RAP1A

Summary

RAP1A (RAP1A, member of RAS oncogene family, HGNC:9855) is a protein-coding gene on chromosome 1p13.2, encoding Ras-related protein Rap-1A (P62834). Counteracts the mitogenic function of Ras, at least partly because it can interact with Ras GAPs and RAF in a competitive manner.

This gene encodes a member of the Ras family of small GTPases. The encoded protein undergoes a change in conformational state and activity, depending on whether it is bound to GTP or GDP. This protein is activated by several types of guanine nucleotide exchange factors (GEFs), and inactivated by two groups of GTPase-activating proteins (GAPs). The activation status of the encoded protein is therefore affected by the balance of intracellular levels of GEFs and GAPs. The encoded protein regulates signaling pathways that affect cell proliferation and adhesion, and may play a role in tumor malignancy. Pseudogenes of this gene have been defined on chromosomes 14 and 17. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 5906 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Kabuki syndrome (Moderate, GenCC)
• GWAS associations: 6
• Clinical variants (ClinVar): 50 total
• Druggable target: yes
• MANE Select transcript: NM_002884

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9855
Approved symbol	RAP1A
Name	RAP1A, member of RAS oncogene family
Location	1p13.2
Locus type	gene with protein product
Status	Approved
Aliases	KREV-1, SMGP21
Ensembl gene	ENSG00000116473
Ensembl biotype	protein_coding
OMIM	179520
Entrez	5906

Gene structure

Transcript identifiers

Ensembl transcripts: 38 — 37 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000356415, ENST00000369709, ENST00000494982, ENST00000687939, ENST00000854991, ENST00000854992, ENST00000854993, ENST00000854994, ENST00000854995, ENST00000854996, ENST00000854997, ENST00000854998, ENST00000854999, ENST00000855000, ENST00000855001, ENST00000855002, ENST00000855003, ENST00000855004, ENST00000855005, ENST00000855006, ENST00000855007, ENST00000855008, ENST00000855009, ENST00000855010, ENST00000855011, ENST00000855012, ENST00000855013, ENST00000855014, ENST00000855015, ENST00000855016, ENST00000947695, ENST00000947696, ENST00000947697, ENST00000947698, ENST00000947699, ENST00000947700, ENST00000947701, ENST00000947702

RefSeq mRNA: 6 — MANE Select: NM_002884 NM_001010935, NM_001291896, NM_001370216, NM_001370217, NM_001394066, NM_002884

CCDS: CCDS840

Canonical transcript exons

ENST00000369709 — 8 exons

Exon	Start	End
ENSE00001301159	111619789	111619934
ENSE00001835102	111712431	111716691
ENSE00003486088	111709149	111709264
ENSE00003493422	111697441	111697497
ENSE00003500155	111691334	111691417
ENSE00003508199	111704343	111704486
ENSE00003508968	111695341	111695409
ENSE00003688012	111703336	111703476

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 99.35.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 33.1909 / max 630.4005, expressed in 1815 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
4644	17.5396	1773
4643	15.6417	1801
4642	0.0097	4

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
blood vessel layer	UBERON:0004797	99.35	gold quality
monocyte	CL:0000576	98.74	gold quality
mononuclear cell	CL:0000842	98.69	gold quality
cauda epididymis	UBERON:0004360	98.65	gold quality
leukocyte	CL:0000738	98.63	gold quality
superficial temporal artery	UBERON:0001614	98.62	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.56	gold quality
popliteal artery	UBERON:0002250	98.54	gold quality
tibial artery	UBERON:0007610	98.54	gold quality
lower esophagus	UBERON:0013473	98.54	gold quality
jejunal mucosa	UBERON:0000399	98.52	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.42	gold quality
mucosa of stomach	UBERON:0001199	98.38	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.34	gold quality
saphenous vein	UBERON:0007318	98.30	gold quality
heart right ventricle	UBERON:0002080	98.28	gold quality
colonic epithelium	UBERON:0000397	98.17	gold quality
trabecular bone tissue	UBERON:0002483	98.06	gold quality
sigmoid colon	UBERON:0001159	98.02	gold quality
lymph node	UBERON:0000029	97.95	gold quality
corpus epididymis	UBERON:0004359	97.94	gold quality
rectum	UBERON:0001052	97.91	gold quality
jejunum	UBERON:0002115	97.90	gold quality
caecum	UBERON:0001153	97.86	gold quality
vermiform appendix	UBERON:0001154	97.86	gold quality
aorta	UBERON:0000947	97.84	gold quality
seminal vesicle	UBERON:0000998	97.77	gold quality
oral cavity	UBERON:0000167	97.74	gold quality
parotid gland	UBERON:0001831	97.69	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.69	gold quality

