RASGRP2

Summary

RASGRP2 (RAS guanyl releasing protein 2, HGNC:9879) is a protein-coding gene on chromosome 11q13.1, encoding RAS guanyl-releasing protein 2 (Q7LDG7). Functions as a calcium- and DAG-regulated nucleotide exchange factor specifically activating Rap through the exchange of bound GDP for GTP.

The protein encoded by this gene is a brain-enriched nucleotide exchanged factor that contains an N-terminal GEF domain, 2 tandem repeats of EF-hand calcium-binding motifs, and a C-terminal diacylglycerol/phorbol ester-binding domain. This protein can activate small GTPases, including RAS and RAP1/RAS3. The nucleotide exchange activity of this protein can be stimulated by calcium and diacylglycerol. Four alternatively spliced transcript variants encoding two different isoforms have been found for this gene.

Source: NCBI Gene 10235 — RefSeq curated summary.

At a glance

• Gene–disease (curated): platelet-type bleeding disorder 18 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 330 total — 19 pathogenic, 16 likely-pathogenic
• Phenotypes (HPO): 9
• MANE Select transcript: NM_001098671

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9879
Approved symbol	RASGRP2
Name	RAS guanyl releasing protein 2
Location	11q13.1
Locus type	gene with protein product
Status	Approved
Aliases	CALDAG-GEFI
Ensembl gene	ENSG00000068831
Ensembl biotype	protein_coding
OMIM	605577
Entrez	10235

Gene structure

Transcript identifiers

Ensembl transcripts: 42 — 33 protein_coding, 6 retained_intron, 3 nonsense_mediated_decay

ENST00000354024, ENST00000377485, ENST00000377486, ENST00000377487, ENST00000377489, ENST00000377494, ENST00000377497, ENST00000394428, ENST00000394429, ENST00000394430, ENST00000394432, ENST00000419843, ENST00000421556, ENST00000430645, ENST00000431822, ENST00000441258, ENST00000445445, ENST00000464324, ENST00000465852, ENST00000480443, ENST00000488071, ENST00000494001, ENST00000497441, ENST00000892270, ENST00000892271, ENST00000892272, ENST00000892273, ENST00000892274, ENST00000892275, ENST00000892276, ENST00000892277, ENST00000892278, ENST00000892279, ENST00000892280, ENST00000892281, ENST00000892282, ENST00000892283, ENST00000892284, ENST00000892285, ENST00000892286, ENST00000956339, ENST00000956340

RefSeq mRNA: 4 — MANE Select: NM_001098671 NM_001098670, NM_001098671, NM_001318398, NM_153819

CCDS: CCDS31598

Canonical transcript exons

ENST00000394432 — 17 exons

Exon	Start	End
ENSE00000863641	64742010	64742112
ENSE00001397825	64726911	64727131
ENSE00001717531	64742794	64742937
ENSE00001879619	64744003	64744142
ENSE00003460552	64728863	64729042
ENSE00003476439	64741439	64741501
ENSE00003496897	64735903	64735980
ENSE00003519012	64735542	64735664
ENSE00003531695	64739360	64739476
ENSE00003589384	64740013	64740163
ENSE00003612118	64735112	64735227
ENSE00003626381	64730053	64730194
ENSE00003633948	64727296	64727360
ENSE00003642262	64729762	64729798
ENSE00003645367	64740948	64741079
ENSE00003654033	64736753	64737034
ENSE00003788276	64739636	64739809

Expression profiles

Bgee: expression breadth ubiquitous, 253 present calls, max score 99.32.

