RANGAP1

Summary

RANGAP1 (Ran GTPase activating protein 1, HGNC:9854) is a protein-coding gene on chromosome 22q13.2, encoding Ran GTPase-activating protein 1 (P46060). GTPase activator for RAN. It is a common-essential gene (DepMap: required in 99.6% of cancer cell lines).

This gene encodes a protein that associates with the nuclear pore complex and participates in the regulation of nuclear transport. The encoded protein interacts with Ras-related nuclear protein 1 (RAN) and regulates guanosine triphosphate (GTP)-binding and exchange. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 5905 — RefSeq curated summary.

At a glance

• GWAS associations: 16
• Clinical variants (ClinVar): 87 total
• Cancer dependency (DepMap): dependent in 99.6% of screened cell lines (common-essential)
• MANE Select transcript: NM_002883

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9854
Approved symbol	RANGAP1
Name	Ran GTPase activating protein 1
Location	22q13.2
Locus type	gene with protein product
Status	Approved
Aliases	Fug1, KIAA1835
Ensembl gene	ENSG00000100401
Ensembl biotype	protein_coding
OMIM	602362
Entrez	5905

Gene structure

Transcript identifiers

Ensembl transcripts: 93 — 93 protein_coding

ENST00000356244, ENST00000405486, ENST00000418067, ENST00000422838, ENST00000446258, ENST00000452543, ENST00000455915, ENST00000705116, ENST00000898474, ENST00000898475, ENST00000898476, ENST00000898477, ENST00000898478, ENST00000898479, ENST00000898480, ENST00000898481, ENST00000898482, ENST00000898483, ENST00000898484, ENST00000898485, ENST00000898486, ENST00000898487, ENST00000898488, ENST00000898489, ENST00000898490, ENST00000898491, ENST00000898492, ENST00000898493, ENST00000898494, ENST00000898495, ENST00000898496, ENST00000898497, ENST00000898498, ENST00000898499, ENST00000898500, ENST00000898501, ENST00000898502, ENST00000932870, ENST00000932871, ENST00000932872, ENST00000932873, ENST00000932874, ENST00000932875, ENST00000932876, ENST00000932877, ENST00000932878, ENST00000932879, ENST00000932880, ENST00000932881, ENST00000932882, ENST00000932883, ENST00000932884, ENST00000932885, ENST00000932886, ENST00000932887, ENST00000932888, ENST00000932889, ENST00000932890, ENST00000932891, ENST00000932892, ENST00000932893, ENST00000932894, ENST00000932895, ENST00000932896, ENST00000962575, ENST00000962576, ENST00000962577, ENST00000962578, ENST00000962579, ENST00000962580, ENST00000962581, ENST00000962582, ENST00000962583, ENST00000962584, ENST00000962585, ENST00000962586, ENST00000962587, ENST00000962588, ENST00000962589, ENST00000962590, ENST00000962591, ENST00000962592, ENST00000962593, ENST00000962594, ENST00000962595, ENST00000962596, ENST00000962597, ENST00000962598, ENST00000962599, ENST00000962600, ENST00000962601, ENST00000962602, ENST00000962603

RefSeq mRNA: 3 — MANE Select: NM_002883 NM_001278651, NM_001317930, NM_002883

CCDS: CCDS14012

Canonical transcript exons

ENST00000356244 — 16 exons

Exon	Start	End
ENSE00000655554	41256711	41256824
ENSE00000655562	41257948	41258106
ENSE00000655571	41261446	41261580
ENSE00000655579	41264664	41264843
ENSE00000655593	41274600	41274727
ENSE00001388340	41256191	41256290
ENSE00001525423	41285986	41286187
ENSE00001615125	41254308	41254494
ENSE00001635042	41251007	41251109
ENSE00001786527	41252872	41252991
ENSE00003125624	41249330	41249451
ENSE00003129660	41249729	41249817
ENSE00003784274	41256021	41256105
ENSE00003787580	41268097	41268156
ENSE00003792004	41280933	41281082
ENSE00003900747	41244779	41246672