Single-cell (SCXA)

Detected in 8 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-100618	yes	322.15
E-HCAD-13	yes	21.06
E-CURD-46	yes	17.77
E-HCAD-25	yes	14.58
E-ANND-3	yes	11.80
E-MTAB-6386	no	267.39
E-MTAB-7303	no	143.29
E-HCAD-8	no	43.65

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ARHGAP35, HNF4A, MSC, TCF3, TWIST1, TWIST2

miRNA regulators (miRDB)

271 targeting RAP1A, 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-3163	100.00	77.23	8605
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754

Literature-anchored findings (GeneRIF, showing 40)

• Consequences of mevalonate depletion. Differential transcriptional, translational, and post-translational up-regulation (PMID:11788600)
• ERK activation by cAMP does not require RAP1 (PMID:12082090)
• role in regulating phorbol 12-myristate 13-acetate-stimulated but not ligand-induced beta 1 integrin-dependent leukocyte adhesion (PMID:12091396)
• Galpha and Gbeta gamma require distinct Src-dependent pathways for its activation (PMID:12221082)
• Rap1 may represent a critical control point in the stromal inhibition of megakaryoytic differentiation. (PMID:12393469)
• cAMP inhibits both Ras and Rap1 activation in primary human T lymphocytes, but only Ras inhibition correlates with blockade of cell cycle progression. (PMID:12393539)
• rap1 inhibits proliferation in keratinocytes (PMID:12891710)
• RAP1A is prominently expressed in the nucleus of squamous carcinomas. (PMID:13679863)
• inherited Rap1 activation defect associated with a pathologic disorder in leukocyte integrin function; we herein term it LAD-III, leukocyte adhesion deficiency syndrome (PMID:14551137)
• Eph/ephrin signaling enhances the ability of platelet agonists to cause aggregation provided that those agonists can increase cytosolic Ca(++) and this is accomplished in part by activating Rap1 (PMID:14576067)
• Rap1 GTPase has functions in malignancy (review) (PMID:14607972)
• Results suggest that membrane localizations of Rap1 are dynamically regulated, and the cell membrane is the principle platform from which Rap1 signaling emanates. (PMID:14757755)
• a previously uncharacterized domain spanning amino acids 85-89 of Rap1A plays a pivotal role in its perinuclear localization and acts dominantly over COOH-terminal lipid modification of Ha-Ras (PMID:15031297)
• mRNA expression of Rap1A protein in the spermatogenic cells of azoospermic was stronger than that in those of the fertile testes (PMID:15064832)
• Rap1 plays a vital role in the establishment of E-cadherin-based cell-cell adhesion (PMID:15254236)
• cAMP-Epac-Rap1 pathway regulates cell spreading and cell adhesion to laminin-5 through the alpha3beta1 integrin but not the alpha6beta4 integrin (PMID:15302884)
• Activation of Epac results in markedly enhanced basal endothelial barrier function by increasing cortical actin and subsequent redistribution of adherens and tight junctional molecules to cell-cell contacts (PMID:15374886)
• Rap1 promotes cell spreading by localizing a subset of Rac GEFs to sites of active lamellipodia extension (PMID:15479739)
• Rap1 activation contributes to directional vascular endothelial cell migration accompanied by extension of microtubules on which RAPL localizes (PMID:15569673)
• MAP1A LC2 is a biological enhancer of EPAC1 activity toward Rap1 and associated downstream signaling mechanisms (PMID:15591041)
• cAMP-Epac-Rap1 signaling promotes decreased cell permeability by enhancing VE-cadherin-mediated adhesion lined by the rearranged cortical actin (PMID:15601837)
• Epac-mediated Rap1 activation may represent an important signaling pathway for promoting sickle cell adhesion. (PMID:15613546)
• the G(alpha)o/i-coupled cannabinoid receptor, by regulating the proteasomal degradation of Rap1GAPII, activates Rap1 to induce neurite outgrowth. (PMID:15657046)
