RAP1GAP

Summary

RAP1GAP (RAP1 GTPase activating protein, HGNC:9858) is a protein-coding gene on chromosome 1p36.12, encoding Rap1 GTPase-activating protein 1 (P47736). GTPase activator for the nuclear Ras-related regulatory protein RAP-1A (KREV-1), converting it to the putatively inactive GDP-bound state.

This gene encodes a type of GTPase-activating-protein (GAP) that down-regulates the activity of the ras-related RAP1 protein. RAP1 acts as a molecular switch by cycling between an inactive GDP-bound form and an active GTP-bound form. The product of this gene, RAP1GAP, promotes the hydrolysis of bound GTP and hence returns RAP1 to the inactive state whereas other proteins, guanine nucleotide exchange factors (GEFs), act as RAP1 activators by facilitating the conversion of RAP1 from the GDP- to the GTP-bound form. In general, ras subfamily proteins, such as RAP1, play key roles in receptor-linked signaling pathways that control cell growth and differentiation. RAP1 plays a role in diverse processes such as cell proliferation, adhesion, differentiation, and embryogenesis. Alternative splicing results in multiple transcript variants encoding distinct proteins.

Source: NCBI Gene 5909 — RefSeq curated summary.

At a glance

• GWAS associations: 12
• Clinical variants (ClinVar): 137 total
• MANE Select transcript: NM_002885

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9858
Approved symbol	RAP1GAP
Name	RAP1 GTPase activating protein
Location	1p36.12
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0474, RAP1GAP1, RAP1GAPII
Ensembl gene	ENSG00000076864
Ensembl biotype	protein_coding
OMIM	600278
Entrez	5909

Gene structure

Transcript identifiers

Ensembl transcripts: 81 — 76 protein_coding, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000317967, ENST00000374757, ENST00000374761, ENST00000374763, ENST00000374765, ENST00000447293, ENST00000464457, ENST00000471600, ENST00000482984, ENST00000495204, ENST00000542643, ENST00000611549, ENST00000877867, ENST00000877868, ENST00000877869, ENST00000877870, ENST00000877871, ENST00000877872, ENST00000877873, ENST00000877874, ENST00000877875, ENST00000877876, ENST00000877877, ENST00000877878, ENST00000877879, ENST00000877880, ENST00000877881, ENST00000877882, ENST00000877883, ENST00000877884, ENST00000877885, ENST00000877886, ENST00000877887, ENST00000877888, ENST00000877889, ENST00000877890, ENST00000877891, ENST00000877892, ENST00000877893, ENST00000877894, ENST00000877895, ENST00000877896, ENST00000877897, ENST00000877898, ENST00000877899, ENST00000877900, ENST00000877901, ENST00000877902, ENST00000933885, ENST00000933886, ENST00000933887, ENST00000933888, ENST00000949923, ENST00000949924, ENST00000949925, ENST00000949926, ENST00000949927, ENST00000949928, ENST00000949929, ENST00000949930, ENST00000949931, ENST00000949932, ENST00000949933, ENST00000949934, ENST00000949935, ENST00000949936, ENST00000949937, ENST00000949938, ENST00000949939, ENST00000949940, ENST00000949941, ENST00000949942, ENST00000949943, ENST00000949944, ENST00000949945, ENST00000949946, ENST00000949947, ENST00000949948, ENST00000949949, ENST00000949950, ENST00000949951

RefSeq mRNA: 94 — MANE Select: NM_002885 NM_001145657, NM_001145658, NM_001330383, NM_001350524, NM_001350525, NM_001350526, NM_001350527, NM_001350528, NM_001388200, NM_001388201, NM_001388202, NM_001388203, NM_001388204, NM_001388205, NM_001388206, NM_001388207, NM_001388208, NM_001388209, NM_001388210, NM_001388211, NM_001388212, NM_001388213, NM_001388214, NM_001388215, NM_001388216, NM_001388217, NM_001388218, NM_001388219, NM_001388220, NM_001388221, NM_001388222, NM_001388223, NM_001388224, NM_001388225, NM_001388226, NM_001388227, NM_001388228, NM_001388229, NM_001388230, NM_001388231, NM_001388233, NM_001388234, NM_001388235, NM_001388236, NM_001388237, NM_001388238, NM_001388239, NM_001388240, NM_001388241, NM_001388242, NM_001388243, NM_001388244, NM_001388245, NM_001388246, NM_001388247, NM_001388248, NM_001388249, NM_001388250, NM_001388251, NM_001388252, NM_001388253, NM_001388254, NM_001388255, NM_001388256, NM_001388258, NM_001388259, NM_001388261, NM_001388263, NM_001388264, NM_001388266, NM_001388267, NM_001388269, NM_001388270, NM_001388273, NM_001388276, NM_001388279, NM_001388280, NM_001388281, NM_001388282, NM_001388283, NM_001388284, NM_001388285, NM_001388286, NM_001388287, NM_001388288, NM_001388289, NM_001388290, NM_001388291, NM_001388292, NM_001388293, NM_001388294, NM_001388295, NM_001388296, NM_002885