FANTOM5 (CAGE): breadth broad, TPM avg 14.4805 / max 826.1015, expressed in 749 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
120429	6.4810	331
120426	2.9120	561
120431	2.7548	426
120433	0.9123	190
120428	0.4491	172
206331	0.3687	131
120434	0.2558	124
206330	0.1371	65
120432	0.1286	62
120427	0.0812	32

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.32	gold quality
spleen	UBERON:0002106	97.74	gold quality
monocyte	CL:0000576	97.65	gold quality
leukocyte	CL:0000738	97.51	gold quality
mononuclear cell	CL:0000842	97.51	gold quality
apex of heart	UBERON:0002098	97.17	gold quality
right coronary artery	UBERON:0001625	96.86	gold quality
blood	UBERON:0000178	96.79	gold quality
popliteal artery	UBERON:0002250	96.79	gold quality
tibial artery	UBERON:0007610	96.79	gold quality
lymph node	UBERON:0000029	96.09	gold quality
left coronary artery	UBERON:0001626	95.56	gold quality
left uterine tube	UBERON:0001303	95.55	gold quality
aorta	UBERON:0000947	95.44	gold quality
vermiform appendix	UBERON:0001154	94.61	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.61	gold quality
coronary artery	UBERON:0001621	94.49	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.40	gold quality
lower esophagus	UBERON:0013473	94.35	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.34	gold quality
thoracic aorta	UBERON:0001515	93.98	gold quality
descending thoracic aorta	UBERON:0002345	93.94	gold quality
ascending aorta	UBERON:0001496	93.92	gold quality
right lung	UBERON:0002167	93.84	gold quality
caudate nucleus	UBERON:0001873	93.67	gold quality
mucosa of stomach	UBERON:0001199	93.64	gold quality
right atrium auricular region	UBERON:0006631	93.54	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.29	gold quality
putamen	UBERON:0001874	93.07	gold quality
body of uterus	UBERON:0009853	92.98	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-MTAB-10018	yes	121.03
E-HCAD-10	yes	16.49
E-MTAB-9067	yes	12.73
E-ANND-3	yes	10.02
E-HCAD-1	yes	5.88

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

17 targeting RASGRP2, 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-513B-5P	99.99	69.96	2150
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-1299	99.77	71.24	2389
HSA-MIR-875-3P	99.63	69.47	2548
HSA-MIR-5695	99.41	67.48	1047
HSA-MIR-940	99.37	66.14	2064
HSA-MIR-6128	99.33	67.83	1581
HSA-MIR-6808-5P	99.31	66.23	2150
HSA-MIR-6893-5P	99.31	66.25	2119
HSA-MIR-6074	98.89	69.64	2187
HSA-MIR-640	98.44	66.93	644
HSA-MIR-6865-3P	97.54	64.67	684
HSA-MIR-6749-5P	89.28	58.87	75

Literature-anchored findings (GeneRIF, showing 24)

