RASGRP1

Summary

RASGRP1 (RAS guanyl releasing protein 1, HGNC:9878) is a protein-coding gene on chromosome 15q14, encoding RAS guanyl-releasing protein 1 (O95267). Functions as a calcium- and diacylglycerol (DAG)-regulated nucleotide exchange factor specifically activating Ras through the exchange of bound GDP for GTP.

This gene is a member of a family of genes characterized by the presence of a Ras superfamily guanine nucleotide exchange factor (GEF) domain. It functions as a diacylglycerol (DAG)-regulated nucleotide exchange factor specifically activating Ras through the exchange of bound GDP for GTP. It activates the Erk/MAP kinase cascade and regulates T-cells and B-cells development, homeostasis and differentiation. Alternatively spliced transcript variants encoding different isoforms have been identified. Altered expression of the different isoforms of this protein may be a cause of susceptibility to systemic lupus erythematosus (SLE).

Source: NCBI Gene 10125 — RefSeq curated summary.

At a glance

• Gene–disease (curated): immunodeficiency 64 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 35
• Clinical variants (ClinVar): 502 total — 22 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 26
• Druggable target: yes
• MANE Select transcript: NM_005739

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9878
Approved symbol	RASGRP1
Name	RAS guanyl releasing protein 1
Location	15q14
Locus type	gene with protein product
Status	Approved
Aliases	CalDAG-GEFII, RASGRP
Ensembl gene	ENSG00000172575
Ensembl biotype	protein_coding
OMIM	603962
Entrez	10125

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 16 protein_coding, 7 retained_intron, 4 nonsense_mediated_decay

ENST00000310803, ENST00000414708, ENST00000450598, ENST00000557875, ENST00000558164, ENST00000558418, ENST00000558432, ENST00000559830, ENST00000560425, ENST00000560929, ENST00000561117, ENST00000561180, ENST00000697777, ENST00000697778, ENST00000697779, ENST00000697780, ENST00000697781, ENST00000697782, ENST00000697783, ENST00000697784, ENST00000697785, ENST00000697786, ENST00000697787, ENST00000697788, ENST00000697789, ENST00000937602, ENST00000941098

RefSeq mRNA: 3 — MANE Select: NM_005739 NM_001128602, NM_001306086, NM_005739

CCDS: CCDS45221, CCDS45222, CCDS76733

Canonical transcript exons

ENST00000310803 — 17 exons

Exon	Start	End
ENSE00001197073	38502312	38502421
ENSE00001197077	38503272	38503376
ENSE00001197083	38505840	38505920
ENSE00001197088	38507726	38508001
ENSE00001197093	38511604	38511720
ENSE00001197098	38512783	38512956
ENSE00001197104	38516197	38516350
ENSE00001197110	38518292	38518423
ENSE00001640623	38488103	38490688
ENSE00001751854	38526299	38526404
ENSE00001781009	38519309	38519371
ENSE00003502261	38494382	38494767
ENSE00003570115	38501143	38501287
ENSE00003589383	38559821	38560005
ENSE00003625522	38500103	38500139
ENSE00003677655	38498794	38498946
ENSE00003847618	38564594	38564814

Expression profiles

Bgee: expression breadth ubiquitous, 248 present calls, max score 97.55.

FANTOM5 (CAGE): breadth broad, TPM avg 12.3418 / max 269.0466, expressed in 894 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
149368	11.8039	866
149365	0.4981	129
149366	0.0359	18
149367	0.0039	3

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pons	UBERON:0000988	97.55	gold quality
cerebellar vermis	UBERON:0004720	95.08	gold quality
Brodmann (1909) area 23	UBERON:0013554	94.21	gold quality
lateral nuclear group of thalamus	UBERON:0002736	94.08	gold quality
endothelial cell	CL:0000115	92.87	gold quality
Brodmann (1909) area 46	UBERON:0006483	89.29	gold quality
cerebellum	UBERON:0002037	89.07	gold quality
endometrium epithelium	UBERON:0004811	88.82	gold quality
cerebellar cortex	UBERON:0002129	88.64	gold quality
entorhinal cortex	UBERON:0002728	88.53	gold quality
cerebellar hemisphere	UBERON:0002245	88.51	gold quality
orbitofrontal cortex	UBERON:0004167	88.33	gold quality
middle temporal gyrus	UBERON:0002771	88.32	gold quality
granulocyte	CL:0000094	87.87	gold quality
right hemisphere of cerebellum	UBERON:0014890	87.55	gold quality
thymus	UBERON:0002370	87.46	gold quality
superior frontal gyrus	UBERON:0002661	87.18	gold quality
paraflocculus	UBERON:0005351	86.94	gold quality
lymph node	UBERON:0000029	86.87	gold quality
parietal lobe	UBERON:0001872	86.61	gold quality
prefrontal cortex	UBERON:0000451	86.38	gold quality
postcentral gyrus	UBERON:0002581	86.19	gold quality
primary visual cortex	UBERON:0002436	86.01	gold quality
blood	UBERON:0000178	85.74	gold quality
buccal mucosa cell	CL:0002336	85.11	gold quality
bone marrow	UBERON:0002371	85.09	gold quality
Brodmann (1909) area 10	UBERON:0013541	84.83	gold quality
occipital lobe	UBERON:0002021	84.77	gold quality
ganglionic eminence	UBERON:0004023	84.12	gold quality
bone marrow cell	CL:0002092	84.07	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.38

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, GFI1

miRNA regulators (miRDB)

162 targeting RASGRP1, 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-9-5P	100.00	72.28	2361
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-568	99.98	69.86	2084
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977

Literature-anchored findings (GeneRIF, showing 40)

