RAP1B

Summary

RAP1B (RAP1B, member of RAS oncogene family, HGNC:9857) is a protein-coding gene on chromosome 12q15, encoding Ras-related protein Rap-1b (P61224). GTP-binding protein that possesses intrinsic GTPase activity. It is a selective cancer dependency (DepMap: 29.1% of cell lines).

This gene encodes a member of the RAS-like small GTP-binding protein superfamily. Members of this family regulate multiple cellular processes including cell adhesion and growth and differentiation. This protein localizes to cellular membranes and has been shown to regulate integrin-mediated cell signaling. This protein also plays a role in regulating outside-in signaling in platelets. Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 3, 5, 6 and 9.

Source: NCBI Gene 5908 — RefSeq curated summary.

At a glance

• Gene–disease (curated): thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies (Strong, GenCC)
• GWAS associations: 4
• Clinical variants (ClinVar): 56 total — 4 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 77
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 1 cancer types
• Cancer dependency (DepMap): dependent in 29.1% of screened cell lines
• MANE Select transcript: NM_001010942

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9857
Approved symbol	RAP1B
Name	RAP1B, member of RAS oncogene family
Location	12q15
Locus type	gene with protein product
Status	Approved
Aliases	K-REV, RAL1B, DKFZp586H0723
Ensembl gene	ENSG00000127314
Ensembl biotype	protein_coding
OMIM	179530
Entrez	5908

Gene structure

Transcript identifiers

Ensembl transcripts: 58 — 53 protein_coding, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000250559, ENST00000341355, ENST00000378985, ENST00000393436, ENST00000422358, ENST00000425247, ENST00000450214, ENST00000453560, ENST00000460800, ENST00000463493, ENST00000485252, ENST00000489473, ENST00000501412, ENST00000534899, ENST00000535492, ENST00000537460, ENST00000538283, ENST00000538877, ENST00000538980, ENST00000539091, ENST00000540209, ENST00000540781, ENST00000541167, ENST00000541216, ENST00000541386, ENST00000541968, ENST00000542018, ENST00000542145, ENST00000543393, ENST00000543697, ENST00000544639, ENST00000545270, ENST00000545720, ENST00000877913, ENST00000877914, ENST00000877915, ENST00000877916, ENST00000877917, ENST00000877918, ENST00000877919, ENST00000877920, ENST00000877921, ENST00000877922, ENST00000934200, ENST00000934201, ENST00000934202, ENST00000954494, ENST00000954495, ENST00000954496, ENST00000954497, ENST00000954498, ENST00000954499, ENST00000954500, ENST00000954501, ENST00000954502, ENST00000954503, ENST00000954504, ENST00000954505

RefSeq mRNA: 6 — MANE Select: NM_001010942 NM_001010942, NM_001251917, NM_001251918, NM_001251921, NM_001251922, NM_015646

CCDS: CCDS58252, CCDS58253, CCDS58254, CCDS8984

Canonical transcript exons

ENST00000250559 — 8 exons

Exon	Start	End
ENSE00002236571	68659280	68671901
ENSE00002259959	68610899	68611043
ENSE00003460043	68651995	68652051
ENSE00003473655	68650400	68650468
ENSE00003477468	68657101	68657217
ENSE00003505440	68648699	68648781
ENSE00003587335	68656306	68656449
ENSE00003613889	68654112	68654252

Expression profiles

Bgee: expression breadth ubiquitous, 145 present calls, max score 99.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 48.7358 / max 390.6148, expressed in 1824 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
126597	43.0929	1824
126598	3.5673	1547
126599	1.6501	717
206779	0.1848	80
126600	0.1237	49
126605	0.1169	45