CCDS: CCDS218, CCDS53276, CCDS53277, CCDS81276

Canonical transcript exons

ENST00000374765 — 25 exons

Exon	Start	End
ENSE00001042668	21613176	21613229
ENSE00001634331	21610120	21610275
ENSE00001653678	21608850	21608936
ENSE00001699035	21608213	21608350
ENSE00001732229	21602804	21602913
ENSE00001754897	21611716	21611816
ENSE00001758731	21609575	21609646
ENSE00001922447	21669254	21669357
ENSE00001924180	21596221	21597264
ENSE00003042892	21606066	21606197
ENSE00003156992	21611452	21611581
ENSE00003496251	21617934	21617972
ENSE00003496904	21612026	21612109
ENSE00003508365	21619025	21619072
ENSE00003538589	21613628	21613706
ENSE00003582755	21613986	21614089
ENSE00003584291	21620015	21620050
ENSE00003608141	21626304	21626397
ENSE00003636516	21617306	21617491
ENSE00003637472	21601684	21601797
ENSE00003642947	21599494	21599617
ENSE00003674251	21597686	21597728
ENSE00003678482	21649761	21649796
ENSE00003717822	21598400	21598502
ENSE00003741946	21597961	21598064

Expression profiles

Bgee: expression breadth ubiquitous, 239 present calls, max score 99.39.

FANTOM5 (CAGE): breadth broad, TPM avg 11.7688 / max 752.8008, expressed in 816 samples.

FANTOM5 promoters (7 alternative TSS)

Promoter ID	TPM avg	Samples expressed
10864	7.7289	450
10858	2.5588	525
10861	0.9968	344
10865	0.2910	93
10862	0.1140	61
10866	0.0543	21
10867	0.0249	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
renal medulla	UBERON:0000362	99.39	gold quality
left lobe of thyroid gland	UBERON:0001120	98.98	gold quality
nucleus accumbens	UBERON:0001882	98.72	gold quality
right lobe of thyroid gland	UBERON:0001119	98.68	gold quality
thyroid gland	UBERON:0002046	98.54	gold quality
parotid gland	UBERON:0001831	98.41	gold quality
putamen	UBERON:0001874	98.37	gold quality
metanephros cortex	UBERON:0010533	98.32	gold quality
caudate nucleus	UBERON:0001873	98.07	gold quality
middle frontal gyrus	UBERON:0002702	97.97	gold quality
right frontal lobe	UBERON:0002810	97.67	gold quality
lateral globus pallidus	UBERON:0002476	97.40	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.36	gold quality
prefrontal cortex	UBERON:0000451	97.15	gold quality
frontal cortex	UBERON:0001870	97.09	gold quality
cerebellar hemisphere	UBERON:0002245	97.09	gold quality
superior frontal gyrus	UBERON:0002661	97.09	gold quality
frontal lobe	UBERON:0016525	97.09	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.08	gold quality
cerebellar cortex	UBERON:0002129	97.06	gold quality
parietal lobe	UBERON:0001872	97.03	gold quality
postcentral gyrus	UBERON:0002581	96.97	gold quality
CA1 field of hippocampus	UBERON:0003881	96.96	gold quality
body of pancreas	UBERON:0001150	96.90	gold quality
orbitofrontal cortex	UBERON:0004167	96.89	gold quality
entorhinal cortex	UBERON:0002728	96.84	gold quality
cingulate cortex	UBERON:0003027	96.79	gold quality
anterior cingulate cortex	UBERON:0009835	96.76	gold quality
cerebellum	UBERON:0002037	96.72	gold quality
neocortex	UBERON:0001950	96.68	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-HCAD-30	yes	745.97
E-ANND-3	yes	16.50
E-GEOD-125970	yes	9.22
E-GEOD-81608	yes	7.39
E-HCAD-10	no	1.86

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EZH2

miRNA regulators (miRDB)