• in response to Src-dependent activation of phospholipase Cgamma1, the Ras guanine nucleotide exchange factor RasGRP1 translocated to the Golgi where it activated Ras (PMID:12845332)
• RasGRP binds to three DAG molecular species, but only DAG-AA and DAG-DHA participate in the modulation of RasGRP-mediated activation of MAP kinases in Jurkat T cells (PMID:14583629)
• RasGRP1 transgene conferred pre-TCR-independent survival and proliferation of immature thymocytes, suggesting that deregulated expression of RasGRP1 promotes lymphomagenesis by expanding the pool of thymocytes which are susceptible to transformation. (PMID:15829980)
• RasGRP1-/- mast cells had markedly reduced degranulation and cytokine production. (PMID:17190838)
• The unusual RasGRP-SOS interplay results in sensitive and robust Ras activation that cannot be achieved with either activator alone. (PMID:17283063)
• CalDAG-GEFI as a critical regulator of inside-out integrin activation in human T lymphocytes, neutrophils, and platelets. (PMID:17576779)
• These results suggest that SKAP55 modulates signal transduction from the T cell antigen receptor to Ras by binding to RasGRP1. (PMID:17658605)
• Essential role for Rap1 GTPase and its guanine exchange factor CalDAG-GEFI in LFA-1 mediated human T-cell adhesion. (PMID:17702895)
• identify 13 new splice variants of the human RasGRP1 gene (PMID:17878389)
• Stimulation of human mast cells by activated T cells leads to N-Ras activation through Ras guanine nucleotide releasing protein 1. (PMID:18760455)
• A proapoptotic signaling pathway involving RasGRP, Erk, and Bim in B cells (PMID:19100522)
• Studied RASGRP1, found 1 locus, mapping to a linkage disequilibrium (LD) block at chr15q14, reached statistical significance by combining results from two markers. (PMID:19465406)
• Data show that the RASGRP1/APTX gene expression ratio was higher in the responder while the AKAP13 expression was higher in the non-responders. (PMID:19960345)
• This is the first study aimed at evaluating CalDAG-GEFI gene sequences in people with mucocutaneous bleeding of unknown cause. (PMID:21815871)
• SDF-1 treatment of T cells induced the formation of a novel molecular signaling complex containing RasGRP1, Galphai2, and ZAP-70. (PMID:21856938)
• Basal LAT-diacylglycerol-RasGRP1 signals in T cells maintain TCRalpha gene expression. (PMID:21966541)
• PAQR10 and PAQR11 are able to interact with RasGRP1, a guanine nucleotide exchange protein of Ras, and increase Golgi localization of RasGRP1. The C1 domain of RasGRP1 is both necessary and sufficient for the interaction of RasGRP1 with PAQR10/PAQR11. (PMID:21968647)
• remission in systemic lupus erythematosus activity associated with decreased RasGRP-1 expression in lymphocytes (PMID:21976405)
• cooperation between aberrant expression of RasGRP1, a strong activator of Ras, and secondary gain-of-function mutations of NOTCH1 have an important role in T-cell leukemogenesis (PMID:22116551)
• A genome-wide association study identifies GRK5 and RASGRP1 as type 2 diabetes loci in Chinese Hans. (PMID:22961080)
• present a crystal structure of a fragment of RasGRP1 in which the Ras-binding site is blocked by an interdomain linker and the membrane-interaction surface of RasGRP1 is hidden within a dimerization interface (PMID:23908768)
• This study aimed to replicate and verify the association of RASGRP1 tag single-nucleotide polymorphisms with T2D in a Chinese Han population. (PMID:26076219)
• Cytokines IL-2/7/9 stimulation activates PI3K/Akt pathways downstream of Ras in RasGRP1 T-cell acute lymphoblastic leukemia (T-ALL). (PMID:26549032)
• Low-level expression of CD-GEFI impairs platelet activation, leading to protection from thrombosis, but not to marked bleeding in mice. (PMID:27417588)
• results demonstrate the critical role of CalDAG-GEFI in rapid alphaIIbbeta3 activation of human platelets. (PMID:27663674)
• This study shows that deficiency in RASGRP1 results in a previously unknown primary immunodeficiency disease, and that RASGRP1 plays role in immune cell signaling and function in T cells, B cells and NK cells. It also identifies a previously unknown role for RASGRP1 in the dynamic regulation of the cytoskeleton, and identify lenalidomide as a potpotential treatment option for this immunodeficiency. (PMID:27776107)
• The rs7170151 in RASGRP1 showed novel associations in IgA nephropathy. (PMID:27804980)
• The marked differences between RasGRP3 and RasGRP1 in membrane interaction necessarily will contribute to their different behavior in cells. (PMID:28912101)
• Histidine 212 is located at the fulcrum of these conformational changes, and structural features in its vicinity are consistent with its function as a pH-dependent switch. (PMID:28952923)
• this study shows that RASGRP1 mutation should be considered in patients with autoimmune lymphoproliferative syndrome-like disease (PMID:29155103)
• RasGRP1 overexpression was an independent prognostic factor in hepatocellular carcinoma (HCC) patients. RasGRP1 is upregulated in HCC and promotes HCC cell proliferation. Thus, RasGRP1 may be a novel therapeutic target for HCC. (PMID:29655291)
• SRSF1 expression levels were significantly lower in T cells from systemic lupus erythematosus (SLE) patients compared to healthy subjects, and correlated inversely with disease activity and positively with levels of RasGRP1-WT and DNMT1. AS to RasGRP1-WT and decreased levels of RasGRP1 protein, whereas overexpression of SRSF1 in SLE T-cells caused recovery of RasGRP1, which in turn induced DNMT1/interleukin-2 expression. (PMID:29905030)
• RASGRP1 deficiency is associated with life-threatening immune dysregulation, severe autoimmune manifestations, and susceptibility to EBV-induced B cell malignancies. Early diagnosis is critical and hematopoietic stem cell transplantation might be considered as curative treatment. (PMID:30030704)
• The expression of VEGF, RasGRP1, and AKT phosphorylation was downregulated in HUVECs exposed to high glucose compared with normal glucose, whereas metformin upregulated the RasGRP1-dependent VEGF signaling and ameliorates the impaired angiogenesis caused by high glucose. RasGRP1 is involved in the VEGF-induced angiogenesis and the pro-angiogenesis effects of metformin under hyperglycemia. (PMID:31120617)
• Mechanistic Characterization of RASGRP1 Variants Identifies an hnRNP-K-Regulated Transcriptional Enhancer Contributing to SLE Susceptibility. (PMID:31164884)
• RasGRP1 is a potential biomarker to stratify anti-EGFR therapy response in colorectal cancer. (PMID:31237864)
• Nurr1 performs its anti-inflammatory function by regulating RasGRP1 expression in neuro-inflammation. (PMID:32612143)
• Novel tumour suppressor roles for GZMA and RASGRP1 in Theileria annulata-transformed macrophages and human B lymphoma cells. (PMID:32830401)
• Dysregulated RASGRP1 expression through RUNX1 mediated transcription promotes autoimmunity. (PMID:33065764)
• Abnormal RasGRP1 Expression in the Post-Mortem Brain and Blood Serum of Schizophrenia Patients. (PMID:35204828)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Rasgrp1	ENSMUSG00000027347
rattus_norvegicus	Rasgrp1	ENSRNOG00000005404