• CalDAG-GEFI plays a role in inside-out signaling to alphaIIbbeta3 (PMID:12239348)
• analyzed the 5’-flanking region of rasgrp2 gene by a luciferase assay, which revealed that not only a promoter but also silencer regions were present upstream of D1E, suggesting rasgrp2 expression is controlled by a combination of promotion and repression (PMID:20606303)
• NIH3T3 cells were found nonpermissive to mtHSV but they became permissive following transformation with the Rasgrp2 gene. This effect was linked to the activation of the Ras-PKR signaling pathway. (PMID:23530823)
• RasGRP2 increases cell viability and cell-matrix adhesion through increased Ras expression and Rap1 activation, respectively, in endothelial cells. (PMID:23563504)
• phosphorylation of CalDAG-GEFI is a critical mechanism by which PKA controls Rap1b-dependent platelet aggregation (PMID:23611601)
• Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding. (PMID:24958846)
• RasGRP2 is exceptional in that its C1 domain has very weak binding affinity (Kd = 2890 +/- 240 nm for [(3)H]phorbol 12,13-dibutyrate. We have identified four amino acid residues responsible for this lack of sensitivity. Replacing Asn(7), Ser(8), Ala(19), and Ile(21) with the corresponding residues from RasGRP1/3 (Thr(7), Tyr(8), Gly(19), and Leu(21), respectively) conferred potent binding affinity (Kd = 1.47 +/- 0.03 nm). (PMID:27022025)
• These studies identify RasGRP2 as a novel substrate of ERK1/2 and define a negative-feedback loop that regulates the BRaf-MEK-ERK signaling cascade. This negative-feedback loop determines the amplitude and duration of active ERK1/2. (PMID:27107697)
• These patients are the first cases of a CalDAG-GEFI deficiency due to homozygous RASGRP2 mutations that are linked to defects in both leukocyte and platelet integrin activation. (PMID:27235135)
• Eleven cases with unexplained bleeding or platelet disorders harbored 11 different, previously unreported RASGRP2 variants that were biallelic and likely pathogenic. (PMID:28637664)
• we here describe a novel mutation in RASGRP2 that affects both expression and function of CalDAG-GEFI and that causes impaired platelet adhesive function and significant bleeding in humans. (PMID:28726538)
• results indicate that CD38 promotes RasGRP2/Rap1-mediated CLL cell adhesion and migration by increasing intracellular Ca2+ levels. (PMID:29970392)
• RASGRP2 was identified to be involved in the pathogenesis of rheumatoid arthritis by promoting adhesion, migration and IL-6 production from fibroblast-like synoviocytes (PMID:30076153)
• RASGRP2 mutation is associated with bleeding disorders. (PMID:31724816)
• RasGRP2 Structure, Function and Genetic Variants in Platelet Pathophysiology. (PMID:32041177)
• A novel missense variant in the RASGRP2 gene in patients with moderate to severe bleeding disorder. (PMID:32609603)
• RasGRP2 inhibits glyceraldehyde-derived toxic advanced glycation end-products from inducing permeability in vascular endothelial cells. (PMID:33536515)
• Mutations in RASGRP2 gene identified in patients misdiagnosed as Glanzmann thrombasthenia patients. (PMID:33711653)
• The Role of RASGRP2 in Vascular Endothelial Cells-A Mini Review. (PMID:34681791)
• CalDAG-GEFI Deficiency in a Family with Symptomatic Heterozygous and Homozygous Carriers of a Likely Pathogenic Variant in RASGRP2. (PMID:34830306)
• Novel RASGRP2 variants in platelet function defects: Indian study. (PMID:35122233)
• RASGRP2 is a potential immune-related biomarker and regulates mitochondrial-dependent apoptosis in lung adenocarcinoma. (PMID:36817422)
• [Study on the Role of RASGRP2 in Vascular Endothelial Cells]. (PMID:37914339)
• NEDD4L-mediated RASGRP2 suppresses high-glucose and oxLDL-induced vascular endothelial cell dysfunctions by activating Rap1 and R-Ras. (PMID:39260747)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	rasgrp2	ENSDARG00000062328
danio_rerio	RASGRP2	ENSDARG00000099092
mus_musculus	Rasgrp2	ENSMUSG00000032946
rattus_norvegicus	Rasgrp2	ENSRNOG00000021098

Paralogs (24): RASGRF1 (ENSG00000058335), 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), RASGRP1 (ENSG00000172575), RASGEF1A (ENSG00000198915), RGL3 (ENSG00000205517), RGL2 (ENSG00000237441)

Protein

Protein identifiers

RAS guanyl-releasing protein 2 — Q7LDG7 (reviewed: Q7LDG7)

Alternative names: Calcium and DAG-regulated guanine nucleotide exchange factor I, Cdc25-like protein, F25B3.3 kinase-like protein

All UniProt accessions (10): Q7LDG7, A6NHE2, A6NJ28, A8MTF9, A8MVK8, C9JKH6, C9JZ82, E7EM78, E7EMB4, E7EWQ7

UniProt curated annotations — full annotation on UniProt →

Function. Functions as a calcium- and DAG-regulated nucleotide exchange factor specifically activating Rap through the exchange of bound GDP for GTP. May also activate other GTPases such as RRAS, RRAS2, NRAS, KRAS but not HRAS. Functions in aggregation of platelets and adhesion of T-lymphocytes and neutrophils probably through inside-out integrin activation. May function in the muscarinic acetylcholine receptor M1/CHRM1 signaling pathway.

Subunit / interactions. Forms a signaling complex with RAP1 and BRAF. Interacts with RAP1. Interacts with F-actin.

Subcellular location. Cytoplasm. Cytosol. Cell membrane. Synapse. Synaptosome. Cell projection. Ruffle membrane.