28 targeting RAP1GAP, 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-6825-5P	99.96	69.81	3431
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-218-5P	99.93	72.22	2103
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-3934-3P	99.76	65.51	1351
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-3612	99.45	66.02	1333
HSA-MIR-650	99.45	65.77	1309
HSA-MIR-4506	99.34	67.47	526
HSA-MIR-4292	99.16	65.57	1767
HSA-MIR-6791-5P	99.16	65.92	1844
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-4695-5P	99.06	64.87	1151
HSA-MIR-2115-5P	98.66	68.07	1191
HSA-MIR-1227-5P	98.65	65.32	1549
HSA-MIR-767-3P	98.61	67.69	1192
HSA-MIR-3127-5P	97.52	65.24	786
HSA-MIR-320E	97.49	65.96	865
HSA-MIR-3173-5P	97.35	65.82	1282
HSA-MIR-6799-3P	97.35	65.60	1302
HSA-MIR-1913	97.07	66.20	1417
HSA-MIR-5685	97.02	64.34	1004
HSA-MIR-4690-3P	97.02	64.72	981
HSA-MIR-215-3P	97.02	68.01	1209
HSA-MIR-6806-5P	96.37	68.74	587

Literature-anchored findings (GeneRIF, showing 39)

• ERK activation by cAMP does not require RAP1 (PMID:12082090)
• Rap1 GTPase has functions in malignancy (review) (PMID:14607972)
• Rap1GAP protein levels are tightly regulated and it may have a role as a tumor suppressor (PMID:14660640)
• the G(alpha)o/i-coupled cannabinoid receptor, by regulating the proteasomal degradation of Rap1GAPII, activates Rap1 to induce neurite outgrowth. (PMID:15657046)
• On ephrinB1 stimulation, the small GTPases Rho and Ras are activated and Rap1 is inactivated. (PMID:15725075)
• data identify rap1GAP as a putative tumor suppressor gene in pancreatic cancer (PMID:16424023)
• Down-regulation of Rap1GAP is associated with oropharyngeal squamous cell carcinoma (PMID:16436672)
• While Rap1GAP(N290A) is completely inactive on wild-type Rap1, it can act on Rap1(T61Q), arguing that Asn290 in trans has a role in catalysis similar to that of the intrinsic Gln in Ras and Rho. (PMID:17300802)
• Data implicate Rap1GAP as a putative tumor/invasion suppressor in the thyroid, and show that downregulation of Rap1GAP contributes to Ras transformation. (PMID:17646383)
• Rap1 increases KRIT-1 targeting to endothelial cell-cell junctions where it suppresses stress fibers and stabilizes junctional integrity. (PMID:17954608)
• Rap1GAP inhibits tumor growth but induces MMP2- and MMP9-mediated SCC invasion and tumor progression, suggesting a role for this protein as a biomarker for early N-stage, aggressive SCCs (PMID:18483282)
• Data propose that over-expression of RAP1GAP gene may play a role in the pathogenesis of myelodysplastic syndrome. (PMID:18551404)
• a role for Rap1GAP depletion in the progression of human thyroid tumors, possibly through unrestrained Rap activity. (PMID:19066305)
• Overexpression of Rap1GAP in melanoma cells blocks Rap1 activation and extracellular signal-regulated kinase (ERK) phosphorylation and inhibits melanoma cell proliferation and survival. (PMID:19147557)
• model in which the Ras GAP-related domain of GAP1(IP4BP) functions to stabilize the switch II region of Rap1, allowing stabilization of the transition state during GTP hydrolysis initiated by the arginine finger (PMID:19433443)
• The expression level of RAP1GAp in myelodysplastic syndrome patients significantly increased as compared with patients with non-malignant blood diseases or AML. (PMID:19549374)
• Epigenetic or genetic loss of Rap1GAP is very common in thyroid cancer, where these events are sufficient to promote cell proliferation and invasion. (PMID:20124489)
• Results suggest that downregulation of Rap1GAP in epithelial tumors where alterations in cell/cell and cell/matrix adhesion are early steps in tumor dissemination supports a role for Rap1GAP depletion in tumor progression. (PMID:20439492)
• Ca2+-dependent monomer and dimer formation switches CAPRI Protein between Ras GTPase-activating protein (GAP) and RapGAP activities (PMID:21460216)