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.47	gold quality
leukocyte	CL:0000738	99.44	gold quality
calcaneal tendon	UBERON:0003701	99.35	gold quality
granulocyte	CL:0000094	99.02	gold quality
lymph node	UBERON:0000029	99.02	gold quality
vermiform appendix	UBERON:0001154	98.91	gold quality
endometrium	UBERON:0001295	98.89	gold quality
smooth muscle tissue	UBERON:0001135	98.88	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	98.87	gold quality
popliteal artery	UBERON:0002250	98.76	gold quality
tibial artery	UBERON:0007610	98.76	gold quality
bone element	UBERON:0001474	98.69	gold quality
bone marrow	UBERON:0002371	98.69	gold quality
artery	UBERON:0001637	98.67	gold quality
subcutaneous adipose tissue	UBERON:0002190	98.66	gold quality
adipose tissue	UBERON:0001013	98.64	gold quality
omental fat pad	UBERON:0010414	98.61	gold quality
gall bladder	UBERON:0002110	98.56	gold quality
bone marrow cell	CL:0002092	98.54	gold quality
islet of Langerhans	UBERON:0000006	98.54	gold quality
placenta	UBERON:0001987	98.54	gold quality
right lung	UBERON:0002167	98.50	gold quality
corpus callosum	UBERON:0002336	98.50	gold quality
adrenal tissue	UBERON:0018303	98.48	gold quality
thoracic mammary gland	UBERON:0005200	98.43	gold quality
aorta	UBERON:0000947	98.38	gold quality
uterus	UBERON:0000995	98.37	gold quality
lung	UBERON:0002048	98.34	gold quality
rectum	UBERON:0001052	98.30	gold quality
upper lobe of left lung	UBERON:0008952	98.29	gold quality

Single-cell (SCXA)

Detected in 21 experiment(s), a significant marker in 16.

Experiment	Marker?	Max mean expression
E-MTAB-10432	yes	6832.44
E-MTAB-7407	yes	4024.76
E-CURD-112	yes	3968.48
E-HCAD-10	yes	3923.21
E-CURD-98	yes	3021.27
E-HCAD-6	yes	1132.79
E-HCAD-4	yes	99.82
E-HCAD-1	yes	85.58
E-CURD-122	yes	45.26
E-MTAB-6701	yes	41.86
E-MTAB-9221	yes	20.96
E-HCAD-9	yes	19.32
E-MTAB-10042	yes	14.48
E-MTAB-9067	yes	13.45
E-MTAB-8410	yes	13.44

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NEUROG2

miRNA regulators (miRDB)

258 targeting RAP1B, 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-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-4262	100.00	73.26	3931
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-9-5P	100.00	72.28	2361
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-LET-7F-2-3P	99.98	70.98	2588