• Rap1 GTPase inhibits leukocyte transmigration by promoting endothelial barrier function. (PMID:15661741)
• JAM1 regulates epithelial cell morphology and beta1 integrin expression by modulating activity of the small GTPase Rap1. (PMID:15677455)
• cGKI inhibited ADP-induced Rap 1 activation induced by the Galpha(i)-coupled P2Y12 receptor alone, i.e. independently of effects on Ca2+-signalling (PMID:15711749)
• On ephrinB1 stimulation, the small GTPases Rho and Ras are activated and Rap1 is inactivated. (PMID:15725075)
• The RAP1A gene mutation is a rare event in myelodysplastic syndromes(MDS) bone marrow cells. (PMID:16118622)
• first evidence of an E-cadherin-modulated endosomal signaling pathway involving Rap1, and suggest that cadherins may have a novel modulatory role in integrin adhesive functions by fine-tuning Rap1 activation (PMID:16219685)
• RT-PCR analysis of mRNA extracted from highly purified reticulocytes confirmed the expression of Rap2b, but not Rap2a, Rap2c, Rap1a or Rap1b. (PMID:16540189)
• TIMP-2 mediated alteration in cell morphology requires Rap1, TIMP-2 may recruit Rap1 to sites of actin cytoskeleton remodeling necessary for cell spreading, and enhanced cell adhesion by TIMP-2 expression may hinder cell migration (PMID:16716258)
• The Epac1-Rap1 pathway is present in both monocytes and macrophages, but only regulates specific immune effector functions (PMID:16751380)
• Results suggest that Dok-4, through activation of the Rap1-ERK1/2 pathway, regulates GDNF-mediated neurite outgrowth during neuronal development. (PMID:16820412)
• The patients with emphysema had significantly higher percentages of type II cells positive for p16INK4a and p21CIP1/WAF1/Sdi1 than the asymptomatic smokers and nonsmokers. (PMID:16888288)
• A study that demonstrated the engagement of beta2 integrins on human neutrophils increased the levels of GTP-bound Rap1 and Rap2 is presented. (PMID:16963453)
• Rap1 mediates cyclic AMP-stimulated neurotensin secretion downstream of both Epac and protein kinase A signaling pathways (PMID:17068197)
• 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)
• These findings raise the possibility that Rgl3 mediates interaction between Ras/Rap-family proteins and profilin II, an important activator of actin polymerization. (PMID:17382517)
• Rap1 regulates malignant transformation mechanisms of hematopoietic progenitors (PMID:17487743)
• IQGAP1 may link the calmodulin and Rap1 signaling pathways (PMID:17517894)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Rap1a	ENSMUSG00000068798
rattus_norvegicus	Rap1a	ENSRNOG00000032463

Paralogs (35): RALA (ENSG00000006451), REM1 (ENSG00000088320), RASL10A (ENSG00000100276), RASD2 (ENSG00000100302), RASL12 (ENSG00000103710), RHEB (ENSG00000106615), RASD1 (ENSG00000108551), RERGL (ENSG00000111404), RASL11A (ENSG00000122035), RAP2C (ENSG00000123728), RAP2A (ENSG00000125249), RRAS (ENSG00000126458), RAP1B (ENSG00000127314), 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-1A — P62834 (reviewed: P62834)

Alternative names: C21KG, G-22K, GTP-binding protein smg p21A, Ras-related protein Krev-1

All UniProt accessions (2): A8KAH9, P62834

UniProt curated annotations — full annotation on UniProt →

Function. Counteracts the mitogenic function of Ras, at least partly because it can interact with Ras GAPs and RAF in a competitive manner. Together with ITGB1BP1, regulates KRIT1 localization to microtubules and membranes. Plays a role in nerve growth factor (NGF)-induced neurite outgrowth. Plays a role in the regulation of embryonic blood vessel formation. Involved in the establishment of basal endothelial barrier function. Facilitates the progressive accumulation of CDH1 at mature desmosome junctions via cAMP-dependent signaling and its interaction with PKP3. May be involved in the regulation of the vascular endothelial growth factor receptor KDR expression at endothelial cell-cell junctions.