Expression profiles

Bgee: expression breadth ubiquitous, 273 present calls, max score 98.44.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 45.0945 / max 308.3490, expressed in 1817 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
194353	43.8793	1817
194354	0.8248	470
194352	0.3332	181
194349	0.0573	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
left testis	UBERON:0004533	98.44	gold quality
right testis	UBERON:0004534	98.43	gold quality
Brodmann (1909) area 10	UBERON:0013541	97.31	gold quality
right frontal lobe	UBERON:0002810	97.09	gold quality
prefrontal cortex	UBERON:0000451	96.58	gold quality
cingulate cortex	UBERON:0003027	96.34	gold quality
anterior cingulate cortex	UBERON:0009835	96.33	gold quality
skin of abdomen	UBERON:0001416	95.98	gold quality
Brodmann (1909) area 9	UBERON:0013540	95.97	gold quality
lower esophagus mucosa	UBERON:0035834	95.80	gold quality
skin of leg	UBERON:0001511	95.79	gold quality
middle frontal gyrus	UBERON:0002702	95.75	gold quality
frontal pole	UBERON:0002795	95.43	gold quality
ventricular zone	UBERON:0003053	95.34	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.34	gold quality
stromal cell of endometrium	CL:0002255	95.28	gold quality
nucleus accumbens	UBERON:0001882	95.26	gold quality
testis	UBERON:0000473	95.20	gold quality
neocortex	UBERON:0001950	94.85	gold quality
frontal cortex	UBERON:0001870	94.80	gold quality
amygdala	UBERON:0001876	94.78	gold quality
putamen	UBERON:0001874	94.77	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	94.77	gold quality
caudate nucleus	UBERON:0001873	94.50	gold quality
esophagus mucosa	UBERON:0002469	94.31	gold quality
right adrenal gland cortex	UBERON:0035827	94.24	gold quality
left adrenal gland cortex	UBERON:0035825	94.16	gold quality
right adrenal gland	UBERON:0001233	94.07	gold quality
spinal cord	UBERON:0002240	94.06	gold quality
left adrenal gland	UBERON:0001234	94.03	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	8.58
E-ANND-3	yes	4.74

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): TCF3

miRNA regulators (miRDB)

60 targeting RANGAP1, 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-4262	100.00	73.26	3931
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
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-511-3P	99.99	68.85	1467
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-6755-5P	99.95	65.59	464
HSA-MIR-552-5P	99.93	68.56	1583
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-4694-3P	99.79	69.53	2640
HSA-MIR-6885-3P	99.75	70.36	3187
HSA-MIR-148A-3P	99.74	73.77	1700
HSA-MIR-148B-3P	99.74	73.75	1700
HSA-MIR-152-3P	99.74	73.75	1703
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-3177-5P	99.65	70.38	1174
HSA-MIR-298	99.63	67.56	1916
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-4472	99.56	66.08	1478
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-1207-5P	99.49	69.11	2983

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.6% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 19)