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 29.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• Relationships between Rap1b, affinity modulation of integrin alpha IIbbeta 3, and the actin cytoskeleton (integrin alpha(IIb)beta(3)) (PMID:11994301)
• Data show that stimulation of a G(i)-dependent signaling pathway causes activation of Rap1B through the action of the PI3K product PtdIns(3,4,5)P(3) and that this process may contribute to potentiation of platelet aggregation. (PMID:12407113)
• RAP1B is prominently expressed in the nucleus of squamous carcinomas. (PMID:13679863)
• PAR-1 and PAR-4 signal Rap1B activation, the ability of thrombin to activate this GTPase independently of secreted ADP involves costimulation of both receptors as well as binding to GPIb-IX-V. (PMID:15078882)
• TPO integrates G(i), but not G(q), stimulation, supports integrin alpha(IIb)beta(3) activation platelet aggregation independently of phospholipase C but requires PI3-kinase and Rap1B (PMID:15863506)
• The RAP1B gene mutation is a rare event in myelodysplastic syndromes(MDS) bone marrow cells, in detecting RAP1B mutations, random mutagenesis was performed in RAP1B exons 2 and 3. (PMID:16118622)
• Rap1b is an important element in integrin-dependent outside-in signaling during platelet adhesion and regulates the cross talk between adhesive receptors. (PMID:16357324)
• These results demonstrate that Rap2b, but not the more abundant Rap1b, is associated to lipid rafts in human platelets. (PMID:18582561)
• Results suggest that Rap1a is a key regulator of fibroblast growth factor 2-induced angiogenesis and together with Rap1b controls endothelial cell functions. (PMID:18625726)
• structure of Epac2 in complex with a cAMP analogue (Sp-cAMPS) and RAP1B by X-ray crystallography and single particle electron microscopy (PMID:18660803)
• Rap1a and Rap1b are essential for the conformational activation of beta1-integrins in endothelial cells (PMID:18805968)
• Inhibition of PI3K or mTOR reduced the level of Rap1B, which acts downstream of Rheb and mTOR. The ubiquitin E3 ligase Smurf2 mediates the restriction of Rap1B by initiating its degradation. (PMID:18842593)
• RAP1 mutation does not play an important role in papillary thyroid carcinoma pathogenesis. (PMID:18948674)
• a mechanistic explanation for the differential effects of Rap1 phosphorylation by PKA on effector protein interaction (PMID:19651783)
• The PTEN-mediated down-regulation of phosphatidylinositol 3-kinase activity may be involved in the regulation of Rap1B-dependent inhibition of Rac1 activity. (PMID:19864456)
• miR-139 decreases proliferation by directly targeting RAP1B (PMID:22642900)
• phosphorylation of CalDAG-GEFI is a critical mechanism by which PKA controls Rap1b-dependent platelet aggregation (PMID:23611601)
• Adenosine signaling reduces prenylation and plasma membrane localization of Rap1B, resulting in enhanced tumor cell scattering and invasiveness. (PMID:23716715)
• High concentrations of extracellular adenosine in the tumor microenvironment can chronically activate A2B receptors to suppress Rap1B prenylation and signaling at the cell membrane, resulting in reduced cell-cell contact and promoting cell scattering. (PMID:23716716)
• optimal cell migration is associated with cycles of Rap1 activation, membrane egress, and inactivation, and requires the regulated phosphorylation of Rap1 by PKA (PMID:23946483)
• findings show Rap1b expression decreased significantly in tubules of renal biopsies from patients with diabetic nephropathy (DN); findings indicate Rap1b ameliorates tubular injury and slows progression of DN by modulation of mitochondrial dysfunction via C/EBP-beta-PGC-1alpha signaling (PMID:24353183)
• TMZ as a standard chemotherapeutic agent for GBM inhibits the Rap1B expression and actin cytoskeleton remodeling to exert its cell killing by upregulating miR-181a/b/c/d subunits (PMID:24573637)
• Hepatitis B virus down-regulated miR-101-3p expression, which resulted in up-regulation of Rap1b, and down-regulation of miR-101-3p or up-regulation of Rap1b promoted proliferation and migration of hepatocellular carcinoma cells (PMID:24697700)
• Rap1b in both smooth muscle and endothelium plays a key role in maintaining blood pressure by controlling normal vascular tone. (PMID:24790136)
• Glucocorticoids mediate induction of microRNA-708 to suppress ovarian cancer metastasis through targeting Rap1B. (PMID:25569036)
• Cholera toxin and beta-adrenergic receptor activation phosphorylate Rap1B and inhibit its prenylation and membrane localization. (PMID:26209110)
• The protein expression of RAP1B and HIF-1 alpha contributed to gastric cancer malignant behavior and poor prognosis. (PMID:26329876)
• In RCC tissues and renal carcinoma cells, miR-28-5p is expressed at a low level and RAP1B is expressed at a high level. miR-28-5p inhibits the tumorigenesis of RCC by directly downregulating RAP1B and influencing the activation of two MAP kinases in the MAPK signaling pathway, p38 and Erk1/2. (PMID:27729617)
• Unlike Rap1B, phosphorylation in the polybasic region of Rap1A does not detectably inhibit its prenylation or its binding to SmgGDS-607. (PMID:27760305)
• describe the methods for expression and purification of the plexin cytoplasmic region in E. coli, and characterization of its GAP activity using a photometric assay. We also provide a protocol for measuring GAP activity of single-chain constructs with Rap covalently linked to the plexin cytoplasmic region (PMID:27787845)
• Data show that RAP1B expression was up-regulated in esophageal squamous cell carcinoma (ESCC) clinical samples and RAP1B interacted with DVL2 and activated Wnt/beta-catenin signaling. (PMID:28119087)
• Aberrant expression of lncRNA AFAP1-AS, a competing endogenous RNA of miR-181a, may involve in the onset and progression of Hirschsprung disease by augmenting the miR-181a target gene, RAP1B. (PMID:28924375)
• Talin-F0 domain binds to Rap1b like canonical Rap1 effectors despite little sequence homology, and disruption of the binding strongly impairs integrin activation, cell adhesion, and cell spreading. (PMID:29170462)
• Rap1b increased Twist 1 expression by targeting its promoter activity to induce proliferation and migration of hepatocellular carcinoma cells. (PMID:29559227)
• findings indicate that CAP1 is a geranylgeranyl-binding partner of Rap1 (PMID:29618512)
• The authors demonstrate for the first time that RAP1 plays both telomeric and nontelomeric roles in regulating human stem cell homeostasis. (PMID:30796637)
• miR-206 inhibits thyroid cancer proliferation and invasion by targeting RAP1B. (PMID:31245877)
• MiR-181a Reduces Platelet Activation via the Inhibition of Endogenous RAP1B. (PMID:31738148)
• miR-200b/c-RAP1B axis represses tumorigenesis and malignant progression of papillary thyroid carcinoma through inhibiting the NF-kappaB/Twist1 pathway. (PMID:31877303)
• MicroRNA-30b-5p functions as a metastasis suppressor in colorectal cancer by targeting Rap1b. (PMID:32112903)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rap1b	ENSDARG00000008867
mus_musculus	Rap1b	ENSMUSG00000052681
rattus_norvegicus	Rap1b	ENSRNOG00000007048
rattus_norvegicus		ENSRNOG00000063623
rattus_norvegicus		ENSRNOG00000066432

