measured of 13 human assays (13 total across all organisms); most potent 9 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
US20250346604, Compound (100)	IC50	80 nM	US-20250346604: TRIAZOLOPYRIDAZINE COMPOUNDS USEFUL AS RAC1 INHIBITORS
US20250346604, Compound (105)	IC50	150 nM	US-20250346604: TRIAZOLOPYRIDAZINE COMPOUNDS USEFUL AS RAC1 INHIBITORS
4-fluoro-N-[3-[3-(1,3-thiazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]phenyl]benzamide	IC50	170 nM	US-20250346604: TRIAZOLOPYRIDAZINE COMPOUNDS USEFUL AS RAC1 INHIBITORS
US20250346604, Compound (200)	IC50	240 nM	US-20250346604: TRIAZOLOPYRIDAZINE COMPOUNDS USEFUL AS RAC1 INHIBITORS
US20250346604, Compound (106)	IC50	270 nM	US-20250346604: TRIAZOLOPYRIDAZINE COMPOUNDS USEFUL AS RAC1 INHIBITORS
3-chloro-4-fluoro-N-[3-[3-(5-methylfuran-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]phenyl]benzamide	IC50	430 nM	US-20250346604: TRIAZOLOPYRIDAZINE COMPOUNDS USEFUL AS RAC1 INHIBITORS
3-chloro-N-[3-[3-(5-methylfuran-2-yl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]phenyl]benzamide	IC50	520 nM	US-20250346604: TRIAZOLOPYRIDAZINE COMPOUNDS USEFUL AS RAC1 INHIBITORS
US20250346604, Compound (304)	IC50	690 nM	US-20250346604: TRIAZOLOPYRIDAZINE COMPOUNDS USEFUL AS RAC1 INHIBITORS
US20250346604, Compound (119)	IC50	1500 nM	US-20250346604: TRIAZOLOPYRIDAZINE COMPOUNDS USEFUL AS RAC1 INHIBITORS

ChEMBL bioactivities

30 potent at pChembl≥5 of 54 total, top 25 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.40	Kd	40	nM	CHEMBL1186585
7.30	Kd	50	nM	CHEMBL1186585
7.00	IC50	100	nM	MBQ-167
6.99	IC50	103	nM	MBQ-167
6.24	EC50	574	nM	CHEMBL496240
6.24	EC50	574	nM	CHEMBL1618254
6.00	IC50	1000	nM	CHEMBL1619630
5.96	IC50	1100	nM	CHEMBL3237589
5.93	IC50	1180	nM	CHEMBL5436670
5.75	IC50	1800	nM	CHEMBL574200
5.70	IC50	2000	nM	KETOROLAC
5.62	Kd	2388	nM	CHEMBL4084193
5.60	IC50	2500	nM	CHEMBL3237584
5.57	IC50	2700	nM	CHEMBL572918
5.57	IC50	2700	nM	CHEMBL574200
5.52	IC50	3000	nM	CHEMBL3237589
5.34	IC50	4600	nM	SANGUINARIUM CHLORIDE
5.28	IC50	5300	nM	CHEMBL548644
5.16	IC50	7000	nM	CHELERYTHRINE CHLORIDE
5.10	IC50	8000	nM	CHEMBL572918
5.08	EC50	8300	nM	CHEMBL5277596
5.07	IC50	8600	nM	CHEMBL575536
5.06	IC50	8700	nM	CHEMBL579882
5.03	IC50	9300	nM	CHEMBL575536
5.00	IC50	1e+04	nM	CHEMBL3216441