Paralogs (24): RASGRF1 (ENSG00000058335), RASGRP2 (ENSG00000068831), RAPGEF3 (ENSG00000079337), RAPGEF4 (ENSG00000091428), SOS2 (ENSG00000100485), RAPGEF1 (ENSG00000107263), RAPGEFL1 (ENSG00000108352), RAPGEF2 (ENSG00000109756), RASGRF2 (ENSG00000113319), SOS1 (ENSG00000115904), RALGPS2 (ENSG00000116191), RAPGEF5 (ENSG00000136237), RALGPS1 (ENSG00000136828), RASGEF1B (ENSG00000138670), RGL1 (ENSG00000143344), RASGEF1C (ENSG00000146090), RASGRP3 (ENSG00000152689), RAPGEF6 (ENSG00000158987), RGL4 (ENSG00000159496), RALGDS (ENSG00000160271), RASGRP4 (ENSG00000171777), RASGEF1A (ENSG00000198915), RGL3 (ENSG00000205517), RGL2 (ENSG00000237441)

Protein

Protein identifiers

RAS guanyl-releasing protein 1 — O95267 (reviewed: O95267)

Alternative names: Calcium and DAG-regulated guanine nucleotide exchange factor II, Ras guanyl-releasing protein

All UniProt accessions (11): O95267, A0A8V8TL86, A0A8V8TLA7, A0A8V8TMY1, A0A8V8TMY7, H0YKM0, H0YKP8, H0YMT0, H0YN83, H0YNG8, H0YNK9

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a calcium- and diacylglycerol (DAG)-regulated nucleotide exchange factor specifically activating Ras through the exchange of bound GDP for GTP. Activates the Erk/MAP kinase cascade. Regulates T-cell/B-cell development, homeostasis and differentiation by coupling T-lymphocyte/B-lymphocyte antigen receptors to Ras. Regulates NK cell cytotoxicity and ITAM-dependent cytokine production by activation of Ras-mediated ERK and JNK pathways. Functions in mast cell degranulation and cytokine secretion, regulating FcERI-evoked allergic responses. May also function in differentiation of other cell types.

Subunit / interactions. Homodimer. Forms a signaling complex with DGKZ and HRAS. Interacts with F-actin. Interacts with SKAP1.

Subcellular location. Cytoplasm. Cytosol. Cell membrane. Golgi apparatus membrane. Endoplasmic reticulum membrane.

Tissue specificity. Expressed in brain with higher expression in cerebellum, cerebral cortex and amygdala. Expressed in the hematopoietic system. Expressed in T-cells (at protein level). Expressed in NK cells (at protein level).

Disease relevance. Systemic lupus erythematosus (SLE) [MIM:152700] A chronic, relapsing, inflammatory, and often febrile multisystemic disorder of connective tissue, characterized principally by involvement of the skin, joints, kidneys and serosal membranes. It is of unknown etiology, but is thought to represent a failure of the regulatory mechanisms of the autoimmune system. The disease is marked by a wide range of system dysfunctions, an elevated erythrocyte sedimentation rate, and the formation of LE cells in the blood or bone marrow. Disease susceptibility is associated with variants affecting the gene represented in this entry. Aberrantly spliced isoforms and/or diminished levels of RASGRP1 are found in a cohort of SLE patients raising the possibility that dysregulation of this signaling protein contributes to the development of autoimmunity in a subset of SLE patients. Immunodeficiency 64 with lymphoproliferation (IMD64) [MIM:618534] An autosomal recessive primary immunodeficiency characterized by recurrent bacterial, viral and fungal infections, variably decreased numbers of T cells, deficiencies of B and NK cells, and increased susceptibility to Epstein-Barr virus (EBV) infection. Patients may develop lymphoproliferation or EBV-associated lymphoma. Some patients may develop features of autoimmunity. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Autoinhibited. Activated by diacylglycerol and calcium binding, which induces a conformational change releasing the autoinhibitory state. Regulated by DGKA. Regulated by DGKZ. Regulated by PLC gamma and F-actin polymerization.

Domain organisation. The phorbol-ester/DAG-type zinc finger is the principal mediator of the targeting to membranes and is required for functional activation through DAG-binding. Two EF-hand domains are present. However, only EF-hand 1 (and not EF-hand 2) binds calcium.

Similarity. Belongs to the RASGRP family.

Isoforms (5)

UniProt ID	Names	Canonical?
O95267-1	1	yes
O95267-2	2, A
O95267-3	3, B
O95267-4	4, C
O95267-5	5, D

RefSeq proteins (3): NP_001122074, NP_001293015, NP_005730* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000651	Ras-like_Gua-exchang_fac_N	Domain
IPR001895	RASGEF_cat_dom	Domain
IPR002048	EF_hand_dom	Domain
IPR002219	PKC_DAG/PE	Domain
IPR008937	Ras-like_GEF	Family
IPR011992	EF-hand-dom_pair	Homologous_superfamily
IPR018247	EF_Hand_1_Ca_BS	Binding_site
IPR020454	DAG/PE-bd	Domain
IPR023578	Ras_GEF_dom_sf	Homologous_superfamily
IPR036964	RASGEF_cat_dom_sf	Homologous_superfamily
IPR046349	C1-like_sf	Homologous_superfamily

Pfam: PF00130, PF00617, PF00618

UniProt features (77 total): helix 28, splice variant 7, mutagenesis site 6, strand 6, turn 6, region of interest 5, binding site 5, domain 4, sequence variant 4, chain 1, coiled-coil region 1, compositionally biased region 1, modified residue 1, sequence conflict 1, zinc finger region 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4L9U	X-RAY DIFFRACTION	1.6
4L9M	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O95267-F1	72.43	0.34

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 (5): 483; 485; 487; 489; 494

Post-translational modifications (1): 184

Mutagenesis-validated functional residues (6):

Position	Phenotype
271	loss of function; prevents ras activation.
483–487	decrease of ras activation indicated by decrease of erk phosphorylation.
494	decrease of ras activation indicated by decrease of erk phosphorylation.
506	increase of ras activation indicated by increase of erk phosphorylation.
508	increase of ras activation indicated by increase of erk phosphorylation.
549	loss of localization to the endoplasmic reticulum and the golgi apparatus.