Paralogs (35): RALA (ENSG00000006451), REM1 (ENSG00000088320), RASL10A (ENSG00000100276), RASD2 (ENSG00000100302), RASL12 (ENSG00000103710), RHEB (ENSG00000106615), RASD1 (ENSG00000108551), RERGL (ENSG00000111404), RAP1A (ENSG00000116473), RASL11A (ENSG00000122035), RAP2C (ENSG00000123728), RAP2A (ENSG00000125249), RRAS (ENSG00000126458), RASL11B (ENSG00000128045), KRAS (ENSG00000133703), RRAS2 (ENSG00000133818), RERG (ENSG00000134533), REM2 (ENSG00000139890), RIT1 (ENSG00000143622), RALB (ENSG00000144118), RIT2 (ENSG00000152214), MRAS (ENSG00000158186), DIRAS3 (ENSG00000162595), GEM (ENSG00000164949), DIRAS2 (ENSG00000165023), RRAD (ENSG00000166592), RHEBL1 (ENSG00000167550), NKIRAS2 (ENSG00000168256), HRAS (ENSG00000174775), DIRAS1 (ENSG00000176490), RAP2B (ENSG00000181467), ERAS (ENSG00000187682), NKIRAS1 (ENSG00000197885), NRAS (ENSG00000213281), RASL10B (ENSG00000270885)

Protein

Protein identifiers

Ras-related protein Rap-1b — P61224 (reviewed: P61224)

Alternative names: GTP-binding protein smg p21B

All UniProt accessions (19): P61224, B7ZB78, E7ESV4, F5GWU8, F5GX62, F5GYB5, F5GYH7, F5GZG1, F5H004, F5H077, F5H0B7, F5H0S2, F5H491, F5H4H0, F5H500, F5H6R7, F5H7Y6, F5H823, F8WBC0

UniProt curated annotations — full annotation on UniProt →

Function. GTP-binding protein that possesses intrinsic GTPase activity. Contributes to the polarizing activity of KRIT1 and CDH5 in the establishment and maintenance of correct endothelial cell polarity and vascular lumen. Required for the localization of phosphorylated PRKCZ, PARD3 and TIAM1 to the cell junction. Plays a role in the establishment of basal endothelial barrier function.

Subunit / interactions. Heterodimer with RAP1GAP. Interacts with EPAC2. Interacts with SGSM1. Interacts with SGSM2. Interacts with SGSM3. Interacts with KRIT1. Interacts with RAP1GDS1.

Subcellular location. Cell membrane. Cytoplasm. Cytosol. Cell junction.

Disease relevance. Thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies (THC11) [MIM:620654] A form of thrombocytopenia, a hematologic disorder defined by a decrease in the number of platelets in circulating blood, resulting in the potential for increased bleeding and decreased ability for clotting. THC11 is an autosomal dominant, syndromic form. Affected individuals have chronic and persistent thrombocytopenia, dysmorphic facial features, and multiple congenital anomalies with involvement of the cardiovascular, genitourinary, neurologic and skeletal systems. Additional features include leukopenia or anemia, poor growth with microcephaly, hypotonia, and mildly impaired intellectual development or learning disabilities. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Activated by binding to the GTPase-activating protein RAP1GAP. Activated by guanine nucleotide-exchange factor (GEF) EPAC2 in a cAMP-dependent manner.