PubChem BioAssay actives

25 with measured affinity, of 205 total; 16 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
2-(morpholin-4-ylmethyl)-5-[5-[7-(trifluoromethyl)quinolin-4-yl]sulfanylpentoxy]pyran-4-one	1974802: Binding affinity to Rac1 (unknown origin) expressed in Escherichia coli BL21 (DE3) cells assessed as dissociation constant by fluorescence anisotropy assay	kd	0.0400	uM
9-ethyl-3-(5-phenyltriazol-1-yl)carbazole	1920869: Inhibition of Rac1 GTPase in human breast cancer cell line treated for 24 hrs by western blot assay	ic50	0.1000	uM
(2R)-2-(6-methoxynaphthalen-2-yl)propanoic acid	1974817: Inhibition of Rac1 in human HeLa cells pretreated for 2 hrs followed by EGF stimulation for 2 mins by flow cytometric analysis	ec50	0.5740	uM
(1S)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid	1920872: Inhibition of Rac1 in human HeLa cells by Flow cytometric G-trap effector binding assay	ec50	0.5740	uM
(1R)-5-benzoyl-2,3-dihydro-1H-pyrrolizine-1-carboxylic acid	1435610: Inhibition of RAC1/CDC42 in human ovarian cancer cells	ic50	1.0000	uM
4-N-(9-ethylcarbazol-3-yl)-2-N-(3-morpholin-4-ylpropyl)pyrimidine-2,4-diamine	1128171: Inhibition of Rac1 in human MDA-MB-435 cells after 24 hrs by G-LISA assay	ic50	1.1000	uM
4-[[1-[5-[7-(trifluoromethyl)quinolin-4-yl]sulfanylpentyl]imidazol-4-yl]methyl]morpholine	1974806: Inhibition of GTP-tagged recombinant Rac1 (unknown origin) PAK binding domain expressed in HEK293T cells by pull- down assay	ic50	1.1800	uM
[(2S,3R,4S,5S)-5-(2-amino-6-oxo-1H-purin-9-yl)-3,4-dihydroxyoxolan-2-yl]methyl phosphono hydrogen phosphate	437569: Inhibition of Rac1b GTPase activity assessed as incorporation of BODIPY-GTP after 40 mins by nucleotide binding competition assay	ic50	1.8000	uM
Ketorolac	1435610: Inhibition of RAC1/CDC42 in human ovarian cancer cells	ic50	2.0000	uM
ethyl (1R,2R,3S,4R,6R)-2-amino-6-[3-(4-aminoanilino)phenyl]-3-phenylsulfanylbicyclo[2.2.1]heptane-2-carboxylate	1128169: Inhibition of Rac1-Tiam1 interaction in human smooth muscle cells assessed as reduction of PDGF-BB stimulated GTP bound Rac1 level preincubated for 4 hrs followed by PDGF-BB stimulation measured after 2 mins by G-LISA assay	ic50	2.5000	uM
5,6-dihydroisoquinolino[2,1-b]isoquinolin-7-ium-2,3,9,10-tetrol chloride	437569: Inhibition of Rac1b GTPase activity assessed as incorporation of BODIPY-GTP after 40 mins by nucleotide binding competition assay	ic50	2.7000	uM
24-methyl-5,7,18,20-tetraoxa-24-azoniahexacyclo[11.11.0.02,10.04,8.014,22.017,21]tetracosa-1(24),2,4(8),9,11,13,15,17(21),22-nonaene chloride	437569: Inhibition of Rac1b GTPase activity assessed as incorporation of BODIPY-GTP after 40 mins by nucleotide binding competition assay	ic50	4.6000	uM
1,2-dimethoxy-12-methyl-[1,3]benzodioxolo[5,6-c]phenanthridin-12-ium chloride	437569: Inhibition of Rac1b GTPase activity assessed as incorporation of BODIPY-GTP after 40 mins by nucleotide binding competition assay	ic50	7.0000	uM
N-(3-acetylphenyl)-5-(3-nitrophenyl)furan-2-carboxamide	1920871: Inhibition of Rac1 in human HPAF-II cell	ec50	8.3000	uM
5-methylbenzo[c]phenanthridin-5-ium-2,3,7,8-tetrol chloride	437569: Inhibition of Rac1b GTPase activity assessed as incorporation of BODIPY-GTP after 40 mins by nucleotide binding competition assay	ic50	8.6000	uM
2-(morpholin-4-ylmethyl)-5-[5-[7-(trifluoromethyl)quinolin-4-yl]sulfanylpentoxy]pyran-4-one;dihydrochloride	1920857: Inhibition of Rac1 GTPase in human MDA-MB-435 cells	ic50	10.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Arsenic Trioxide	increases expression, affects localization, decreases expression, increases activity, increases reaction (+1 more)	6
Simvastatin	increases activity, increases localization, increases prenylation, decreases expression, affects localization (+2 more)	6
sodium arsenite	affects cotreatment, increases localization, decreases reaction, increases activity, affects reaction (+1 more)	4
Lovastatin	affects localization, decreases reaction, decreases activity, increases expression	4
Cannabidiol	decreases reaction, increases expression, decreases expression, affects cotreatment	3
Tetradecanoylphorbol Acetate	affects reaction, increases expression, affects cotreatment	3
Reactive Oxygen Species	decreases reaction, increases abundance, increases expression, increases reaction	3
Cadmium Chloride	increases expression	3
geranylgeranyl pyrophosphate	decreases reaction, increases localization, increases activity	2
bisphenol A	decreases expression, increases expression	2
NSC 23766	increases activity, affects binding, increases phosphorylation, decreases reaction	2
Atorvastatin	decreases reaction, increases localization, affects cotreatment, decreases expression	2
Vehicle Emissions	affects expression, increases reaction, decreases expression, increases expression	2
Azathioprine	affects binding, decreases reaction, decreases activity, affects response to substance	2
Copper	affects binding, increases expression, decreases expression	2
Glucose	decreases reaction, increases localization, affects localization, affects reaction	2
Guanosine Triphosphate	increases expression, affects binding, increases abundance	2
Ivermectin	decreases expression, affects cotreatment	2
Lipopolysaccharides	decreases reaction, increases activity, increases localization, increases prenylation	2
Oxygen	increases expression, affects cotreatment, decreases expression, decreases reaction	2
Plant Extracts	decreases reaction, increases abundance, increases expression, decreases expression	2
Smoke	decreases expression, increases abundance	2
Ursodeoxycholic Acid	increases expression, affects expression, decreases reaction	2
Particulate Matter	increases reaction, affects reaction, increases expression, increases phosphorylation, increases secretion (+1 more)	2
aristolochic acid I	decreases reaction, increases activity	1
ZINC69391	decreases activity	1
bisphenol F	increases expression	1
TAK-243	decreases sumoylation	1
2,4,6-tribromophenol	decreases expression	1
farnesyl pyrophosphate	decreases reaction, increases activity, increases localization	1