Subunit / interactions. Found in a complex, at least composed of ITGB1BP1, KRIT1 and RAP1A. Interacts (active GTP-bound form preferentially) with KRIT1 (via C-terminus FERM domain); the interaction does not induce the opening conformation of KRIT1. Found in a complex composed of CDH1, RAP1A and PKP3; PKP3 acts as a scaffold protein within the complex, the complex is required for CDH1 localization to mature desmosome cell junctions. In its GTP-bound form interacts with PLCE1 and RADIL. Interacts with SGSM1, SGSM2 and SGSM3. Interacts (via GTP-bound active form) with RAPGEF2 (via Ras-associating domain). Interacts with TBC1D21. Interacts with RAP1GDS1.

Subcellular location. Cell membrane. Cytoplasm. Perinuclear region. Cell junction. Early endosome.

Activity regulation. Activated by guanine nucleotide-exchange factors (GEF) EPAC and EPAC2 in a cAMP-dependent manner, and GFR.

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

RefSeq proteins (6): NP_001010935, NP_001278825, NP_001357145, NP_001357146, NP_001380995, NP_002875* (*=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 (24 total): helix 7, strand 6, binding site 4, turn 2, chain 1, propeptide 1, short sequence motif 1, modified residue 1, lipid moiety-binding region 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
4KVG	X-RAY DIFFRACTION	1.65
1C1Y	X-RAY DIFFRACTION	1.9
3KUC	X-RAY DIFFRACTION	1.92
1GUA	X-RAY DIFFRACTION	2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P62834-F1	92.17	0.80

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; 29–35; 60; 116–119

Post-translational modifications (2): 181, 181

Function

Pathways and Gene Ontology

Reactome pathways

16 pathways

ID	Pathway
R-HSA-170968	Frs2-mediated activation
R-HSA-170984	ARMS-mediated activation
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-381676	Glucagon-like Peptide-1 (GLP1) regulates insulin secretion
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-9649948	Signaling downstream of RAS mutants
R-HSA-9656223	Signaling by RAF1 mutants

MSigDB gene sets: 582 (showing top): GOBP_ENDOTHELIAL_CELL_DEVELOPMENT, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOBP_REGULATION_OF_VASCULOGENESIS, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_CARBOHYDRATE_TRANSPORT, GOBP_EPITHELIUM_DEVELOPMENT, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, MORF_MSH3, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOCC_SECRETORY_GRANULE

GO Biological Process (26): nervous system development (GO:0007399), response to carbohydrate (GO:0009743), positive regulation of neuron projection development (GO:0010976), synaptic vesicle exocytosis (GO:0016079), Rap protein signal transduction (GO:0032486), negative regulation of collagen biosynthetic process (GO:0032966), nerve growth factor signaling pathway (GO:0038180), positive regulation of GTPase activity (GO:0043547), positive regulation of protein kinase activity (GO:0045860), positive regulation of D-glucose import across plasma membrane (GO:0046326), positive regulation of phagocytosis (GO:0050766), positive regulation of Fc receptor mediated stimulatory signaling pathway (GO:0060369), establishment of endothelial barrier (GO:0061028), positive regulation of ERK1 and ERK2 cascade (GO:0070374), cellular response to cAMP (GO:0071320), protein localization to plasma membrane (GO:0072659), response to antineoplastic agent (GO:0097327), liver regeneration (GO:0097421), regulation of neurotransmitter receptor localization to postsynaptic specialization membrane (GO:0098696), regulation of cell junction assembly (GO:1901888), cellular response to forskolin (GO:1904322), cellular response to nerve growth factor stimulus (GO:1990090), negative regulation of synaptic vesicle exocytosis (GO:2000301), positive regulation of vasculogenesis (GO:2001214), signal transduction (GO:0007165), small GTPase-mediated signal transduction (GO:0007264)