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

Isoforms (4)

UniProt ID	Names	Canonical?
P61224-1	1	yes
P61224-2	2
P61224-3	3
P61224-4	4

RefSeq proteins (6): NP_001010942, NP_001238846, NP_001238847, NP_001238850, NP_001238851, NP_056461 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001806	Small_GTPase	Family
IPR005225	Small_GTP-bd	Domain
IPR020849	Small_GTPase_Ras-type	Family
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR038851	Rap1	Family

Pfam: PF00071

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (49 total): strand 9, helix 9, mutagenesis site 8, sequence variant 4, binding site 4, modified residue 3, splice variant 3, sequence conflict 2, turn 2, chain 1, propeptide 1, lipid moiety-binding region 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

23 structures.

PDB	Method	Resolution (Å)
4HDO	X-RAY DIFFRACTION	1.67
6OQ4	X-RAY DIFFRACTION	1.75
6OQ3	X-RAY DIFFRACTION	1.85
6UZK	X-RAY DIFFRACTION	1.92
4DXA	X-RAY DIFFRACTION	1.95
4HDQ	X-RAY DIFFRACTION	1.95
8SU8	X-RAY DIFFRACTION	2.01
8T09	X-RAY DIFFRACTION	2.15
3CF6	X-RAY DIFFRACTION	2.2
8T7V	X-RAY DIFFRACTION	2.25
7C7I	X-RAY DIFFRACTION	2.28
7C7J	X-RAY DIFFRACTION	2.39
4MH0	X-RAY DIFFRACTION	2.4
4MGY	X-RAY DIFFRACTION	2.6
4MGK	X-RAY DIFFRACTION	2.7
5KHO	X-RAY DIFFRACTION	2.78
4MGI	X-RAY DIFFRACTION	2.8
6KYK	X-RAY DIFFRACTION	2.82
4MGZ	X-RAY DIFFRACTION	3
6AXF	X-RAY DIFFRACTION	3.1
4M8N	X-RAY DIFFRACTION	3.29
3BRW	X-RAY DIFFRACTION	3.4
6BA6	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P61224-F1	92.33	0.81

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 (4): 10–18; 57–61; 116–119; 147–149

Post-translational modifications (4): 181, 181, 39, 179

Mutagenesis-validated functional residues (8):

Position	Phenotype
25	impairs interaction with krit1.
32	25-fold reduction in rap1gap-stimulated gtpase activity.
32	2-fold reduction in rap1gap-stimulated gtpase activity.
37	strong reduction in nucleotide exchange with epac2.
38	impairs interaction with krit1.
63	abolishes complex formation with rap1gap. loss gtpase activity.
64	abolishes complex formation with rap1gap. loss gtpase activity.
179	abolishes phosphorylation by pka.

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-354192	Integrin signaling
R-HSA-354194	GRB2:SOS provides linkage to MAPK signaling for Integrins
R-HSA-372708	p130Cas linkage to MAPK signaling for integrins
R-HSA-392517	Rap1 signalling
R-HSA-5674135	MAP2K and MAPK activation
R-HSA-6798695	Neutrophil degranulation
R-HSA-6802946	Signaling by moderate kinase activity BRAF mutants
R-HSA-6802948	Signaling by high-kinase activity BRAF mutants
R-HSA-6802952	Signaling by BRAF and RAF1 fusions
R-HSA-6802955	Paradoxical activation of RAF signaling by kinase inactive BRAF
R-HSA-8875555	MET activates RAP1 and RAC1
R-HSA-8950505	Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation
R-HSA-9649948	Signaling downstream of RAS mutants
R-HSA-9656223	Signaling by RAF1 mutants

MSigDB gene sets: 622 (showing top): GSE45365_NK_CELL_VS_BCELL_UP, GOBP_ENDOTHELIAL_CELL_DEVELOPMENT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_EPITHELIUM_DEVELOPMENT, REACTOME_INNATE_IMMUNE_SYSTEM, GNF2_MSN, DORSAM_HOXA9_TARGETS_UP, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, REACTOME_PLATELET_AGGREGATION_PLUG_FORMATION