• A polycomb-mediated repression of rap1GAP was demonstrated that involves EZH2, a histone methyltransferase in head and neck cancers. It was also shown that the loss of miR-101 expression correlates with EZH2 upregulation and rap1GAP downregulation. (PMID:21532618)
• These studies establish that the direct physical interaction of Rap1 with KRIT1 enables the translocation of microtubule-sequestered KRIT1 to junctions, thereby supporting junctional integrity and cardiovascular development (PMID:21633110)
• Rap1GAP is a more effective inhibitor of cell-matrix adhesion compared to cell-cell adhesion. (PMID:21785277)
• Human kidney cells evidence increased EP4 and decreased Rap1GAP expression levels in the malignant compared with benign samples. (PMID:21832044)
• Over-expression of Rap1GAP attenuated levels of both cadherins and integrins that are known to regulate the cancer cells invasion in renal cel carcinoma. (PMID:22266190)
• Results demonstrated that Rap1GAP promoted leukemia cell differentiation and apoptosis, but increased leukemia cell invasion in vitro. (PMID:22614916)
• Downregulation of RAP1GAP in thyroid tumors enhances SRC-dependent signals that regulate cellular architecture and motility. (PMID:22696507)
• findings identify Rap1GAP as a critical regulator of aggressive tumor cell behavior and suggest that the level of Rap1GAP expression influences the migratory mechanisms that are operative in tumor cells. (PMID:23864657)
• kidney biopsies from glomerulosclerosis patients exhibited increased RAP1GAP, resulting in diminished glomerular RAP1 activation (PMID:24642466)
• Rap1GAP is ubiquitinated and degraded through proteasome pathway in mitosis. Rap1GAP interacts with PLK1 in vivo. (PMID:25329897)
• results have shown a novel role of PLCepsilon in the maintenance of endothelial barrier function, via its CDC25 GEF domain and lipase activity, and subsequent up-regulation of Rap1 activity (PMID:27612188)
• Findings suggest that RAP1 GTPase activating protein (Rap1GAP) is an important tumor suppressor with high prognostic value in endometrioid adenocarcinoma (EAC). (PMID:28196746)
• Rap1GAP may play a significant role in gastric cancer progression and act as a valuable prognostic marker for gastric cancer. (PMID:29758923)
• This is the first mechanistic study of Rap1Gap in breast cancer progression. Decreases in Rap1Gap expression led to changes in adherens junctions via reduction in E-cadherin levels, to cytoskeletal remodeling, and to increases in ERK activation that are correlated with an invasive phenotype in DCIS (PMID:30144784)
• Shank3 Binds to and Stabilizes the Active Form of Rap1 and HRas GTPases via Its NTD-ANK Tandem with Distinct Mechanisms. (PMID:31879129)
• RAP1GAP Functions as a Tumor Suppressor Gene and Is Regulated by DNA Methylation in Differentiated Thyroid Cancer. (PMID:34311462)
• Downregulation of Rap1GAP Expression Activates the TGF-beta/Smad3 Pathway to Inhibit the Expression of Sodium/Iodine Transporter in Papillary Thyroid Carcinoma Cells. (PMID:34840979)
• Simulated Microgravity Increases the Permeability of HUVEC Monolayer through Up-Regulation of Rap1GAP and Decreased Rap2 Activation. (PMID:35054818)
• CpG Island Methylation of the Rap1Gap Gene in Medullary Thyroid Cancer. (PMID:35429959)
• Downregulating miR-184 relieves calcium oxalate crystal-mediated renal cell damage via activating the Rap1 signaling pathway. (PMID:38154105)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	rap1gapb	ENSDARG00000053272
danio_rerio	rap1gapa	ENSDARG00000056554
mus_musculus	Rap1gap	ENSMUSG00000041351
rattus_norvegicus	Rap1gap	ENSRNOG00000013825
drosophila_melanogaster	RapGAP1	FBGN0264895
caenorhabditis_elegans		WBGENE00018734