Tissue specificity. Detected in platelets, neutrophils and T lymphocytes (at protein level). Expressed in brain where it is enriched in the striatum. Also expressed in the hematopoietic system. Detected in heart, brain, lung, placenta, liver, skeletal muscle and kidney.

Post-translational modifications. Isoform 2 is palmitoylated and myristoylated.

Disease relevance. Bleeding disorder, platelet-type, 18 (BDPLT18) [MIM:615888] A disorder characterized by increased bleeding tendency due to platelet dysfunction. Clinical features include epistaxis, hematomas, bleeding after tooth extraction, and menorrhagia. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Isoform 1 and isoform 2 are differently regulated by calcium and DAG.

Domain organisation. The N-terminal Ras-GEF domain mediates association with F-actin.

Miscellaneous. The corresponding protein is not undetectable.

Similarity. Belongs to the RASGRP family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q7LDG7-1	1, CalDAG-GEFI, CalDAG-GEFIa	yes
Q7LDG7-2	2, RasGRP2
Q7LDG7-3	3, CalDAG-GEFIb
Q7LDG7-4	4

RefSeq proteins (4): NP_001092140, NP_001092141, NP_001305327, NP_722541 (=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
IPR023578	Ras_GEF_dom_sf	Homologous_superfamily
IPR036964	RASGEF_cat_dom_sf	Homologous_superfamily
IPR046349	C1-like_sf	Homologous_superfamily

Pfam: PF00130, PF00617, PF00618, PF13499

UniProt features (70 total): helix 28, binding site 10, sequence variant 7, modified residue 5, domain 4, splice variant 4, strand 3, turn 2, region of interest 2, lipid moiety-binding region 2, chain 1, zinc finger region 1, initiator methionine 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6AXF	X-RAY DIFFRACTION	3.1
2MA2	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q7LDG7-F1	77.48	0.44

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 (10): 443; 445; 450; 468; 470; 472; 474; 479; 439; 441

Post-translational modifications (7): 116, 117, 147, 554, 576, 2, 7

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-114508	Effects of PIP2 hydrolysis
R-HSA-2871837	FCERI mediated NF-kB activation
R-HSA-354192	Integrin signaling
R-HSA-392517	Rap1 signalling

MSigDB gene sets: 364 (showing top): REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_PLATELET_AGGREGATION_PLUG_FORMATION, PEREZ_TP63_TARGETS, LFA1_Q6, REACTOME_PLATELET_ACTIVATION_SIGNALING_AND_AGGREGATION, KEGG_MAPK_SIGNALING_PATHWAY, SP3_Q3, STEARMAN_LUNG_CANCER_EARLY_VS_LATE_DN, GOBP_GROWTH, GOBP_REGULATION_OF_GTPASE_ACTIVITY, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, TGACCTY_ERR1_Q2, GOCC_RUFFLE, GGGTGGRR_PAX4_03

GO Biological Process (6): regulation of cell growth (GO:0001558), signal transduction (GO:0007165), Ras protein signal transduction (GO:0007265), positive regulation of GTPase activity (GO:0043547), cellular response to calcium ion (GO:0071277), small GTPase-mediated signal transduction (GO:0007264)

GO Molecular Function (7): 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), GTPase regulator activity (GO:0030695), metal ion binding (GO:0046872)

GO Cellular Component (8): cytosol (GO:0005829), plasma membrane (GO:0005886), ruffle membrane (GO:0032587), neuron projection (GO:0043005), synapse (GO:0045202), cytoplasm (GO:0005737), membrane (GO:0016020), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-6 pathways:

Category	Pathways
G alpha (q) signalling events	1
Platelet activation, signaling and aggregation	1
Fc epsilon receptor (FCERI) signaling	1
Signal Transduction	1
Platelet Aggregation (Plug Formation)	1
Adaptive Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
GTPase activity	2
cell growth	1
regulation of growth	1
regulation of cellular component organization	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
regulation of GTPase activity	1
positive regulation of hydrolase activity	1
response to calcium ion	1
cellular response to metal ion	1
intracellular signaling cassette	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
metal ion binding	1
transition metal ion binding	1
binding	1
lipid binding	1
nucleoside-triphosphatase regulator activity	1
cation binding	1
cytoplasm	1
membrane	1
cell periphery	1
ruffle	1
cell projection membrane	1
leading edge membrane	1
plasma membrane bounded cell projection	1
cell junction	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1672 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RASGRP2	FERMT3	Q86UX7	898
RASGRP2	RAP1B	P09526	768
RASGRP2	RAP1A	P10113	712
RASGRP2	NRXN2	Q9P2S2	670
RASGRP2	ITGB3	P05106	665
RASGRP2	ITGB2	P05107	644
RASGRP2	TLN1	Q9Y490	634
RASGRP2	RABIF	P47224	631
RASGRP2	RASD1	Q9Y272	571
RASGRP2	RASA3	Q14644	571
RASGRP2	ITGB1	P05556	523
RASGRP2	ICAM1	P05362	513
RASGRP2	NRAS	P01111	487
RASGRP2	RASA1	P20936	481
RASGRP2	RAP1GAP	P47736	476

IntAct

5 interactions, top by confidence:

A	B	Type	Score
RASGRP2	ALAD	psi-mi:“MI:0915”(physical association)	0.400
	RASGRP2	psi-mi:“MI:0915”(physical association)	0.000
DISP3	RASGRP2	psi-mi:“MI:0915”(physical association)	0.000
RASGRP2	FAM118B	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (11): RASGRP2 (Reconstituted Complex), RASGRP2 (Affinity Capture-MS), PTCHD2 (Two-hybrid), RASGRP2 (Affinity Capture-RNA), ALAD (Affinity Capture-MS), RASGRP2 (Protein-peptide), RASGRP2 (Affinity Capture-MS), RASGRP2 (Cross-Linking-MS (XL-MS)), RASGRP2 (Two-hybrid), RASGRP2 (Affinity Capture-RNA), APP (Reconstituted Complex)

ESM2 similar proteins: A5PK26, A6N9I4, F1LYQ8, F1M386, F1MSG6, F1PBJ0, F8VPU2, O00329, O15068, O35904, O94887, O95398, P0C643, Q0VGW0, Q15027, Q32N25, Q3TBD2, Q3U5C8, Q4R623, Q5R9B2, Q5RAB8, Q5RB40, Q5ZLD2, Q60695, Q61210, Q63406, Q64096, Q66K14, Q68DX3, Q68EF8, Q6DCK3, Q6P112, Q7LDG7, Q8BH88, Q8CHG7, Q8IV61, Q8K2H4, Q8TEU7, Q8VCC8, Q8WUY9

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
MAPK1	“down-regulates activity”	RASGRP2	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	19
Likely pathogenic	16
Uncertain significance	111
Likely benign	124
Benign	38