• the RanGAP1 consensus sumoylation site and SUMO-1 C terminus are both conformationally flexible (PMID:15355965)
• the 3.0-A crystal structure of a four-protein complex of Ubc9, a Nup358/RanBP2 E3 ligase domain (IR1-M) and SUMO-1 conjugated to the carboxy-terminal domain of RanGAP1 (PMID:15931224)
• RanGAP1 is phosphorylated on Ser-358 in vivo & in vitro. Phosphorylated RanGAP1, but not a mutant at 358S, formed a stable ternary complex with Ran and RanBP1 in vivo, suggesting that its 358S phosphorylation affects the Ran system. (PMID:16428860)
• The results of this study strengthen the conclusion that mel-18 functions as an anti-SUMO E3 factor, and extend its targets to include regulation of the sumoylation of the important cellular protein RanGAP1. (PMID:18706886)
• Analysis of the dynamics of E2(Ubc9)-SUMO-Target(RanGAP1) in the absence and presence of E3(RanBP2) revealed that two different allosteric sites regulate the ligase activity. (PMID:21216249)
• Determinants of small ubiquitin-like modifier 1 (SUMO1) protein specificity, E3 ligase, and SUMO-RanGAP1 binding activities of nucleoporin RanBP2. (PMID:22194619)
• Differentiation of human coronary artery smooth muscle cell to a contractile phenotype by stepwise serum depletion leads to significant reduction of RanGAP1 protein levels. (PMID:24988324)
• immune cell adaptor SLP-76 binds directly to SUMO-RanGAP1 of cytoplasmic fibrils of the nuclear pore complex, and this interaction is needed for optimal NFATc1 and NF-kappaB p65 nuclear entry in T cells (PMID:26321253)
• our results elucidate that RanGAP1 is actively transported between the nuclear and cytoplasmic compartments, and that the cytoplasmic and NPC localization of RanGAP1 is dependent on CRM1-mediated nuclear export. (PMID:26506250)
• RanGAP1 upregulation is associated with drug resistance in Chronic Myeloid Leukemia. (PMID:27228340)
• Abnormal localization of RanGAP1 was found in cortex of Huntington’s disease patients. (PMID:28384474)
• NUSAP1 contributes to accurate chromosome segregation by acting as a co-factor for RanBP2-RanGAP1-UBC9 during cell division. (PMID:28900032)
• Circular RNA circ-RanGAP1 regulates VEGFA expression by targeting miR-877-3p to facilitate gastric cancer invasion and metastasis. (PMID:31811909)
• The RanBP2/RanGAP1-SUMO complex gates beta-arrestin2 nuclear entry to regulate the Mdm2-p53 signaling axis. (PMID:33649538)
• CircRNA_0079586 and circRNA_RanGAP1 are involved in the pathogenesis of intracranial aneurysms rupture by regulating the expression of MPO. (PMID:34611229)
• Loss of RanGAP1 drives chromosome instability and rapid tumorigenesis of osteosarcoma. (PMID:36696903)
• SUMOylation mediates the disassembly of the Smad4 nuclear export complex via RanGAP1 in KELOIDS. (PMID:36916534)
• Hepatitis B virus core protein stabilizes RANGAP1 to upregulate KDM2A and facilitate hepatocarcinogenesis. (PMID:37845585)
• Impact of RANGAP1 SUMOylation on Smad4 nuclear export by bioinformatic analysis and cell assays. (PMID:38801243)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	rangap1a	ENSDARG00000041317
danio_rerio	rangap1b	ENSDARG00000056059
mus_musculus	Rangap1	ENSMUSG00000022391
rattus_norvegicus	Rangap1	ENSRNOG00000031789
drosophila_melanogaster	RanGAP	FBGN0003346
caenorhabditis_elegans		WBGENE00004303

Protein

Protein identifiers

Ran GTPase-activating protein 1 — P46060 (reviewed: P46060)

All UniProt accessions (5): P46060, B0QYT4, B0QYT5, B0QYT6, H0Y4Q3

UniProt curated annotations — full annotation on UniProt →

Function. GTPase activator for RAN. Converts cytoplasmic GTP-bound RAN to GDP-bound RAN, which is essential for RAN-mediated nuclear import and export. Mediates dissociation of cargo from nuclear export complexes containing XPO1, RAN and RANBP2 after nuclear export.

Subunit / interactions. Homodimer. Interacts with RAN. Forms a complex with RANBP2/NUP358, NXF1 and NXT1. Forms a tight complex in association with RANBP2/NUP358 and UBE2I/UBC9, the ubiquitin-conjugating enzyme E2. Interacts with UBE2I; the interaction conjugates SUMO1 to RANGAP1, and subsequently stabilizes interactions of sumoylated RANGAP1 with RANBP2/NUP358. The complex composed of RANBP2, SUMO1, RANGAP1 and UBE2I associates with nuclear pore complexes. Identified in a complex composed of RAN, RANBP2, sumoylated RANGAP1, UBE2I and XPO1. Identified in a complex composed of RAN, RANGAP1 and RANBP1. Interacts with TRAF6. Interacts with SUMO1 and SENP1. Interacts (when sumoylated) with MYCBP2; interaction inhibits MYCBP2 E3 ubiquitin-protein ligase activity and promotes MYCBP2 translocation to the nucleus.