Paralogs (6): SIPA1L3 (ENSG00000105738), SIPA1L2 (ENSG00000116991), RAP1GAP2 (ENSG00000132359), GARNL3 (ENSG00000136895), SIPA1L1 (ENSG00000197555), SIPA1 (ENSG00000213445)

Protein

Protein identifiers

Rap1 GTPase-activating protein 1 — P47736 (reviewed: P47736)

All UniProt accessions (6): P47736, F2Z357, J3KPC5, Q5T3T0, Q5T3T1, X6R8W7

UniProt curated annotations — full annotation on UniProt →

Function. GTPase activator for the nuclear Ras-related regulatory protein RAP-1A (KREV-1), converting it to the putatively inactive GDP-bound state.

Subunit / interactions. Homodimer and heterodimer with RAP1B.

Subcellular location. Golgi apparatus membrane.

Tissue specificity. Significant expression seen in the brain, kidney and pancreas. Abundant in the cerebral cortex and expressed at much lower levels in the spinal cord. Not detected in the lymphoid tissues.

Induction. By 12-O-tetradecanoylphorbol-13-acetate (TPA) in promyelocytic HL-60 cells.

Isoforms (4)

UniProt ID	Names	Canonical?
P47736-1	1	yes
P47736-2	2
P47736-3	3
P47736-4	4

RefSeq proteins (94): NP_001139129, NP_001139130, NP_001317312, NP_001337453, NP_001337454, NP_001337455, NP_001337456, NP_001337457, NP_001375129, NP_001375130, NP_001375131, NP_001375132, NP_001375133, NP_001375134, NP_001375135, NP_001375136, NP_001375137, NP_001375138, NP_001375139, NP_001375140, NP_001375141, NP_001375142, NP_001375143, NP_001375144, NP_001375145, NP_001375146, NP_001375147, NP_001375148, NP_001375149, NP_001375150, NP_001375151, NP_001375152, NP_001375153, NP_001375154, NP_001375155, NP_001375156, NP_001375157, NP_001375158, NP_001375159, NP_001375160, NP_001375162, NP_001375163, NP_001375164, NP_001375165, NP_001375166, NP_001375167, NP_001375168, NP_001375169, NP_001375170, NP_001375171, NP_001375172, NP_001375173, NP_001375174, NP_001375175, NP_001375176, NP_001375177, NP_001375178, NP_001375179, NP_001375180, NP_001375181, NP_001375182, NP_001375183, NP_001375184, NP_001375185, NP_001375187, NP_001375188, NP_001375190, NP_001375192, NP_001375193, NP_001375195, NP_001375196, NP_001375198, NP_001375199, NP_001375202, NP_001375205, NP_001375208, NP_001375209, NP_001375210, NP_001375211, NP_001375212, NP_001375213, NP_001375214, NP_001375215, NP_001375216, NP_001375217, NP_001375218, NP_001375219, NP_001375220, NP_001375221, NP_001375222, NP_001375223, NP_001375224, NP_001375225, NP_002876* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000331	Rap/Ran_GAP_dom	Domain
IPR003109	GoLoco_motif	Conserved_site
IPR035974	Rap/Ran-GAP_sf	Homologous_superfamily
IPR050989	Rap1_Ran_GAP	Family

Pfam: PF02145, PF02188, PF21022

UniProt features (63 total): strand 14, helix 11, mutagenesis site 9, modified residue 7, compositionally biased region 5, splice variant 5, sequence variant 3, region of interest 3, domain 2, turn 2, chain 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1SRQ	X-RAY DIFFRACTION	2.9
3BRW	X-RAY DIFFRACTION	3.4

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P47736-F1	70.94	0.49

Functional residue map

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

Post-translational modifications (7): 441, 484, 499, 515, 541, 542, 17

Mutagenesis-validated functional residues (9):

Position	Phenotype
100	impaired dimerization; when associated with e-173.
173	impaired dimerization; when associated with e-100.
207	reduces gtpase activation.
267	abolishes gtpase activation.
286	reduces gtpase activation.
287	abolishes gtpase activation.
290	abolishes gtpase activation.
291	abolishes gtpase activation.
388	reduces gtpase activation.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-392517	Rap1 signalling
R-HSA-8853659	RET signaling
R-HSA-1266738	Developmental Biology
R-HSA-1280218	Adaptive Immune System
R-HSA-168256	Immune System
R-HSA-422475	Axon guidance
R-HSA-9675108	Nervous system development

MSigDB gene sets: 192 (showing top): GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, MODULE_418, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_UP, GEORGES_CELL_CYCLE_MIR192_TARGETS, GOBP_REGULATION_OF_GTPASE_ACTIVITY, GOBP_REGULATION_OF_SMALL_GTPASE_MEDIATED_SIGNAL_TRANSDUCTION, TGACCTY_ERR1_Q2, GOBP_VESICLE_MEDIATED_TRANSPORT, RIZKI_TUMOR_INVASIVENESS_3D_DN, GOMF_GTPASE_BINDING, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_CELL_ADHESION, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION

GO Biological Process (14): adaptive immune response (GO:0002250), phagocytosis (GO:0006909), signal transduction (GO:0007165), positive regulation of cell-cell adhesion (GO:0022409), regulation of GTPase activity (GO:0043087), positive regulation of GTPase activity (GO:0043547), negative regulation of neuron differentiation (GO:0045665), positive regulation of phagocytosis (GO:0050766), regulation of small GTPase mediated signal transduction (GO:0051056), establishment of localization in cell (GO:0051649), cell-cell adhesion (GO:0098609), negative regulation of microvillus assembly (GO:1903697), negative regulation of thyroid gland epithelial cell proliferation (GO:1904442), cellular response to glial cell derived neurotrophic factor (GO:1990792)

GO Molecular Function (6): GTPase activity (GO:0003924), GTPase activator activity (GO:0005096), small GTPase binding (GO:0031267), protein homodimerization activity (GO:0042803), protein binding (GO:0005515), GTPase regulator activity (GO:0030695)