GO Molecular Function (10): GTPase activity (GO:0003924), G protein activity (GO:0003925), guanyl-nucleotide exchange factor activity (GO:0005085), GTP binding (GO:0005525), GDP binding (GO:0019003), small GTPase binding (GO:0031267), protein-containing complex binding (GO:0044877), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (20): cytoplasm (GO:0005737), early endosome (GO:0005769), late endosome (GO:0005770), cytosol (GO:0005829), plasma membrane (GO:0005886), endosome membrane (GO:0010008), cell junction (GO:0030054), guanyl-nucleotide exchange factor complex (GO:0032045), specific granule membrane (GO:0035579), neuron projection (GO:0043005), phagocytic vesicle (GO:0045335), perinuclear region of cytoplasm (GO:0048471), extracellular exosome (GO:0070062), anchoring junction (GO:0070161), sperm midpiece (GO:0097225), presynapse (GO:0098793), glutamatergic synapse (GO:0098978), endosome (GO:0005768), endomembrane system (GO:0012505), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-11 pathways:

Category	Pathways
Oncogenic MAPK signaling	5
Prolonged ERK activation events	2
Integrin signaling	2
Signal Transduction	1
Platelet Aggregation (Plug Formation)	1
Regulation of insulin secretion	1
Adaptive Immune System	1
RAF/MAP kinase cascade	1
Innate Immune System	1
MET promotes cell motility	1
Signaling by RAS mutants	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	8
endosome	3
GTPase activity	2
guanyl ribonucleotide binding	2
binding	2
cytoplasm	2
synapse	2
system development	1
response to oxygen-containing compound	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
neurotransmitter secretion	1
regulated exocytosis	1
establishment of localization in cell	1
presynapse	1
vesicle-mediated transport in synapse	1
synaptic vesicle cycle	1
signal release from synapse	1
small GTPase-mediated signal transduction	1
negative regulation of biosynthetic process	1
negative regulation of collagen metabolic process	1
collagen biosynthetic process	1
regulation of collagen biosynthetic process	1
neurotrophin signaling pathway	1
cellular response to nerve growth factor stimulus	1
regulation of GTPase activity	1
positive regulation of hydrolase activity	1
positive regulation of protein phosphorylation	1
protein kinase activity	1
positive regulation of kinase activity	1
regulation of protein kinase activity	1
positive regulation of D-glucose transmembrane transport	1
regulation of D-glucose import across plasma membrane	1
D-glucose import across plasma membrane	1
phagocytosis	1
positive regulation of endocytosis	1
regulation of phagocytosis	1
Fc receptor mediated stimulatory signaling pathway	1
positive regulation of signal transduction	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

105 interactions, top by confidence:

A	B	Type	Score
PDE6D	ARL3	psi-mi:“MI:0914”(association)	0.920
PPP2R1A	STRN	psi-mi:“MI:0914”(association)	0.880
EXOC6	EXOC5	psi-mi:“MI:0914”(association)	0.840
RAP1A	RASSF5	psi-mi:“MI:0915”(physical association)	0.650
KIFAP3	KIF3C	psi-mi:“MI:0914”(association)	0.640
RAP1GDS1	DIRAS1	psi-mi:“MI:0914”(association)	0.640
RAF1	RAP1A	psi-mi:“MI:0407”(direct interaction)	0.620
RAP1A	RAF1	psi-mi:“MI:0407”(direct interaction)	0.620
Rassf5	RAP1A	psi-mi:“MI:0407”(direct interaction)	0.610
RAP1A	Rassf5	psi-mi:“MI:0915”(physical association)	0.610
Rassf5	RAP1A	psi-mi:“MI:0915”(physical association)	0.610
MTNR1A	PGRMC1	psi-mi:“MI:0914”(association)	0.530
MGST3	GAPDHS	psi-mi:“MI:0914”(association)	0.530
CPLX2	DEGS1	psi-mi:“MI:0914”(association)	0.530
TMEM31	PSMD11	psi-mi:“MI:0914”(association)	0.530
GPC3	CLGN	psi-mi:“MI:0914”(association)	0.530
WASHC3	WASH3P	psi-mi:“MI:0914”(association)	0.530
ANKH	FAM234B	psi-mi:“MI:0914”(association)	0.530
	VAPB	psi-mi:“MI:0914”(association)	0.500
RAP1A	RAPGEF1	psi-mi:“MI:0407”(direct interaction)	0.440
YWHAZ	RAP1A	psi-mi:“MI:0407”(direct interaction)	0.440
RAP1A	RAPGEF2	psi-mi:“MI:0407”(direct interaction)	0.440