Function

Pathways and Gene Ontology

Reactome pathways

6 pathways

ID	Pathway
R-HSA-114508	Effects of PIP2 hydrolysis
R-HSA-1169092	Activation of RAS in B cells
R-HSA-2871837	FCERI mediated NF-kB activation
R-HSA-354192	Integrin signaling
R-HSA-392517	Rap1 signalling
R-HSA-5673001	RAF/MAP kinase cascade

MSigDB gene sets: 567 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_NATURAL_KILLER_CELL_DIFFERENTIATION, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_VESICLE_LOCALIZATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOBP_B_CELL_ACTIVATION, REACTOME_PLATELET_AGGREGATION_PLUG_FORMATION, PEREZ_TP63_TARGETS, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, KEGG_MAPK_SIGNALING_PATHWAY, MODULE_45

GO Biological Process (26): positive regulation of protein phosphorylation (GO:0001934), inflammatory response to antigenic stimulus (GO:0002437), signal transduction (GO:0007165), Ras protein signal transduction (GO:0007265), natural killer cell activation (GO:0030101), cell differentiation (GO:0030154), secretory granule localization (GO:0032252), positive regulation of natural killer cell differentiation (GO:0032825), positive regulation of T cell differentiation in thymus (GO:0033089), T cell proliferation (GO:0042098), B cell proliferation (GO:0042100), T cell activation (GO:0042110), B cell activation (GO:0042113), mast cell degranulation (GO:0043303), positive regulation of MAP kinase activity (GO:0043406), positive regulation of natural killer cell mediated cytotoxicity (GO:0045954), positive regulation of Ras protein signal transduction (GO:0046579), vesicle transport along microtubule (GO:0047496), regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051896), regulation of ERK1 and ERK2 cascade (GO:0070372), activation of GTPase activity (GO:0090630), positive regulation of immune system process (GO:0002684), small GTPase-mediated signal transduction (GO:0007264), positive regulation of natural killer cell activation (GO:0032816), leukocyte activation (GO:0045321), regulation of intracellular signal transduction (GO:1902531)

GO Molecular Function (9): guanyl-nucleotide exchange factor activity (GO:0005085), calcium ion binding (GO:0005509), zinc ion binding (GO:0008270), lipid binding (GO:0008289), diacylglycerol binding (GO:0019992), phosphatidylcholine binding (GO:0031210), identical protein binding (GO:0042802), GTPase regulator activity (GO:0030695), metal ion binding (GO:0046872)

GO Cellular Component (9): Golgi membrane (GO:0000139), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), cytosol (GO:0005829), plasma membrane (GO:0005886), membrane (GO:0016020), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), endomembrane system (GO:0012505)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
G alpha (q) signalling events	1
Platelet activation, signaling and aggregation	1
Downstream signaling events of B Cell Receptor (BCR)	1
Fc epsilon receptor (FCERI) signaling	1
Signal Transduction	1
Platelet Aggregation (Plug Formation)	1
Adaptive Immune System	1
MAPK1/MAPK3 signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
lymphocyte activation	3
cytoplasm	3
lymphocyte proliferation	2
cation binding	2
endomembrane system	2
intracellular membrane-bounded organelle	2
regulation of protein phosphorylation	1
protein phosphorylation	1
positive regulation of protein modification process	1
positive regulation of phosphorylation	1
inflammatory response	1
immune response	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
small GTPase-mediated signal transduction	1
cellular developmental process	1
vesicle localization	1
natural killer cell differentiation	1
positive regulation of natural killer cell activation	1
regulation of natural killer cell differentiation	1
positive regulation of lymphocyte differentiation	1
T cell differentiation in thymus	1
regulation of T cell differentiation in thymus	1
positive regulation of T cell differentiation	1
T cell activation	1
B cell activation	1
mast cell activation involved in immune response	1
mast cell mediated immunity	1
lysosome localization	1
leukocyte degranulation	1
establishment of organelle localization	1
MAP kinase activity	1
regulation of MAP kinase activity	1
positive regulation of MAPK cascade	1
positive regulation of protein serine/threonine kinase activity	1
positive regulation of leukocyte mediated cytotoxicity	1

Protein interactions and networks

STRING

1922 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RASGRP1	DGKA	P23743	865
RASGRP1	RABIF	P47224	827
RASGRP1	RASA4	O43374	825
RASGRP1	FERMT3	Q86UX7	794
RASGRP1	GRB2	P29354	789
RASGRP1	LCP2	Q13094	747
RASGRP1	RASA1	P20936	663
RASGRP1	RASAL1	O95294	657
RASGRP1	PLCG1	P19174	626
RASGRP1	PLCG2	P16885	621
RASGRP1	DGKZ	Q13574	613
RASGRP1	GRAP2	O75791	607
RASGRP1	DGKQ	P52824	592
RASGRP1	ITK	Q08881	585
RASGRP1	ZAP70	P43403	580

IntAct

8 interactions, top by confidence:

A	B	Type	Score
Dlg4	RASGRP1	psi-mi:“MI:0407”(direct interaction)	0.440
CEP164	RASGRP1	psi-mi:“MI:0914”(association)	0.350
HSPA4L	RASGRP1	psi-mi:“MI:0914”(association)	0.350
RAB3D	ATXN7	psi-mi:“MI:0914”(association)	0.350
VHL	RASGRP1	psi-mi:“MI:0915”(physical association)	0.000
PPM1B	RASGRP1	psi-mi:“MI:0915”(physical association)	0.000
FMR1	RASGRP1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (9): RASGRP1 (Affinity Capture-MS), RASGRP1 (Affinity Capture-MS), RASGRP1 (Affinity Capture-RNA), RASGRP1 (Affinity Capture-Western), RASGRP1 (Affinity Capture-MS), RASGRP1 (Affinity Capture-MS), RASGRP1 (Affinity Capture-MS), RASGRP1 (Proximity Label-MS), RASGRP1 (Co-fractionation)

ESM2 similar proteins: A0A0G2JXN2, A2AWP8, O88842, O95267, P29590, P52734, P98174, Q1LY10, Q29RM4, Q2TBA3, Q3TAA7, Q3U0J8, Q3UTZ3, Q496Y0, Q4VX76, Q568M3, Q58D15, Q5BIM1, Q5JSP0, Q5R5M3, Q5R5T1, Q5REJ9, Q5W0U4, Q68FF6, Q69Z89, Q69ZK0, Q6PFY8, Q7TNM2, Q7Z4K8, Q7Z5H3, Q7Z6J4, Q80V85, Q8BY35, Q8BZ52, Q8C190, Q8N1F8, Q8TCU6, Q8WVR3, Q96JH8, Q99N48