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
139647	NM_001098671.2(RASGRP2):c.742G>T (p.Gly248Trp)	Pathogenic
1677270	NM_001098671.2(RASGRP2):c.337C>T (p.Arg113Ter)	Pathogenic
1677271	NM_001098671.2(RASGRP2):c.1142C>T (p.Ser381Phe)	Pathogenic
1679094	NM_001098671.2(RASGRP2):c.706C>T (p.Gln236Ter)	Pathogenic
2019503	NM_001098671.2(RASGRP2):c.270dup (p.Asp91Ter)	Pathogenic
2114720	NM_001098671.2(RASGRP2):c.243C>G (p.Tyr81Ter)	Pathogenic
2730192	NM_001098671.2(RASGRP2):c.973del (p.Ala325fs)	Pathogenic
2737271	NM_001098671.2(RASGRP2):c.1195_1196dup (p.Pro401fs)	Pathogenic
2772846	NM_001098671.2(RASGRP2):c.204dup (p.Asn69fs)	Pathogenic
3691677	NM_001098671.2(RASGRP2):c.893del (p.Gly298fs)	Pathogenic
4086478	NM_001098671.2(RASGRP2):c.163A>T (p.Lys55Ter)	Pathogenic
4728966	NM_001098671.2(RASGRP2):c.972del (p.Ala325fs)	Pathogenic
4819244	RASGRP2, SER381PHE	Pathogenic
4819245	Q236*	Pathogenic
4819246	R113*	Pathogenic
4819247	G305D	Pathogenic
4819248	C296Y	Pathogenic
4819249	RASGRP2, IVS2, G-C, -1	Pathogenic
812732	NM_001098671.2(RASGRP2):c.1479dup (p.Arg494fs)	Pathogenic
1677269	NM_001098671.2(RASGRP2):c.887G>A (p.Cys296Tyr)	Likely pathogenic
1684408	NM_001098671.2(RASGRP2):c.742G>C (p.Gly248Arg)	Likely pathogenic
2748895	NM_001098671.2(RASGRP2):c.239+1G>A	Likely pathogenic
2999092	NM_001098671.2(RASGRP2):c.1173+1G>A	Likely pathogenic
3053141	NM_001098671.2(RASGRP2):c.1412+2T>C	Likely pathogenic
417937	NM_001098671.2(RASGRP2):c.1480dup (p.Arg494fs)	Likely pathogenic
4541632	NM_001098671.2(RASGRP2):c.742G>A (p.Gly248Arg)	Likely pathogenic
627041	NM_001098671.2(RASGRP2):c.239+2T>G	Likely pathogenic
627154	NM_001098671.2(RASGRP2):c.866A>G (p.Tyr289Cys)	Likely pathogenic
627169	NM_001098671.2(RASGRP2):c.999G>C (p.Lys333Asn)	Likely pathogenic
627184	NM_001098671.2(RASGRP2):c.914G>A (p.Gly305Asp)	Likely pathogenic

SpliceAI

3292 predictions. Top by Δscore:

Variant	Effect	Δscore
11:64729039:CAGG:C	acceptor_gain	1.0000
11:64729043:C:CC	acceptor_gain	1.0000
11:64735105:T:TA	donor_gain	1.0000
11:64735110:A:AC	donor_gain	1.0000
11:64735111:C:CC	donor_gain	1.0000
11:64735223:ACAGA:A	acceptor_gain	1.0000
11:64735224:CAGA:C	acceptor_gain	1.0000
11:64735224:CAGAC:C	acceptor_gain	1.0000
11:64735226:GA:G	acceptor_gain	1.0000
11:64735226:GAC:G	acceptor_loss	1.0000
11:64735227:AC:A	acceptor_loss	1.0000
11:64735228:C:CC	acceptor_gain	1.0000
11:64735229:T:G	acceptor_loss	1.0000
11:64735236:C:CT	acceptor_gain	1.0000
11:64735238:C:CT	acceptor_gain	1.0000
11:64735248:C:CT	acceptor_gain	1.0000
11:64735250:C:CT	acceptor_gain	1.0000
11:64735256:C:CT	acceptor_gain	1.0000
11:64735256:C:T	acceptor_gain	1.0000
11:64735257:A:T	acceptor_gain	1.0000
11:64735665:C:CC	acceptor_gain	1.0000
11:64735896:C:CA	donor_gain	1.0000
11:64736750:CAC:C	donor_loss	1.0000
11:64736751:A:AC	donor_gain	1.0000
11:64736751:ACCG:A	donor_loss	1.0000
11:64736752:C:CT	donor_gain	1.0000
11:64737030:CAGAG:C	acceptor_gain	1.0000
11:64737031:AGAG:A	acceptor_gain	1.0000
11:64737032:GAG:G	acceptor_gain	1.0000
11:64737033:AG:A	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000200549 (11:64740952 T>C,G), RS1000545106 (11:64742707 G>A,C,T), RS1000615019 (11:64741208 C>A,T), RS1000692502 (11:64736243 C>T), RS1000723233 (11:64736627 A>C), RS1000859029 (11:64728348 T>C), RS1000938385 (11:64742429 G>A), RS1001076490 (11:64727466 A>C), RS1001337385 (11:64729511 A>C,G), RS1001745483 (11:64728888 A>G,T), RS1001787201 (11:64741631 G>A), RS1001883358 (11:64737170 C>T), RS1001908153 (11:64735802 A>G), RS1002335679 (11:64730866 G>A,T), RS1002485713 (11:64730302 G>A,T)