BioGRID (203): RAP1A (Affinity Capture-RNA), ARHGDIA (Co-fractionation), CDC42 (Co-fractionation), ECHS1 (Co-fractionation), RAB5A (Co-fractionation), RAB5B (Co-fractionation), RAB5C (Co-fractionation), RAB7A (Co-fractionation), RAB8A (Co-fractionation), RAB8B (Co-fractionation), UQCRC2 (Co-fractionation), RAP1A (Two-hybrid), BIN1 (Reconstituted Complex), BMX (Reconstituted Complex), SMARCA2 (Reconstituted Complex)

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

16 interactions.

A	Effect	B	Mechanism
RAP1GDS1	up-regulates	RAP1A	binding
DEF6	“up-regulates activity”	RAP1A	binding
TWIST2	“down-regulates quantity by repression”	RAP1A	“transcriptional regulation”
TWIST1	“down-regulates quantity by repression”	RAP1A	“transcriptional regulation”
RAPGEF5	“up-regulates activity”	RAP1A	“guanine nucleotide exchange factor”
RAP1A	“up-regulates activity”	CAMK1
RAP1A	“up-regulates activity”	BRAF	binding
RAPGEF2	“up-regulates activity”	RAP1A	“guanine nucleotide exchange factor”
RAP1GAP	“down-regulates activity”	RAP1A	binding
PKA	“up-regulates activity”	RAP1A	phosphorylation
RAP1A	“up-regulates quantity”	PLCE1	binding
RAPGEF4	“up-regulates quantity”	RAP1A	binding
RAP1A	“up-regulates activity”	“AL/b2 integrin”	binding
PRKACA	“down-regulates activity”	RAP1A	phosphorylation
RAPGEF4	“up-regulates activity”	RAP1A	“guanine nucleotide exchange factor”
RAPGEF3	“up-regulates activity”	RAP1A	“guanine nucleotide exchange factor”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 131 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	7	12.8×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	7
Likely benign	9
Benign	16

Top pathogenic / likely-pathogenic (0)

SpliceAI

2345 predictions. Top by Δscore:

Variant	Effect	Δscore
1:111542312:G:GT	donor_gain	1.0000
1:111542389:G:GT	donor_gain	1.0000
1:111602298:G:GT	donor_gain	1.0000
1:111691330:TCAG:T	acceptor_loss	1.0000
1:111691331:CA:C	acceptor_loss	1.0000
1:111691332:A:AG	acceptor_gain	1.0000
1:111691332:AGATC:A	acceptor_gain	1.0000
1:111691333:G:GT	acceptor_gain	1.0000
1:111691333:GA:G	acceptor_gain	1.0000
1:111691333:GAT:G	acceptor_gain	1.0000
1:111691333:GATC:G	acceptor_gain	1.0000
1:111691333:GATCG:G	acceptor_gain	1.0000
1:111691415:CTGG:C	donor_loss	1.0000
1:111691417:GGTA:G	donor_loss	1.0000
1:111691418:G:A	donor_loss	1.0000
1:111691418:G:GG	donor_gain	1.0000
1:111691419:TAA:T	donor_loss	1.0000
1:111695339:A:AG	acceptor_gain	1.0000
1:111695340:G:GG	acceptor_gain	1.0000
1:111695340:GAC:G	acceptor_gain	1.0000
1:111695340:GACA:G	acceptor_gain	1.0000
1:111695406:AAAGG:A	donor_loss	1.0000
1:111695407:AAGGT:A	donor_loss	1.0000
1:111695408:AGG:A	donor_loss	1.0000
1:111695409:GGT:G	donor_loss	1.0000
1:111695410:G:T	donor_loss	1.0000
1:111695411:T:A	donor_loss	1.0000
1:111697440:GCAA:G	acceptor_gain	1.0000
1:111697493:GGACA:G	donor_gain	1.0000
1:111697494:G:T	donor_gain	1.0000