Diamond homologs: A4IJ06, A6N9I4, A8KBH6, O14795, O45818, O94806, O95267, P04409, P05126, P05128, P05129, P05130, P05696, P05771, P05772, P09215, P09216, P0C643, P10102, P10829, P10830, P13677, P13678, P15882, P16054, P17252, P20444, P23298, P24723, P27715, P28867, P30337, P34578, P34722, P34885, P52757, P63318, P68403, P68404, P83099

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
E2F1	“up-regulates quantity by expression”	RASGRP1	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	22
Likely pathogenic	6
Uncertain significance	205
Likely benign	225
Benign	16

Top pathogenic / likely-pathogenic (28)

Variant ID	HGVS	Classification
1071497	NM_005739.4(RASGRP1):c.1725C>A (p.Cys575Ter)	Pathogenic
1073795	NM_005739.4(RASGRP1):c.1633C>T (p.Gln545Ter)	Pathogenic
1074232	NM_005739.4(RASGRP1):c.727del (p.Thr243fs)	Pathogenic
1381980	NM_005739.4(RASGRP1):c.2180G>A (p.Trp727Ter)	Pathogenic
2022859	NM_005739.4(RASGRP1):c.1307_1314dup (p.Arg439fs)	Pathogenic
2042216	NM_005739.4(RASGRP1):c.865C>T (p.Gln289Ter)	Pathogenic
2072737	NM_005739.4(RASGRP1):c.877_879delinsT (p.Thr293fs)	Pathogenic
2106438	NM_005739.4(RASGRP1):c.1780C>T (p.Arg594Ter)	Pathogenic
2707362	NM_005739.4(RASGRP1):c.219dup (p.Asp74Ter)	Pathogenic
2741616	NM_005739.4(RASGRP1):c.945dup (p.Val316fs)	Pathogenic
2806584	NM_005739.4(RASGRP1):c.1518_1519del (p.Phe506fs)	Pathogenic
2837377	NM_005739.4(RASGRP1):c.1024C>T (p.Arg342Ter)	Pathogenic
3649933	NM_005739.4(RASGRP1):c.353C>A (p.Ser118Ter)	Pathogenic
3769164	NM_005739.4(RASGRP1):c.1232_1233del (p.His411fs)	Pathogenic
4537509	NM_005739.4(RASGRP1):c.1720+1G>A	Pathogenic
4538511	NM_005739.4(RASGRP1):c.1720+2T>C	Pathogenic
4769429	NM_005739.4(RASGRP1):c.811C>T (p.Arg271Ter)	Pathogenic
666277	NM_005739.4(RASGRP1):c.736C>T (p.Arg246Ter)	Pathogenic
666278	NM_005739.4(RASGRP1):c.771G>A (p.Trp257Ter)	Pathogenic
666279	NM_005739.4(RASGRP1):c.641C>T (p.Thr214Ile)	Pathogenic
666280	NM_005739.4(RASGRP1):c.964A>T (p.Lys322Ter)	Pathogenic
666281	NM_005739.4(RASGRP1):c.1910_1911insAG (p.Ala638fs)	Pathogenic
2005183	NM_005739.4(RASGRP1):c.1720+1G>C	Likely pathogenic
2010230	NM_005739.4(RASGRP1):c.521+1G>C	Likely pathogenic
2431603	NM_005739.4(RASGRP1):c.1418_1428+3del	Likely pathogenic
2841352	NM_005739.4(RASGRP1):c.1428+1G>A	Likely pathogenic
3243877	NC_000015.9:g.(?38786563)(38810644_?)dup	Likely pathogenic
3722427	NM_005739.4(RASGRP1):c.1324-2A>G	Likely pathogenic

SpliceAI

3115 predictions. Top by Δscore:

Variant	Effect	Δscore
15:38501141:A:AC	donor_gain	1.0000
15:38501142:C:CC	donor_gain	1.0000
15:38501142:CAAAT:C	donor_gain	1.0000
15:38502311:CCTGT:C	donor_gain	1.0000
15:38502418:CAGA:C	acceptor_gain	1.0000
15:38502419:AGA:A	acceptor_gain	1.0000
15:38502420:GA:G	acceptor_gain	1.0000
15:38502420:GAC:G	acceptor_loss	1.0000
15:38502421:AC:A	acceptor_loss	1.0000
15:38502422:C:CC	acceptor_gain	1.0000
15:38502422:C:CG	acceptor_loss	1.0000
15:38502424:G:C	acceptor_gain	1.0000
15:38502424:G:GC	acceptor_gain	1.0000
15:38505838:A:AC	donor_gain	1.0000
15:38505839:C:CC	donor_gain	1.0000
15:38507743:AGT:A	donor_gain	1.0000
15:38507839:T:A	donor_gain	1.0000
15:38512952:GAGAA:G	acceptor_gain	1.0000
15:38512953:AGAA:A	acceptor_gain	1.0000
15:38512954:GAA:G	acceptor_gain	1.0000
15:38512954:GAAC:G	acceptor_loss	1.0000
15:38512955:AA:A	acceptor_gain	1.0000
15:38512957:C:CC	acceptor_gain	1.0000
15:38512958:T:C	acceptor_loss	1.0000
15:38516195:A:AC	donor_gain	1.0000
15:38516195:A:AG	donor_loss	1.0000
15:38516196:C:CC	donor_gain	1.0000
15:38516196:C:CT	donor_loss	1.0000
15:38516354:T:TC	acceptor_gain	1.0000
15:38516360:G:C	acceptor_gain	1.0000