Disease associations

OMIM: gene MIM:605577 | disease phenotypes: MIM:615888

GenCC curated gene-disease

Disease	Classification	Inheritance
platelet-type bleeding disorder 18	Definitive	Autosomal recessive
osteopetrosis	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
platelet-type bleeding disorder 18	Definitive	AR

Mondo (3): platelet-type bleeding disorder 18 (MONDO:0014386), thrombocytopenia (MONDO:0002049), osteopetrosis (MONDO:0017198)

Orphanet (1): Bleeding disorder due to CalDAG-GEFI deficiency (Orphanet:420566)

HPO phenotypes

9 total (9 of 9 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000132	Menorrhagia
HP:0000421	Epistaxis
HP:0000978	Bruising susceptibility
HP:0003010	Prolonged bleeding time
HP:0004866	Impaired ADP-induced platelet aggregation
HP:0006298	Prolonged bleeding after dental extraction
HP:0008148	Impaired epinephrine-induced platelet aggregation
HP:0011463	Childhood onset

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST001163_5	Urate levels	6.000000e-11

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D010022	Osteopetrosis	C05.116.099.708.702.678
D013921	Thrombocytopenia	C15.378.140.855; C15.378.243.937

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs2230414	RASGRP2		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, increases methylation	7
entinostat	increases expression, affects cotreatment	2
Nickel	increases expression	2
Silicon Dioxide	decreases methylation, decreases expression	2
Particulate Matter	increases expression	2
aristolochic acid I	increases expression	1
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
butyraldehyde	increases expression	1
perfluorooctanoic acid	decreases expression	1
pentanal	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
perfluorohexanesulfonic acid	decreases expression	1
dorsomorphin	increases expression, affects cotreatment	1
bisphenol S	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	increases expression	1
Decitabine	affects expression	1
Panobinostat	affects cotreatment, increases expression	1
Air Pollutants	affects expression, increases abundance	1
Vehicle Emissions	increases expression	1
Benzo(a)pyrene	increases methylation	1
Carbamazepine	affects expression	1
Cisplatin	affects expression	1
Dexamethasone	affects cotreatment, decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D8UE	Ubigene HCT 116 RASGRP2 KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00039858	PHASE4	COMPLETED	Evaluation of Argatroban Injection in Pediatric Patients Requiring Anticoagulant Alternatives to Heparin
NCT00239733	PHASE4	TERMINATED	Anti-D for Treating Thrombocytopenia in Adults Infected With Hepatitis C Virus With or Without HIV Co-Infection
NCT00907478	PHASE4	COMPLETED	Study on Bone Marrow Morphology in Adults Receiving Romiplostim for Treatment of Thrombocytopenia Associated With Immune Thrombocytopenia Purpura (ITP)
NCT01727401	PHASE4	TERMINATED	Thromboprophylaxis of Venous Thromboembolism in Acutely-ill Medical Inpatients With Thrombocytopenia
NCT02032134	PHASE4	TERMINATED	Protocol for the Infusion of Buffy Coat-derived Cryopreserved Platelets in Patients With Severe Thrombocytopenia
NCT02267993	PHASE4	COMPLETED	Efficacy and Safety of rhTPO for the Treatment of Thrombocytopenia After Chemotherapy in AML Patients
NCT03633019	PHASE4	UNKNOWN	High-dose Use of rhTPO in CIT Patients
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04906083	PHASE4	UNKNOWN	Avatrombopag in Patients With End-stage Liver Disease and Thrombocytopenia
NCT05217719	PHASE4	UNKNOWN	Effects of Recombinant Human Thrombopoietin on Platelet Levels in ICU Patients