GO Cellular Component (9): Golgi membrane (GO:0000139), cytoplasm (GO:0005737), early endosome (GO:0005769), cytosol (GO:0005829), membrane (GO:0016020), axon (GO:0030424), dendrite (GO:0030425), neuronal cell body (GO:0043025), Golgi apparatus (GO:0005794)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Adaptive Immune System	1
Axon guidance	1
Immune System	1
Nervous system development	1
Developmental Biology	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
GTPase activity	4
cellular anatomical structure	3
cytoplasm	2
neuron projection	2
immune response	1
endocytosis	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
regulation of cell-cell adhesion	1
positive regulation of cell adhesion	1
cell-cell adhesion	1
regulation of hydrolase activity	1
regulation of GTPase activity	1
positive regulation of hydrolase activity	1
neuron differentiation	1
negative regulation of cell differentiation	1
regulation of neuron differentiation	1
phagocytosis	1
positive regulation of endocytosis	1
regulation of phagocytosis	1
small GTPase-mediated signal transduction	1
regulation of intracellular signal transduction	1
establishment of localization	1
cellular localization	1
cell adhesion	1
microvillus assembly	1
regulation of microvillus assembly	1
negative regulation of plasma membrane bounded cell projection assembly	1
negative regulation of epithelial cell proliferation	1
negative regulation of developmental process	1
negative regulation of multicellular organismal process	1
regulation of thyroid gland epithelial cell proliferation	1
thyroid gland epithelial cell proliferation	1
cellular response to growth factor stimulus	1
response to glial cell derived neurotrophic factor	1
ribonucleoside triphosphate phosphatase activity	1
enzyme activator activity	1

Protein interactions and networks

STRING

856 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RAP1GAP	RAP1A	P10113	860
RAP1GAP	RASA1	P20936	835
RAP1GAP	RAP1B	P09526	783
RAP1GAP	RAP2A	P10114	702
RAP1GAP	TSC1	Q92574	602
RAP1GAP	RALGDS	Q12967	600
RAP1GAP	LRPAP1	P30533	591
RAP1GAP	AFDN	P55196	564
RAP1GAP	RAPGEF1	Q13905	548
RAP1GAP	RAPGEF3	O95398	545
RAP1GAP	RAPGEF4	Q8WZA2	543
RAP1GAP	GPSM1	Q86YR5	502
RAP1GAP	TBR1	Q16650	496
RAP1GAP	PCP2	Q8IVA1	477
RAP1GAP	RASGRP2	Q7LDG7	476

IntAct

45 interactions, top by confidence:

A	B	Type	Score
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
GNAI3	RGS12	psi-mi:“MI:0914”(association)	0.640
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
DNALI1	RAP1GAP	psi-mi:“MI:0915”(physical association)	0.560
KLF11	RAP1GAP	psi-mi:“MI:0915”(physical association)	0.560
RAP1GAP	YWHAZ	psi-mi:“MI:0915”(physical association)	0.540
RAP1GAP	RAP1B	psi-mi:“MI:0915”(physical association)	0.520
RAP1GAP	RAP1GAP2	psi-mi:“MI:0915”(physical association)	0.500
RAP1GAP	Dlg4	psi-mi:“MI:0407”(direct interaction)	0.440
CSNK1G2	RAP1GAP	psi-mi:“MI:0915”(physical association)	0.370
DYNC1I1	RAP1GAP	psi-mi:“MI:0915”(physical association)	0.370
RAP1GAP	MAP1LC3B	psi-mi:“MI:0915”(physical association)	0.370
RAP1GAP	MAPK6	psi-mi:“MI:0915”(physical association)	0.370
Xpo1	IFT56	psi-mi:“MI:0914”(association)	0.350
MAPK1	SEC16A	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
RAP1GAP	VPS26A	psi-mi:“MI:0914”(association)	0.350
ZNF330	SEMG1	psi-mi:“MI:0914”(association)	0.350
SFN	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270
YWHAB	E2F8	psi-mi:“MI:2364”(proximity)	0.270
YWHAE	E2F8	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (56): RAP1GAP (Two-hybrid), RAP1GAP (Affinity Capture-Western), RAP1GAP (Affinity Capture-Western), BTRC (Affinity Capture-Western), FBXW11 (Affinity Capture-Western), PLK1 (Affinity Capture-Western), RAP1GAP (Affinity Capture-Western), RAP1GAP (Biochemical Activity), RAP1GAP (Affinity Capture-MS), RAP1GAP (Affinity Capture-MS), RAP1GAP (Affinity Capture-MS), RAP1GAP (Affinity Capture-MS), RAP1GAP (Affinity Capture-Western), MLLT4 (Affinity Capture-Western), RAP1GAP (Affinity Capture-RNA)