AlphaMissense

5250 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
15:38498895:C:G	C591S	1.000
15:38498896:A:G	C591R	1.000
15:38498896:A:T	C591S	1.000
15:38498918:G:C	C583W	1.000
15:38498919:C:A	C583F	1.000
15:38498919:C:G	C583S	1.000
15:38498919:C:T	C583Y	1.000
15:38498920:A:G	C583R	1.000
15:38498920:A:T	C583S	1.000
15:38498927:G:C	H580Q	1.000
15:38498927:G:T	H580Q	1.000
15:38498929:G:C	H580D	1.000
15:38498929:G:T	H580N	1.000
15:38498942:G:C	C575W	1.000
15:38498943:C:A	C575F	1.000
15:38498943:C:G	C575S	1.000
15:38498943:C:T	C575Y	1.000
15:38498944:A:G	C575R	1.000
15:38498944:A:T	C575S	1.000
15:38500107:A:C	C572W	1.000
15:38500108:C:G	C572S	1.000
15:38500108:C:T	C572Y	1.000
15:38500109:A:G	C572R	1.000
15:38500109:A:T	C572S	1.000
15:38500117:C:T	G569E	1.000
15:38500118:C:G	G569R	1.000
15:38500118:C:T	G569R	1.000
15:38500122:T:A	K567N	1.000
15:38500122:T:G	K567N	1.000
15:38500132:C:A	G564V	1.000

dbSNP variants (sampled 300 via entrez): RS1000029745 (15:38504045 G>A), RS1000053756 (15:38517703 G>T), RS1000191109 (15:38542958 T>C), RS1000203505 (15:38539891 G>A), RS1000277224 (15:38539695 A>G), RS1000294010 (15:38543081 G>A), RS1000395314 (15:38509634 G>A), RS1000434395 (15:38546786 C>T), RS1000439563 (15:38489975 A>C), RS1000464565 (15:38504562 T>C), RS1000559969 (15:38509809 C>T), RS1000592052 (15:38496547 A>T), RS1000648506 (15:38561343 A>C), RS1000719128 (15:38529637 A>G), RS1000719814 (15:38560949 G>T)

Disease associations

OMIM: gene MIM:603962 | disease phenotypes: MIM:618534, MIM:181500

GenCC curated gene-disease

Disease	Classification	Inheritance
immunodeficiency 64	Strong	Autosomal recessive
autoimmune lymphoproliferative syndrome	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
immunodeficiency 64	Definitive	AR

Mondo (3): immunodeficiency 64 (MONDO:0032803), schizophrenia (MONDO:0005090), autoimmune lymphoproliferative syndrome (MONDO:0017979)

Orphanet (2): EBV-induced lymphoproliferative disease due to RASGRP1 deficiency (Orphanet:664699), NON RARE IN EUROPE: Schizophrenia (Orphanet:3140)

HPO phenotypes

26 total (27 of 26 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001433	Hepatosplenomegaly
HP:0001508	Failure to thrive
HP:0001744	Splenomegaly
HP:0001890	Autoimmune hemolytic anemia
HP:0001973	Autoimmune thrombocytopenia
HP:0002110	Bronchiectasis
HP:0002716	Lymphadenopathy
HP:0002719	Recurrent infections
HP:0002783	Recurrent lower respiratory tract infections
HP:0003237	Increased circulating IgG concentration
HP:0003261	Increased circulating IgA concentration
HP:0003493	Antinuclear antibody positivity
HP:0003496	Increased circulating IgM level
HP:0004315	Decreased circulating IgG concentration
HP:0012191	B-cell lymphoma
HP:0025289	Cervical lymphadenopathy
HP:0025379	Anti-thyroid peroxidase antibody positivity
HP:0031379	Abnormal T cell proliferation
HP:0031381	Decreased mitogen-induced T-cell proliferation
HP:0031394	Abnormal CD4:CD8 ratio
HP:0032069	Anti-thyroglobulin antibody positivity
HP:0032218	Decreased CD4+ T cell proportion
HP:0033207	Increased CD21low B cell proportion
HP:0100721	Mediastinal lymphadenopathy
HP:0100759	Clubbing of fingers
HP:0100753	Schizophrenia

GWAS associations

35 associations (top):

Study	Trait	p-value
GCST000220_5	Bipolar disorder	4.000000e-07
GCST000244_2	Type 1 diabetes	4.000000e-06
GCST001191_17	Type 1 diabetes	2.000000e-07
GCST001666_2	Type 2 diabetes	4.000000e-09
GCST001729_20	Crohn’s disease	4.000000e-09
GCST002211_9	Psychosis (atypical)	4.000000e-06
GCST002318_29	Rheumatoid arthritis	9.000000e-06
GCST002318_98	Rheumatoid arthritis	2.000000e-18
GCST002318_99	Rheumatoid arthritis	3.000000e-14
GCST004132_91	Crohn’s disease	1.000000e-06
GCST004758_5	Type 2 diabetes	6.000000e-06
GCST005351_7	Carboplatin disposition in epthelial ovarian cancer	6.000000e-06
GCST005531_82	Multiple sclerosis	1.000000e-06
GCST005536_6	Type 1 diabetes	4.000000e-10
GCST005568_48	Rheumatoid arthritis (ACPA-positive)	5.000000e-11
GCST005569_22	Rheumatoid arthritis	2.000000e-08
GCST005752_53	Systemic lupus erythematosus	9.000000e-06
GCST006048_16	Rheumatoid arthritis (ACPA-positive)	2.000000e-17
GCST006959_137	Rheumatoid arthritis	3.000000e-16
GCST006959_55	Rheumatoid arthritis	2.000000e-12
GCST007344_126	Estimated glomerular filtration rate	1.000000e-08
GCST007847_83	Type 2 diabetes	1.000000e-10
GCST007932_25	Medication use (thyroid preparations)	2.000000e-18
GCST008462_9	Plasma factor V levels in venous thrombosis (conditioned on rs6027)	4.000000e-06
GCST009379_197	Type 2 diabetes	4.000000e-14
GCST009379_198	Type 2 diabetes	2.000000e-19
GCST009391_229	Metabolite levels	9.000000e-06
GCST009873_7	Autoimmune traits (pleiotropy)	2.000000e-08
GCST009877_10	Rheumatoid arthritis	2.000000e-09
GCST010118_102	Type 2 diabetes	2.000000e-14

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0009933	Thyroid preparation use measurement
EFO:0010491	glycocholate measurement
EFO:0008463	glucagon measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D056735	Autoimmune Lymphoproliferative Syndrome	C15.604.515.138; C16.320.089; C20.111.288; C20.683.515.124

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5953 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — EF-hand domain containing proteins

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
RasGRP activator 1	Binding	9.6	pKi