ChEMBL screening assays

74 unique, capped per target: 74 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3241050	Binding	Inhibition of Rac1-Tiam1 interaction in human smooth muscle cells assessed as reduction of PDGF-BB stimulated GTP bound Rac1 level at 10 uM preincubated for 4 hrs followed by PDGF-BB stimulation measured after 2 mins by G-LISA assay relativ	2-Amino-3-(phenylsulfanyl)norbornane-2-carboxylate: an appealing scaffold for the design of Rac1-Tiam1 protein-protein interaction inhibitors. — J Med Chem

Cellosaurus cell lines

23 cell lines: 22 cancer cell line, 1 spontaneously immortalized cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1170	DEL	Cancer cell line	Male
CVCL_1303	IGR-1	Cancer cell line	Male
CVCL_1693	SHP-77	Cancer cell line	Male
CVCL_2960	IHH-4	Cancer cell line	Male
CVCL_3219	TMH-1	Cancer cell line	Male
CVCL_6300	KTC-1	Cancer cell line	Male
CVCL_6796	WM3060	Cancer cell line	Male
CVCL_A2CS	KTC1res.1	Cancer cell line	Male
CVCL_A2CT	KTC1res.2	Cancer cell line	Male
CVCL_A427	HTh104	Cancer cell line	Female

Clinical trials (associated diseases)

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