Subcellular location. Cytoplasm. Nucleus. Nucleoplasm. Nucleus envelope. Chromosome. Centromere. Kinetochore. Cytoskeleton. Spindle.

Tissue specificity. Highly expressed in brain, thymus and testis.

Post-translational modifications. Phosphorylation occurs before nuclear envelope breakdown and continues throughout mitosis. Phosphorylated by the M-phase kinase cyclin B/Cdk1, in vitro. Differential timimg of dephosphorylation occurs during phases of mitosis. The phosphorylated form remains associated with RANBP2/NUP358 and the SUMO E2-conjugating enzyme, UBE2I, on nuclear pore complex (NPC) disassembly and during mitosis. Sumoylated. Sumoylation is necessary for targeting to the nuclear envelope (NE), and for association with mitotic spindles and kinetochores during mitosis. Also required for interaction with RANBP2 and is mediated by UBE2I. Desumoylated by HINT1.

Similarity. Belongs to the RNA1 family.

RefSeq proteins (3): NP_001265580, NP_001304859, NP_002874* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001611	Leu-rich_rpt	Repeat
IPR009109	Ran_GTPase_activating_1_C	Domain
IPR027038	RanGap	Family
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR036720	RanGAP1_C_sf	Homologous_superfamily

Pfam: PF07834, PF13516

UniProt features (78 total): helix 26, strand 13, modified residue 10, cross-link 8, repeat 6, mutagenesis site 4, compositionally biased region 2, site 2, turn 2, initiator methionine 1, chain 1, sequence variant 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
2GRR	X-RAY DIFFRACTION	1.3
2GRO	X-RAY DIFFRACTION	1.7
2GRQ	X-RAY DIFFRACTION	1.7
2GRN	X-RAY DIFFRACTION	1.8
2GRP	X-RAY DIFFRACTION	2.05
3UIP	X-RAY DIFFRACTION	2.29
5D2M	X-RAY DIFFRACTION	2.4
3UIN	X-RAY DIFFRACTION	2.6
3UIO	X-RAY DIFFRACTION	2.6
2IY0	X-RAY DIFFRACTION	2.77
2IO2	X-RAY DIFFRACTION	2.9
9B62	ELECTRON MICROSCOPY	2.9
1Z5S	X-RAY DIFFRACTION	3.01
2IO3	X-RAY DIFFRACTION	3.2

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P46060-F1	87.13	0.75

Functional residue map

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

Catalytic / active sites (2): 562 (hydrophobic interaction with ube2i); 565 (hydrophobic interaction with ube2i)

Post-translational modifications (18): 2, 24, 301, 358, 409, 428, 435, 436, 442, 524, 8, 8, 15, 279, 452, 524, 524, 586

Mutagenesis-validated functional residues (4):

Position	Phenotype
91	abolishes ran gtpase activation.
356	no effect on phosphorylation.
358	strongly decreased phosphorylation. no effect on sumoylation.
524	loss of cross-link to sumo1. abolishes association with nuclear pores during interphase, and with mitotic spindles durin

Function

Pathways and Gene Ontology

Reactome pathways

10 pathways

ID	Pathway
R-HSA-141444	Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal
R-HSA-165054	Rev-mediated nuclear export of HIV RNA
R-HSA-2467813	Separation of Sister Chromatids
R-HSA-2500257	Resolution of Sister Chromatid Cohesion
R-HSA-4615885	SUMOylation of DNA replication proteins
R-HSA-5663220	RHO GTPases Activate Formins
R-HSA-68877	Mitotic Prometaphase
R-HSA-9615933	Postmitotic nuclear pore complex (NPC) reformation
R-HSA-9648025	EML4 and NUDC in mitotic spindle formation
R-HSA-9793242	SUMOylation of nuclear envelope proteins