ChEMBL bioactivities

17 potent at pChembl≥5 of 17 total, top 17 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.60	Ki	0.25	nM	CHEMBL519741
9.39	Ki	0.41	nM	CHEMBL3289012
9.24	Ki	0.58	nM	CHEMBL519741
9.16	Ki	0.69	nM	CHEMBL3289014
9.06	Ki	0.87	nM	CHEMBL3289013
8.81	Ki	1.55	nM	CHEMBL3289011
7.65	Ki	22.6	nM	CHEMBL4097154
7.65	Ki	22.6	nM	CHEMBL4070999
7.50	Ki	31.3	nM	CHEMBL4075373
7.40	Ki	40	nM	CHEMBL4069954
7.20	Ki	63.3	nM	CHEMBL4099579
6.88	Ki	133	nM	CHEMBL4081576
6.18	Ki	666	nM	CHEMBL4066764
6.07	EC50	860	nM	CHEMBL4169454
6.01	EC50	970	nM	CHEMBL4169454
5.43	EC50	3730	nM	CHEMBL4169454
5.31	EC50	4880	nM	CHEMBL4169454

PubChem BioAssay actives

17 with measured affinity, of 22 total; 13 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
[(4E)-2-(hydroxymethyl)-4-[(1-methylindol-3-yl)methylidene]-5-oxooxolan-2-yl]methyl 2-propylpentanoate	1152267: Displacement of [3H]PDBu from recombinant RasGRP1 C1 domain (unknown origin) after 10 mins by scintillation counting analysis in presence of phosphatidylserine	ki	0.0003	uM
[(4E)-2-(hydroxymethyl)-4-[(1-methylindol-5-yl)methylidene]-5-oxooxolan-2-yl]methyl 2-propylpentanoate	1152267: Displacement of [3H]PDBu from recombinant RasGRP1 C1 domain (unknown origin) after 10 mins by scintillation counting analysis in presence of phosphatidylserine	ki	0.0004	uM
[(4E)-2-(hydroxymethyl)-4-[(1-methylindol-7-yl)methylidene]-5-oxooxolan-2-yl]methyl 2-propylpentanoate	1152267: Displacement of [3H]PDBu from recombinant RasGRP1 C1 domain (unknown origin) after 10 mins by scintillation counting analysis in presence of phosphatidylserine	ki	0.0007	uM
[(4E)-2-(hydroxymethyl)-4-[(1-methylindol-6-yl)methylidene]-5-oxooxolan-2-yl]methyl 2-propylpentanoate	1152267: Displacement of [3H]PDBu from recombinant RasGRP1 C1 domain (unknown origin) after 10 mins by scintillation counting analysis in presence of phosphatidylserine	ki	0.0009	uM
[(4E)-2-(hydroxymethyl)-4-[(1-methylindol-4-yl)methylidene]-5-oxooxolan-2-yl]methyl 2-propylpentanoate	1152267: Displacement of [3H]PDBu from recombinant RasGRP1 C1 domain (unknown origin) after 10 mins by scintillation counting analysis in presence of phosphatidylserine	ki	0.0015	uM
[(4Z)-2-(hydroxymethyl)-4-(4-methyl-3-propan-2-ylpentylidene)-5-oxooxolan-2-yl]methyl 1-methylindole-3-carboxylate	1466024: Displacement of [20-3H]phorbol 12,13-dibutyrate from RasGRP1 (unknown origin) in the presence of porcine brain phosphatidylserine by scintillation counting	ki	0.0226	uM
[2-(hydroxymethyl)-4-[[4-[2-(4-methylphenyl)ethynyl]phenyl]methylidene]-5-oxooxolan-2-yl]methyl 1-methylindole-3-carboxylate	1466024: Displacement of [20-3H]phorbol 12,13-dibutyrate from RasGRP1 (unknown origin) in the presence of porcine brain phosphatidylserine by scintillation counting	ki	0.0226	uM
[(4E)-2-(hydroxymethyl)-4-(4-methyl-3-propan-2-ylpentylidene)-5-oxooxolan-2-yl]methyl 1-methylindole-3-carboxylate	1466024: Displacement of [20-3H]phorbol 12,13-dibutyrate from RasGRP1 (unknown origin) in the presence of porcine brain phosphatidylserine by scintillation counting	ki	0.0313	uM
[(4E)-2-(hydroxymethyl)-4-[[4-[2-(4-methylphenyl)ethynyl]phenyl]methylidene]-5-oxooxolan-2-yl]methyl 1-methylindole-3-carboxylate	1466024: Displacement of [20-3H]phorbol 12,13-dibutyrate from RasGRP1 (unknown origin) in the presence of porcine brain phosphatidylserine by scintillation counting	ki	0.0400	uM
[(4E)-4-decylidene-2-(hydroxymethyl)-5-oxooxolan-2-yl]methyl 1-methylindole-3-carboxylate	1466024: Displacement of [20-3H]phorbol 12,13-dibutyrate from RasGRP1 (unknown origin) in the presence of porcine brain phosphatidylserine by scintillation counting	ki	0.0633	uM
[(4E)-2-(hydroxymethyl)-5-oxo-4-(2-propylpentylidene)oxolan-2-yl]methyl 1-methylindole-3-carboxylate	1466024: Displacement of [20-3H]phorbol 12,13-dibutyrate from RasGRP1 (unknown origin) in the presence of porcine brain phosphatidylserine by scintillation counting	ki	0.1330	uM
[2-(hydroxymethyl)-5-oxo-4-propan-2-ylideneoxolan-2-yl]methyl 1-methylindole-3-carboxylate	1466024: Displacement of [20-3H]phorbol 12,13-dibutyrate from RasGRP1 (unknown origin) in the presence of porcine brain phosphatidylserine by scintillation counting	ki	0.6660	uM
[(4E)-2-(hydroxymethyl)-4-[(1-methylindol-3-yl)methylidene]-5-oxooxolan-2-yl]methyl 2,2-dimethylpropanoate	1505442: Activation of GFP-tagged RasGRP1 (unknown origin) expressed in HEK293 cells after 30 mins by immunoblot method	ec50	0.8600	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression, increases methylation	7
Estradiol	affects cotreatment, decreases expression, increases expression	6
Benzo(a)pyrene	decreases expression, increases expression, affects methylation	4
bisphenol A	affects expression, affects methylation, affects cotreatment, decreases methylation, increases expression	3
trichostatin A	affects cotreatment, increases expression	3
Acetaminophen	increases expression, affects cotreatment, decreases expression	2
Ethinyl Estradiol	affects expression	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Progesterone	increases reaction, affects cotreatment, decreases expression, affects expression	2
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression	2
Tobacco Smoke Pollution	decreases methylation, increases expression	2
Genistein	increases expression	2
aristolochic acid I	decreases expression	1
methyleugenol	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
6-hydroxy-5-((p- sulfophenyl)azo)-2-naphthalenesulfonic acid disodium salt	increases expression, affects cotreatment	1
2,5,2’,5’-tetrachlorobiphenyl	decreases expression	1
afimoxifene	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
perfluorooctanoic acid	increases expression	1
ochratoxin A	decreases expression	1
potassium chromate(VI)	increases expression	1
nickel sulfate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression, decreases expression	1
pentanal	increases expression	1
avobenzone	decreases expression	1
homosalate	affects cotreatment, increases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3294522	Binding	Displacement of [3H]PDBu from recombinant RasGRP1 C1 domain (unknown origin) after 10 mins by scintillation counting analysis in presence of phosphatidylserine	Synthesis, biological, and biophysical studies of DAG-indololactones designed as selective activators of RasGRP. — Bioorg Med Chem