ESM2 similar proteins: A1Z7A6, A2ALS5, A5PF44, A7KAX9, A8E7C5, A8JQ65, B3LXF2, B3NYS4, B4I4Y1, B4JHJ7, B4K6T8, B4PRE2, B4R0A5, G3X9J0, G5EFI8, O35412, O35711, O43166, O60292, P43125, P47736, Q14693, Q22744, Q2NKQ1, Q2PE14, Q3V0G7, Q4P3S3, Q5JCS6, Q5SVL6, Q5VVW2, Q5ZJY3, Q5ZMV8, Q684P5, Q80TE4, Q811P8, Q8BPQ7, Q8C0T5, Q8C8U0, Q8CDA1, Q91ZP3

Diamond homologs: A2ALS5, A5PF44, G3X9J0, O35412, O43166, O60292, P46062, P47736, P49815, P49816, Q3V0G7, Q54EH3, Q55AN8, Q5JCS6, Q5SVL6, Q5VVW2, Q5ZJY3, Q5ZMV8, Q61037, Q684P5, Q75J96, Q80TE4, Q8C0T5, Q96FS4, Q9P2F8, Q2PPJ7, Q9UUG9, A3KGS3, P86411, Q6GYQ0, Q8BUL6, Q9HB21, Q54TK4, Q9VB98, O55007, Q6GYP7, Q54SS8

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
CDK1	unknown	RAP1GAP	phosphorylation
BTRC	down-regulates	RAP1GAP	ubiquitination
PLK1	down-regulates	RAP1GAP	phosphorylation
RAP1GAP	“down-regulates activity”	GNAZ	binding
RAP1GAP	“down-regulates activity”	RAP1A	binding
RAP1GAP	“down-regulates activity”	ERK1/2	binding
RAP1GAP	“down-regulates activity”	AKT	binding
PRKACA	unknown	RAP1GAP	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 36 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Activation of BAD and translocation to mitochondria	7	197.4×	2e-13
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	7	174.2×	3e-13
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	7	174.2×	3e-13
Activation of BH3-only proteins	7	128.7×	2e-12
Intrinsic Pathway for Apoptosis	8	86.8×	1e-12
RHO GTPases activate PKNs	7	82.2×	5e-11
FOXO-mediated transcription	5	62.2×	2e-07
Apoptosis	9	56.0×	1e-12

GO biological processes:

GO term	Partners	Fold	FDR
protein targeting	5	57.2×	3e-06
intracellular protein localization	7	22.9×	3e-06
protein phosphorylation	5	10.6×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	92
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

5530 predictions. Top by Δscore:

Variant	Effect	Δscore
1:21597956:CGTA:C	donor_loss	1.0000
1:21597957:GTAC:G	donor_loss	1.0000
1:21597959:A:AC	donor_gain	1.0000
1:21597960:C:CC	donor_gain	1.0000
1:21597960:C:CG	donor_loss	1.0000
1:21597960:CCAG:C	donor_gain	1.0000
1:21598060:GGGGC:G	acceptor_gain	1.0000
1:21598065:C:CC	acceptor_gain	1.0000
1:21598066:T:C	acceptor_loss	1.0000
1:21598385:G:GA	donor_gain	1.0000
1:21598397:TACCT:T	donor_loss	1.0000
1:21598399:C:CT	donor_loss	1.0000
1:21598435:T:A	donor_gain	1.0000
1:21598498:CTCTC:C	acceptor_gain	1.0000
1:21598500:CTC:C	acceptor_gain	1.0000
1:21598501:TC:T	acceptor_gain	1.0000
1:21598501:TCC:T	acceptor_loss	1.0000
1:21598502:CC:C	acceptor_gain	1.0000
1:21598503:C:CC	acceptor_gain	1.0000
1:21598503:CTGG:C	acceptor_loss	1.0000
1:21598514:G:C	acceptor_gain	1.0000
1:21598514:G:GC	acceptor_gain	1.0000
1:21599489:CTCAC:C	donor_loss	1.0000
1:21599490:TCAC:T	donor_loss	1.0000
1:21599492:A:AC	donor_gain	1.0000
1:21599492:A:AT	donor_loss	1.0000
1:21599493:C:CC	donor_gain	1.0000
1:21599493:CCAGG:C	donor_gain	1.0000
1:21599613:CCGCT:C	acceptor_gain	1.0000
1:21599614:CGCT:C	acceptor_gain	1.0000