NCT05255003	PHASE4	RECRUITING	STrategies for Anticoagulation in Patients With thRombocytopenia and Cancer-associated Thrombosis
NCT05382013	PHASE4	UNKNOWN	Efficacy and Safety of Avatrombopag for Treating TCP in HBV-ACLF Patients Receiving ALSS Treatment
NCT05944458	PHASE4	COMPLETED	Efficacy of Intravenous N-Acetylcysteine in Preventing Linezolid-Induced Thrombocytopenia in Critically Ill Patients
NCT06562738	PHASE4	RECRUITING	Clinical Study on Efficacy and Safety of Hetrombopag in the Preoperative Patients of Thrombocytopenia
NCT00004402	PHASE3	COMPLETED	Phase III Randomized Study of Interferon Gamma in Children With Severe, Congenital Osteopetrosis
NCT00037791	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00039910	PHASE3	COMPLETED	Safety and Efficacy of (PN-152,243)/PN-196,444 in the Prevention of Thrombocytopenia
NCT00073580	PHASE3	COMPLETED	Angiomax in Patients With HIT/HITTS Type II Undergoing Off-Pump Coronary Artery Bypass Grafting (CABG) (CHOOSE)
NCT00102323	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Refractory to Splenectomy
NCT00102336	PHASE3	COMPLETED	AMG 531 Treatment of Thrombocytopenic Subjects With Immune (Idiopathic) Thrombocytopenic Purpura (ITP) Prior to Splenectomy
NCT00116688	PHASE3	COMPLETED	Open Label Extension Study of Romiplostim (AMG 531) in Thrombocytopenic Patients With Immune (Idiopathic) Thrombocytopenic Purpura (ITP)
NCT00128713	PHASE3	COMPLETED	Optimal Platelet Dose Strategy for Management of Thrombocytopenia
NCT00151866	PHASE3	COMPLETED	Efficacy of Transfusions With Platelets Stored in Platelet Additive Solution II Versus Plasma
NCT00261924	PHASE3	COMPLETED	Efficacy and Safety Study of Platelets Treated for Pathogen Inactivation and Stored for Up to Seven Days
NCT00415532	PHASE3	COMPLETED	Romiplostim (AMG 531) Versus Medical Standard of Care for Immune (Idiopathic) Thrombocytopenic Purpura
NCT00420914	PHASE3	TERMINATED	Strategies for Transfusion of Platelets (SToP)
NCT00501345	PHASE3	TERMINATED	Aspirin in Patients With Myocardial Infarction and Thrombocytopenia
NCT00508820	PHASE3	COMPLETED	An Open Label Study of Romiplostim in Adult Thrombocytopenic Subjects With ITP
NCT00678587	PHASE3	TERMINATED	Eltrombopag To Reduce The Need For Platelet Transfusion In Subjects With Chronic Liver Disease And Thrombocytopenia Undergoing Elective Invasive Procedures
NCT01438840	PHASE3	COMPLETED	Efficacy and Safety of Oral E5501 Plus Standard of Care for the Treatment of Thrombocytopenia in Adults With Chronic Immune Thrombocytopenia (Amendment 02)
NCT01444417	PHASE3	COMPLETED	Safety and Efficacy Study of Romiplostim to Treat Immune Thrombocytopenia (ITP) in Pediatric Patients
NCT01805648	PHASE3	UNKNOWN	Efficacy and Safety Study of Maintenance Treatment With rhTPO in Thrombocytopenic Subjects With ITP
NCT02244658	PHASE3	UNKNOWN	Recombinant Human Thrombopoietin (rhTPO) in Management of Chemotherapy-induced Thrombocytopenia in Acute Myelocytic Leukemia
NCT02389621	PHASE3	COMPLETED	Safety and Efficacy Study of Lusutrombopag for Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Elective Invasive Procedures
NCT02444728	PHASE3	TERMINATED	Cyclophosphamide and Hydroxychloroquine for Thrombocytopenia in SLE
NCT02487563	PHASE3	COMPLETED	Prospective Study of Patients With Thrombocytopenia Following HSCT
NCT02578901	PHASE3	COMPLETED	American Trial Using Tranexamic Acid in Thrombocytopenia
NCT03326843	PHASE3	TERMINATED	Avatrombopag for the Treatment of Thrombocytopenia in Adults Scheduled for a Surgical Procedure
NCT03515096	PHASE3	COMPLETED	Eltrombopag vs. rhTPO to Increase Platelet Level After HSCT
NCT05563064	PHASE3	UNKNOWN	Effect of Herbal Formulation on Thrombocytes Count