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D7Z6	Ubigene A-549 RASGRP1 KO	Cancer cell line	Male
CVCL_D9QB	Ubigene HEK293 RASGRP1 KO	Transformed cell line	Female
CVCL_TI53	HAP1 RASGRP1 (-) 1	Cancer cell line	Male
CVCL_TI54	HAP1 RASGRP1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00000374	PHASE4	COMPLETED	Treatment for First-Episode Schizophrenia
NCT00001656	PHASE4	COMPLETED	Comparison of Clozapine vs Olanzapine in Childhood-Onset Psychotic Disorders
NCT00007774	PHASE4	COMPLETED	To Determine if Olanzapine is More Cost Effective Than Haloperidol for the Treatment of Schizophrenia
NCT00014001	PHASE4	COMPLETED	CATIE- Schizophrenia Trial
NCT00018668	PHASE4	COMPLETED	Antipsychotic Response in Schizophrenia
NCT00034801	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Depression in Patients With Schizophrenia
NCT00034905	PHASE4	COMPLETED	A Comparison of Seroquel vs. Risperidone in Schizophrenia
NCT00036088	PHASE4	COMPLETED	Olanzapine Versus An Active Comparator in the Treatment of Schizophrenia
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044655	PHASE4	COMPLETED	Switching Medication to Treat Schizophrenia
NCT00048828	PHASE4	COMPLETED	Treating Drug-Resistant Childhood Schizophrenia
NCT00053703	PHASE4	COMPLETED	Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS)
NCT00056498	PHASE4	COMPLETED	Risperidone Treatment in Schizophrenia Patients Who Are Currently Taking Clozapine
NCT00061802	PHASE4	COMPLETED	Efficacy and Safety of Two Atypical Antipsychotics vs. Placebo in Patients With an Acute Exacerbation of Either Schizophrenia or Schizoaffective Disorder
NCT00080327	PHASE4	COMPLETED	Study of Three Doses of Aripiprazole in Patients With Acute Schizophrenia
NCT00088049	PHASE4	COMPLETED	Study of Olanzapine vs. Aripiprazole in the Treatment of Schizophrenia
NCT00090012	PHASE4	COMPLETED	Comparison of Continuing Olanzapine to Switching to Quetiapine in Overweight or Obese Patients With Schizophrenia and Schizoaffective Disorder
NCT00100776	PHASE4	COMPLETED	Efficacy of High Dose Olanzapine for the Treatment of Schizophrenia and Schizoaffective Disorder
NCT00103571	PHASE4	COMPLETED	Olanzapine Versus Aripiprazole in the Treatment of Acutely Ill Patients With Schizophrenia
NCT00108368	PHASE4	COMPLETED	The Effects of Risperidone and Olanzapine on Thinking
NCT00114595	PHASE4	COMPLETED	Ethyl-Eicosapentaenoic Acid and Tardive Dyskinesia
NCT00130923	PHASE4	COMPLETED	Risperidone Long-acting Versus Oral Risperidone in Patients With Schizophrenia and Alcohol Use Disorder
NCT00137020	PHASE4	COMPLETED	Clinical Effect Of Cross Titration Of Antipsychotics With Ziprasidone In Schizophrenia Or Schizoaffective Disorder
NCT00140166	PHASE4	COMPLETED	Treatment of Acute Schizophrenia With Vitamin Therapy
NCT00145847	PHASE4	COMPLETED	Naltrexone Treatment of Alcohol Abuse in Schizophrenia
NCT00148564	PHASE4	COMPLETED	Energy Homeostasis Under Treatment With Atypical Antipsychotics
NCT00156715	PHASE4	COMPLETED	Efficacy of Quetiapine in the Treatment of Patients With Schizophrenia and a Comorbid Substance Use Disorder
NCT00158223	PHASE4	COMPLETED	Effectiveness of Pimozide in Augmenting the Effects of Clozapine in the Treatment of Schizophrenia
NCT00159081	PHASE4	COMPLETED	One Year Drug Treatment in First-Episode Schizophrenia
NCT00159120	PHASE4	COMPLETED	Maintenance Treatment vs. Stepwise Drug Discontinuation in First-Episode Schizophrenia
NCT00159133	PHASE4	COMPLETED	Prodrome-Based Early Intervention With Antipsychotics vs. Benzodiazepines in First-Episode Schizophrenia
NCT00159757	PHASE4	TERMINATED	12 Week Open, Non-Comparative Switch Study Of Oral Ziprazidone In Previously Treated Schizophrenic Patients
NCT00167817	PHASE4	COMPLETED	Effect of Switch to Aripiprazole on Health and Smoking Parameters in Patients With Schizophrenia: A Pilot Study
NCT00169026	PHASE4	TERMINATED	Alcoholism and Schizophrenia: Effects of Clozapine
NCT00169039	PHASE4	TERMINATED	Clozapine Versus Chlorpromazine for Treatment-Unresponsive Schizophrenia
NCT00169065	PHASE4	COMPLETED	Effectiveness of Clozapine Versus Olanzapine for Treatment-resistant Schizophrenia
NCT00169091	PHASE4	TERMINATED	Clozapine Versus Haloperidol for Treating the First Episode of Schizophrenia
NCT00176423	PHASE4	COMPLETED	Efficacy Study of Galantamine for Cognitive Impairments in Schizophrenia
NCT00176436	PHASE4	COMPLETED	Atomoxetine for Treatment of Weight Gain in Olanzapine or Clozapine Patients
NCT00177008	PHASE4	COMPLETED	Aripiprazole for the Treatment of Schizophrenia With Co-Morbid Social Anxiety