AlphaMissense

4386 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:21608307:A:G	L401P	1.000
1:21608331:A:G	L393P	1.000
1:21608340:C:G	R390P	1.000
1:21608862:A:C	F382L	1.000
1:21608862:A:T	F382L	1.000
1:21608863:A:C	F382C	1.000
1:21608863:A:G	F382S	1.000
1:21608864:A:G	F382L	1.000
1:21608880:G:C	C376W	1.000
1:21608881:C:T	C376Y	1.000
1:21608893:G:T	A372D	1.000
1:21608894:C:G	A372P	1.000
1:21608902:A:G	L369P	1.000
1:21608904:C:A	K368N	1.000
1:21608904:C:G	K368N	1.000
1:21609634:C:G	A338P	1.000
1:21609639:A:T	V336D	1.000
1:21610176:G:C	H315D	1.000
1:21610180:G:C	F313L	1.000
1:21610180:G:T	F313L	1.000
1:21610181:A:C	F313C	1.000
1:21610181:A:G	F313S	1.000
1:21610182:A:G	F313L	1.000
1:21610187:G:A	S311F	1.000
1:21610187:G:T	S311Y	1.000
1:21610202:G:T	P306H	1.000
1:21610208:A:G	F304S	1.000
1:21610232:A:T	V296D	1.000
1:21610238:G:T	A294D	1.000
1:21610239:C:G	A294P	1.000

dbSNP variants (sampled 300 via entrez): RS1000048086 (1:21627252 A>G), RS1000134795 (1:21660446 G>A), RS1000176768 (1:21639301 CT>C,CTT), RS1000294428 (1:21639697 G>A,C), RS1000304943 (1:21601610 G>A), RS1000308226 (1:21605607 G>A), RS1000372531 (1:21640910 T>G), RS1000394441 (1:21647181 G>C), RS1000398778 (1:21618155 C>A), RS1000423766 (1:21605373 C>T), RS1000457360 (1:21645174 AATG>A), RS1000529183 (1:21622037 C>A,T), RS1000581625 (1:21621722 G>T), RS1000583777 (1:21596193 T>G), RS1000622002 (1:21611389 A>G)

Disease associations

OMIM: gene MIM:600278 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

12 associations (top):

Study	Trait	p-value
GCST000248_1	Liver enzyme levels	7.000000e-15
GCST004406_5	Neurocognitive impairment in HIV-1 infection (continuous)	3.000000e-06
GCST004611_102	High light scatter reticulocyte count	5.000000e-23
GCST004612_192	High light scatter reticulocyte percentage of red cells	1.000000e-23
GCST004628_2	Immature fraction of reticulocytes	3.000000e-52
GCST006979_859	Heel bone mineral density	1.000000e-22
GCST009091_2	Abdominal aortic calcification levels	3.000000e-08
GCST009391_456	Metabolite levels	1.000000e-06
GCST009391_498	Metabolite levels	9.000000e-07
GCST009652_43	Serum alkaline phosphatase levels	7.000000e-18
GCST90002385_600	High light scatter reticulocyte count	3.000000e-19
GCST90002396_114	Mean reticulocyte volume	2.000000e-13

EFO canonical traits (8, from GWAS)

EFO ID	Trait name
EFO:0004533	alkaline phosphatase measurement
EFO:0007998	cognitive impairment measurement
EFO:0007986	reticulocyte count
EFO:0009270	heel bone mineral density
EFO:0010272	abdominal aortic calcification measurement
EFO:0010522	phosphoenolpyruvic acid measurement
EFO:0010521	phosphocreatine measurement
EFO:0010701	mean reticulocyte volume

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases methylation, increases abundance, increases expression	5
Benzo(a)pyrene	affects methylation, increases expression	5
Tetrachlorodibenzodioxin	increases expression	4
Tobacco Smoke Pollution	affects expression, increases expression	3
Valproic Acid	increases expression, affects expression, affects cotreatment	3
bisphenol A	affects cotreatment, increases methylation, decreases expression	2
Rosiglitazone	decreases expression, increases expression	2
Arsenic	increases abundance, increases expression, decreases expression	2
Cyclosporine	decreases expression, increases expression	2
Aflatoxin B1	decreases methylation, increases expression	2
FR900359	decreases phosphorylation	1
dicrotophos	increases expression	1
methyleugenol	increases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	decreases expression	1
bis(tri-n-butyltin)oxide	decreases expression	1
sodium arsenate	decreases expression, increases abundance	1
terbufos	decreases methylation	1
beta-lapachone	decreases expression	1
arsenite	increases methylation	1
mono-(2-ethylhexyl)phthalate	decreases methylation, increases abundance	1
sulforaphane	increases expression	1
butyraldehyde	decreases expression	1
sulindac sulfide	increases expression	1
benzo(e)pyrene	decreases methylation	1
aflatoxin B2	increases methylation	1
pentanal	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
Am 580	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TI47	HAP1 RAP1GAP (-) 1	Cancer cell line	Male
CVCL_XS13	HAP1 RAP1GAP (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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