MSigDB gene sets: 238 (showing top): PID_HDAC_CLASSI_PATHWAY, ELVIDGE_HYPOXIA_DN, YAO_TEMPORAL_RESPONSE_TO_PROGESTERONE_CLUSTER_10, WANG_CLIM2_TARGETS_UP, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_ACTIVATION_OF_GTPASE_ACTIVITY, GOBP_REGULATION_OF_GTPASE_ACTIVITY, GOBP_REGULATION_OF_PROTEIN_EXPORT_FROM_NUCLEUS, GOMF_GTPASE_BINDING, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_NUCLEAR_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_POSITIVE_REGULATION_OF_CATALYTIC_ACTIVITY, GOBP_PEPTIDYL_LYSINE_MODIFICATION, GOBP_REGULATION_OF_HYDROLASE_ACTIVITY

GO Biological Process (8): signal transduction (GO:0007165), protein sumoylation (GO:0016925), negative regulation of protein export from nucleus (GO:0046826), response to axon injury (GO:0048678), nuclear export (GO:0051168), activation of GTPase activity (GO:0090630), cellular response to vasopressin (GO:1904117), cellular response to peptide hormone stimulus (GO:0071375)

GO Molecular Function (6): RNA binding (GO:0003723), GTPase activator activity (GO:0005096), small GTPase binding (GO:0031267), ubiquitin protein ligase binding (GO:0031625), cadherin binding (GO:0045296), protein binding (GO:0005515)

GO Cellular Component (21): kinetochore (GO:0000776), nucleus (GO:0005634), nuclear envelope (GO:0005635), nuclear pore (GO:0005643), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), centriole (GO:0005814), cytosol (GO:0005829), aggresome (GO:0016235), dendrite (GO:0030425), nuclear membrane (GO:0031965), nuclear pore cytoplasmic filaments (GO:0044614), perinuclear region of cytoplasm (GO:0048471), mitotic spindle (GO:0072686), SUMO ligase complex (GO:0106068), axon cytoplasm (GO:1904115), cytoplasmic periphery of the nuclear pore complex (GO:1990723), chromosome, centromeric region (GO:0000775), chromosome (GO:0005694), spindle (GO:0005819), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Mitotic Prometaphase	2
SUMO E3 ligases SUMOylate target proteins	2
Amplification of signal from the kinetochores	1
Late Phase of HIV Life Cycle	1
Interactions of Rev with host cellular proteins	1
Mitotic Anaphase	1
RHO GTPase Effectors	1
M Phase	1
Nuclear Envelope (NE) Reassembly	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membraneless organelle	4
cellular anatomical structure	4
nucleus	2
nuclear envelope	2
nuclear protein-containing complex	2
cytoplasm	2
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
peptidyl-lysine modification	1
protein modification by small protein conjugation	1
protein export from nucleus	1
negative regulation of nucleocytoplasmic transport	1
regulation of protein export from nucleus	1
maintenance of protein location in nucleus	1
negative regulation of intracellular protein transport	1
response to wounding	1
nucleocytoplasmic transport	1
intercellular transport	1
positive regulation of GTPase activity	1
cellular response to peptide hormone stimulus	1
response to vasopressin	1
cellular response to hormone stimulus	1
response to peptide hormone	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
nucleic acid binding	1
GTPase activity	1
enzyme activator activity	1
GTPase regulator activity	1
GTPase binding	1
ubiquitin-like protein ligase binding	1
cell adhesion molecule binding	1
binding	1
condensed chromosome, centromeric region	1
supramolecular complex	1
intracellular membrane-bounded organelle	1
endomembrane system	1

Protein interactions and networks

STRING

2988 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RANGAP1	RANBP2	P49792	999
RANGAP1	UBE2I	P50550	998
RANGAP1	SUMO1	P55856	998
RANGAP1	RGPD1	P0C839	998
RANGAP1	RANBP1	P43487	998
RANGAP1	RAN	P17080	972
RANGAP1	RCC1	P18754	956
RANGAP1	SUMO2	P55855	949
RANGAP1	XPO1	O14980	936
RANGAP1	LCP2	Q13094	915
RANGAP1	SAE1	Q9UBE0	911
RANGAP1	UBA2	Q9UBT2	908
RANGAP1	RANBP3	Q9H6Z4	903
RANGAP1	SENP7	Q9BQF6	900
RANGAP1	NUTF2	P13662	897