GO Biological Process (15): cell population proliferation (GO:0008283), calcium-ion regulated exocytosis (GO:0017156), Rap protein signal transduction (GO:0032486), positive regulation of integrin activation (GO:0033625), negative regulation of calcium ion-dependent exocytosis (GO:0045955), establishment of localization in cell (GO:0051649), establishment of endothelial barrier (GO:0061028), positive regulation of ERK1 and ERK2 cascade (GO:0070374), cellular response to cAMP (GO:0071320), modification of postsynaptic structure (GO:0099010), regulation of cell junction assembly (GO:1901888), regulation of establishment of cell polarity (GO:2000114), negative regulation of synaptic vesicle exocytosis (GO:2000301), signal transduction (GO:0007165), small GTPase-mediated signal transduction (GO:0007264)

GO Molecular Function (8): GTPase activity (GO:0003924), G protein activity (GO:0003925), GTP binding (GO:0005525), GDP binding (GO:0019003), protein-containing complex binding (GO:0044877), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (11): lipid droplet (GO:0005811), cytosol (GO:0005829), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), membrane (GO:0016020), azurophil granule membrane (GO:0035577), extracellular exosome (GO:0070062), glutamatergic synapse (GO:0098978), cytoplasm (GO:0005737), endomembrane system (GO:0012505), anchoring junction (GO:0070161)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Oncogenic MAPK signaling	5
Integrin signaling	2
Signal Transduction	1
Platelet Aggregation (Plug Formation)	1
Adaptive Immune System	1
RAF/MAP kinase cascade	1
Innate Immune System	1
MET promotes cell motility	1
Interleukin-12 signaling	1
Signaling by RAS mutants	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
cellular process	2
negative regulation of regulated secretory pathway	2
guanyl ribonucleotide binding	2
binding	2
regulated exocytosis	1
small GTPase-mediated signal transduction	1
positive regulation of protein-containing complex assembly	1
integrin activation	1
regulation of integrin activation	1
calcium-ion regulated exocytosis	1
regulation of calcium ion-dependent exocytosis	1
establishment of localization	1
cellular localization	1
endothelial cell development	1
positive regulation of MAPK cascade	1
ERK1 and ERK2 cascade	1
regulation of ERK1 and ERK2 cascade	1
response to cAMP	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
modification of synaptic structure	1
cell junction assembly	1
regulation of cellular component biogenesis	1
regulation of cellular component organization	1
establishment of cell polarity	1
regulation of establishment or maintenance of cell polarity	1
synaptic vesicle exocytosis	1
regulation of synaptic vesicle exocytosis	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
intracellular signaling cassette	1
ribonucleoside triphosphate phosphatase activity	1
GTPase activity	1
molecular function regulator activity	1
purine ribonucleoside triphosphate binding	1
anion binding	1
nucleoside phosphate binding	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

180 interactions, top by confidence:

A	B	Type	Score
	TOMM70	psi-mi:“MI:0914”(association)	0.980
STAM	HGS	psi-mi:“MI:0914”(association)	0.860
EAF1	ELL2	psi-mi:“MI:0914”(association)	0.840
RIN1	NRAS	psi-mi:“MI:0914”(association)	0.840
MED28	MED19	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
Rapgef4	RAP1B	psi-mi:“MI:0407”(direct interaction)	0.660
RAP1GDS1	DIRAS1	psi-mi:“MI:0914”(association)	0.640
FAM174A	GAK	psi-mi:“MI:0914”(association)	0.640
RALGDS	RAP1B	psi-mi:“MI:0915”(physical association)	0.570
RAP1B	RASSF5	psi-mi:“MI:0915”(physical association)	0.560
RALGDS	RAP1B	psi-mi:“MI:0915”(physical association)	0.560
RAP1B	RALGDS	psi-mi:“MI:0915”(physical association)	0.560
RAP1B	MTUS2	psi-mi:“MI:0915”(physical association)	0.560
CALR	RAP1B	psi-mi:“MI:0915”(physical association)	0.560
DLST	RAP1B	psi-mi:“MI:0915”(physical association)	0.560
RAP1B	NEK7	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (216): RASSF5 (Two-hybrid), RAP1B (Two-hybrid), RAP1B (Affinity Capture-MS), RAP1B (Affinity Capture-MS), RAP1B (Affinity Capture-MS), RAP1B (Affinity Capture-MS), CDC42 (Co-fractionation), RAB5A (Co-fractionation), RAB5B (Co-fractionation), RAB5C (Co-fractionation), RAB7A (Co-fractionation), RAB8A (Co-fractionation), RAB8B (Co-fractionation), STX12 (Co-fractionation), STX7 (Co-fractionation)