AlphaMissense

1204 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:111691388:G:C	G10R	1.000
1:111691403:G:A	G15R	1.000
1:111691403:G:C	G15R	1.000
1:111691403:G:T	G15W	1.000
1:111691404:G:A	G15E	1.000
1:111691404:G:T	G15V	1.000
1:111691410:C:T	S17F	1.000
1:111695365:T:C	F28L	1.000
1:111695367:T:A	F28L	1.000
1:111695367:T:G	F28L	1.000
1:111697481:T:C	L56P	1.000
1:111697483:G:A	D57N	1.000
1:111697483:G:C	D57H	1.000
1:111697484:A:C	D57A	1.000
1:111697484:A:G	D57G	1.000
1:111697484:A:T	D57V	1.000
1:111697485:T:A	D57E	1.000
1:111697485:T:G	D57E	1.000
1:111697492:G:A	G60R	1.000
1:111697492:G:C	G60R	1.000
1:111697492:G:T	G60W	1.000
1:111697493:G:A	G60E	1.000
1:111703342:T:C	F64L	1.000
1:111703343:T:C	F64S	1.000
1:111703343:T:G	F64C	1.000
1:111703344:T:A	F64L	1.000
1:111703344:T:G	F64L	1.000
1:111703381:G:C	G77R	1.000
1:111703382:G:A	G77D	1.000
1:111703384:T:C	F78L	1.000

dbSNP variants (sampled 300 via entrez): RS1000022401 (1:111612190 G>A,C), RS1000038056 (1:111544076 T>G), RS1000080783 (1:111680100 C>T), RS1000088595 (1:111543861 T>G), RS1000137338 (1:111584534 C>T), RS1000138301 (1:111673487 A>G), RS1000145265 (1:111715801 A>G), RS1000152480 (1:111618438 C>T), RS1000159577 (1:111566834 TGGA>T), RS1000174208 (1:111624165 C>G), RS1000233808 (1:111699504 C>G), RS1000244115 (1:111667379 T>C), RS1000254176 (1:111549412 G>A), RS1000258678 (1:111579379 G>A,C), RS1000289783 (1:111579088 C>A,G)

Disease associations

OMIM: gene MIM:179520 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
Kabuki syndrome	Moderate	Autosomal dominant

Mondo (1): Kabuki syndrome (MONDO:0016512)

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST000698_5	Osteoporosis-related phenotypes	4.000000e-08
GCST006054_2	High altitude adaptation	2.000000e-08
GCST007216_8	Crohn’s disease	4.000000e-08
GCST008595_13	Cognitive ability, years of educational attainment or schizophrenia (pleiotropy)	3.000000e-08
GCST010577_9	Crohn’s disease	7.000000e-06
GCST90002388_623	Lymphocyte count	6.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0009105	high altitude adaptation
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0004587	lymphocyte count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537705	Kabuki syndrome (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL1255139 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.85	EC50	140	nM	CHEMBL159171
6.30	Kd	500	nM	DESULFO-YESSOTOXIN
5.40	Kd	4000	nM	YESSOTOXIN