ESM2 similar proteins: A5A6J7, A6NIZ1, O42277, P01111, P01112, P01116, P03967, P05774, P08556, P08642, P08644, P08645, P12825, P15064, P18262, P18613, P20171, P22123, P22981, P23175, P32883, P34729, P61223, P61224, P62833, P62834, P62835, P62836, P79800, Q04970, Q05147, Q07983, Q18246, Q2MJK3, Q4R9D4, Q5EFX7, Q5F352, Q5RD87, Q5RDM6, Q5ZHX1

Diamond homologs: A5A6J7, A6NIZ1, A8NU18, B3M185, B3NZR4, B4GFJ8, B4HKC7, B4JFU8, B4LY29, B4NJ72, B4PUP5, C4YKT4, G4MZY8, O42277, O42785, O93856, P01111, P01112, P01113, P01115, P01116, P01119, P01120, P03967, P05774, P08556, P08642, P08644, P08645, P08646, P08647, P0CQ42, P0CQ43, P0CY32, P10114, P12825, P13856, P15064, P18613, P20171

SIGNOR signaling

6 interactions.

A	Effect	B	Mechanism
RAP1GDS1	up-regulates	RAP1B	binding
PRKACA	up-regulates	RAP1B	phosphorylation
DEF6	“up-regulates activity”	RAP1B	binding
RAP1B	“up-regulates activity”	“AL/b2 integrin”	binding
RAPGEF4	“up-regulates activity”	RAP1B	“guanine nucleotide exchange factor”
RAPGEF3	“up-regulates activity”	RAP1B	“guanine nucleotide exchange factor”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 209 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.

GO biological processes:

GO term	Partners	Fold	FDR
Ras protein signal transduction	9	10.0×	4e-04
protein folding	10	5.6×	9e-03

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 1 cancer types — BLCA.

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	4
Likely pathogenic	2
Uncertain significance	11
Likely benign	7
Benign	14

Top pathogenic / likely-pathogenic (6)

Variant ID	HGVS	Classification
2672306	NM_001010942.3(RAP1B):c.35G>T (p.Gly12Val)	Pathogenic
2672307	NM_001010942.3(RAP1B):c.178G>C (p.Gly60Arg)	Pathogenic
2672309	NM_001010942.3(RAP1B):c.35G>A (p.Gly12Glu)	Pathogenic
2674587	NM_001010942.3(RAP1B):c.178G>A (p.Gly60Arg)	Pathogenic
1300148	NM_001010942.3(RAP1B):c.176C>G (p.Ala59Gly)	Likely pathogenic
3906924	NM_001010942.3(RAP1B):c.34G>A (p.Gly12Arg)	Likely pathogenic

SpliceAI

1544 predictions. Top by Δscore:

Variant	Effect	Δscore
12:68611051:GA:G	donor_gain	1.0000
12:68611053:G:GG	donor_gain	1.0000
12:68650396:TCA:T	acceptor_loss	1.0000
12:68650397:CAGA:C	acceptor_loss	1.0000
12:68650398:A:AG	acceptor_gain	1.0000
12:68650398:AG:A	acceptor_loss	1.0000
12:68650398:AGACT:A	acceptor_gain	1.0000
12:68650399:G:GA	acceptor_gain	1.0000
12:68650399:GA:G	acceptor_gain	1.0000
12:68650399:GAC:G	acceptor_gain	1.0000
12:68650399:GACT:G	acceptor_gain	1.0000
12:68650399:GACTG:G	acceptor_gain	1.0000
12:68650465:AAAG:A	donor_loss	1.0000
12:68650466:AAGGT:A	donor_loss	1.0000
12:68650467:AGG:A	donor_loss	1.0000
12:68650468:GGT:G	donor_loss	1.0000
12:68650469:GTAT:G	donor_loss	1.0000
12:68650470:T:A	donor_loss	1.0000
12:68651994:GCAA:G	acceptor_gain	1.0000
12:68654105:A:AG	acceptor_gain	1.0000
12:68654105:ATT:A	acceptor_gain	1.0000
12:68654106:T:G	acceptor_gain	1.0000
12:68654107:T:A	acceptor_gain	1.0000
12:68654109:TAGG:T	acceptor_gain	1.0000
12:68654109:TAGGA:T	acceptor_gain	1.0000
12:68654110:A:AG	acceptor_gain	1.0000
12:68654110:AG:A	acceptor_gain	1.0000
12:68654110:AGGA:A	acceptor_gain	1.0000
12:68654110:AGGAG:A	acceptor_gain	1.0000
12:68654111:G:GC	acceptor_gain	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000100402 (12:68638833 G>A), RS1000135546 (12:68622078 C>T), RS1000229791 (12:68655896 C>T), RS1000242222 (12:68617380 T>C), RS1000256142 (12:68648945 G>A,T), RS1000296038 (12:68636714 C>G,T), RS1000327080 (12:68643871 GAA>G,GA,GAAA), RS1000378239 (12:68650004 T>G), RS1000410620 (12:68649656 G>A), RS1000417570 (12:68655027 C>T), RS1000437630 (12:68615486 G>A), RS1000468513 (12:68654760 A>C), RS1000630011 (12:68661870 C>G,T), RS1000667886 (12:68662063 A>T), RS1000717040 (12:68668084 G>T)

Disease associations

OMIM: gene MIM:179530 | disease phenotypes: MIM:620654

GenCC curated gene-disease

Disease	Classification	Inheritance
thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies	Moderate	AD

Mondo (1): thrombocytopenia 11 with multiple congenital anomalies and dysmorphic facies (MONDO:0958000)

Orphanet (0):

HPO phenotypes

77 total (30 of 77 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000023	Inguinal hernia
HP:0000076	Vesicoureteral reflux
HP:0000089	Renal hypoplasia
HP:0000122	Unilateral renal agenesis
HP:0000194	Open mouth
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000319	Smooth philtrum
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000384	Preauricular skin tag
HP:0000403	Recurrent otitis media
HP:0000414	Bulbous nose
HP:0000426	Prominent nasal bridge
HP:0000480	Retinal coloboma
HP:0000483	Astigmatism
HP:0000494	Downslanted palpebral fissures
HP:0000518	Cataract
HP:0000540	Hypermetropia
HP:0000582	Upslanted palpebral fissure
HP:0000612	Iris coloboma
HP:0000639	Nystagmus
HP:0000678	Dental crowding
HP:0000685	Hypoplasia of teeth

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST000589_1	White blood cell count	3.000000e-08
GCST010266_11	Femoral neck bone mineral density and trunk fat mass adjusted by trunk lean mass	3.000000e-07
GCST010268_5	Femoral neck bone mineral density	9.000000e-07
GCST011743_2	HDL cholesterol levels in HIV infection	1.000000e-05

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007785	femoral neck bone mineral density
EFO:0004612	high density lipoprotein cholesterol measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases abundance, increases expression	3
Air Pollutants	increases abundance, increases oxidation, decreases expression, affects cotreatment	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Particulate Matter	decreases expression, increases abundance, decreases reaction, increases expression	2
FR900359	increases phosphorylation	1
ginger extract	affects cotreatment, affects expression, increases abundance	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
bisphenol A	affects expression, increases abundance, decreases expression, affects cotreatment	1
mono-(2-ethylhexyl)phthalate	increases expression, increases reaction	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
ochratoxin A	affects binding	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
bisphenol B	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases reaction, increases expression	1
jinfukang	decreases expression	1
bisphenol AF	increases expression	1
Oxaliplatin	decreases expression	1
Sunitinib	increases expression	1
Zoledronic Acid	increases expression	1
Arsenic Trioxide	increases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Cyclic AMP	affects binding, increases abundance	1
Arsenic	decreases expression, increases abundance	1
Vehicle Emissions	decreases reaction, increases expression	1
Cadmium	increases palmitoylation, decreases reaction, increases abundance	1
Chelating Agents	affects binding, increases expression	1
Cisplatin	decreases expression	1

Clinical trials (associated diseases)

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