PubChem BioAssay actives

4 with measured affinity, of 9 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-(2-cyclohexylethyl)-23-oxo-8-oxa-1,15,17,21-tetrazapentacyclo[19.2.2.13,7.19,13.015,19]heptacosa-3,5,7(27),9,11,13(26),16,18-octaene-10-carbonitrile	711467: Inhibition of Rap1a	ec50	0.1400	uM
(1R,3S,5R,7S,9R,11S,13R,14S,16R,18S,20R,22S,25R,27S,30S,31R,33S,34R,35R,37S,40S,42R,44S,46R,48S)-13-(2-hydroxyethyl)-40-[(2R,3E)-2-hydroxy-5-methylideneocta-3,7-dien-2-yl]-13,25,27,30,35-pentamethyl-39-methylidene-4,8,12,17,21,26,32,36,41,45,49-undecaoxaundecacyclo[25.22.0.03,25.05,22.07,20.09,18.011,16.031,48.033,46.035,44.037,42]nonatetracontane-14,34-diol	528312: Binding affinity to RAP1A in human RBC membrane by surface plasmon resonance analysis with inverted configuration	kd	0.5000	uM
disodium;[(1R,3S,5R,7S,9R,11S,13R,14S,16R,18S,20R,22S,25R,27S,30S,31R,33S,35R,37S,40S,42R,44S,46R,48S)-40-[(2R,3E)-2-hydroxy-5-methylideneocta-3,7-dien-2-yl]-13,25,27,30,35-pentamethyl-39-methylidene-13-(2-sulfonatooxyethyl)-4,8,12,17,21,26,32,36,41,45,49-undecaoxaundecacyclo[25.22.0.03,25.05,22.07,20.09,18.011,16.031,48.033,46.035,44.037,42]nonatetracontan-14-yl] sulfate	528310: Binding affinity to RAP1A in human RBC membrane by Western blot analysis	kd	4.0000	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Zoledronic Acid	decreases prenylation, increases expression, decreases geranoylation, decreases reaction, decreases expression	7
Simvastatin	decreases geranoylation, decreases reaction, decreases expression, decreases prenylation	4
Risedronic Acid	decreases prenylation	3
geranylgeraniol	decreases reaction, affects cotreatment, decreases expression, decreases geranoylation	2
sodium arsenite	increases expression	2
Mevalonic Acid	increases expression, decreases geranoylation, decreases reaction, affects reaction	2
Valproic Acid	increases expression, affects cotreatment	2
Cyclosporine	decreases expression, increases expression, affects cotreatment	2
bisphenol F	increases expression	1
dicrotophos	decreases expression	1
beauvericin	affects cotreatment, increases expression	1
2,4,6-tribromophenol	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
decabromobiphenyl ether	increases expression	1
quercitrin	affects expression	1
terbufos	decreases methylation	1
arsenite	affects binding, increases reaction	1
geranyl pyrophosphate	affects cotreatment, decreases expression	1
mono-(2-ethylhexyl)phthalate	increases expression, decreases expression, increases reaction	1
afimoxifene	decreases expression	1
tetrabromobisphenol A	increases expression	1
ochratoxin A	affects binding	1
hydroquinone	affects expression, affects reaction, affects cotreatment	1
perillyl alcohol	affects reaction, increases expression	1
perillaldehyde	affects reaction, increases expression	1
nivalenol	increases expression	1
ochratoxin B	affects binding	1
nefazodone	affects cotreatment, decreases expression	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1273311	Binding	Binding affinity to RAP1A in human RBC membrane by Western blot analysis	Detection of Rap1A as a yessotoxin binding protein from blood cell membranes. — Bioorg Med Chem Lett

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D4Y3	Calu6 Krev-2	Cancer cell line	Female
CVCL_D4Y4	Calu6 Krev-4	Cancer cell line	Female
CVCL_D4Y5	Calu6 Krev-7	Cancer cell line	Female
CVCL_D4Y6	Calu6 Krev-8	Cancer cell line	Female
CVCL_D4Y7	Calu6 Krev-9	Cancer cell line	Female
CVCL_D8UD	Ubigene HCT 116 RAP1A KO	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04722315	EARLY_PHASE1	COMPLETED	Study of Modified Atkins Diet in Kabuki Syndrome
NCT01314534	Not specified	COMPLETED	French Kabuki Syndrome Network. Epidemiology, Management of Patients and Research by Array-CGH
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT03547609	Not specified	COMPLETED	Assessment of Memory in Children With Kabuki Syndrom