IntAct

230 interactions, top by confidence:

A	B	Type	Score
SUMO1	RANGAP1	psi-mi:“MI:0915”(physical association)	0.960
RANGAP1	SUMO1	psi-mi:“MI:0915”(physical association)	0.960
RANGAP1	SUMO1	psi-mi:“MI:0195”(covalent binding)	0.960
RANGAP1	SUMO1	psi-mi:“MI:0407”(direct interaction)	0.960
UBE2I	RANGAP1	psi-mi:“MI:0407”(direct interaction)	0.950
UBE2I	RANGAP1	psi-mi:“MI:0915”(physical association)	0.950
RANGAP1	UBE2I	psi-mi:“MI:0915”(physical association)	0.950
UBE2I	RANGAP1	psi-mi:“MI:0403”(colocalization)	0.950
RANGAP1	SUMO2	psi-mi:“MI:0915”(physical association)	0.750
MED19	MED19	psi-mi:“MI:0914”(association)	0.730
RANBP2	RANGAP1	psi-mi:“MI:0407”(direct interaction)	0.710
RANGAP1	RANBP2	psi-mi:“MI:0407”(direct interaction)	0.710
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
HTT	RANGAP1	psi-mi:“MI:0915”(physical association)	0.670

BioGRID (435): RANGAP1 (Biochemical Activity), RANGAP1 (Biochemical Activity), RANGAP1 (Reconstituted Complex), UBE2I (Reconstituted Complex), RANGAP1 (Biochemical Activity), RANGAP1 (Affinity Capture-MS), RANGAP1 (Affinity Capture-MS), RANGAP1 (Biochemical Activity), RANGAP1 (Affinity Capture-MS), RANGAP1 (Biochemical Activity), RANGAP1 (Biochemical Activity), RANGAP1 (Biochemical Activity), RANGAP1 (Biochemical Activity), RANGAP1 (Biochemical Activity), RANGAP1 (Biochemical Activity)

ESM2 similar proteins: A0A0R4IXF6, A0JPI9, A1A5Q0, A6H639, O00203, O13046, O13066, O60308, O60502, O70252, P23711, P34342, P41391, P46060, P46061, P59328, Q0VAA2, Q13367, Q2TAF3, Q32NU8, Q32PG1, Q3TPE9, Q3UHZ5, Q4R642, Q5E915, Q5JU00, Q5RAG3, Q5ZIJ9, Q6DIP5, Q6GNY1, Q6P5Q4, Q7YRF1, Q7Z7L7, Q804S5, Q80SY4, Q80ZJ6, Q86YT6, Q8K3X6, Q8N8V4, Q8VIJ5

Diamond homologs: O13066, P34342, P41391, P46060, P46061, Q9LE82, Q9M651, Q9VIW3, P11745, Q0WQ91, Q9C500, Q9FMH6, Q9M7N6, P59046, Q86W24

SIGNOR signaling

8 interactions.

A	Effect	B	Mechanism
CDK1	up-regulates	RANGAP1	phosphorylation
CSNK2A1	up-regulates	RANGAP1	phosphorylation
CyclinB/CDK1	up-regulates	RANGAP1	phosphorylation
RANGAP1	“down-regulates quantity by destabilization”	MYCBP2	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 191 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
Rev-mediated nuclear export of HIV RNA	12	30.4×	7e-13
Nuclear import of Rev protein	11	29.6×	1e-11
Postmitotic nuclear pore complex (NPC) reformation	9	29.4×	8e-10
SUMOylation of SUMOylation proteins	11	28.7×	1e-11
NEP/NS2 Interacts with the Cellular Export Machinery	10	27.7×	2e-10
SUMOylation of DNA replication proteins	13	25.8×	7e-13
Transport of Ribonucleoproteins into the Host Nucleus	9	25.7×	3e-09
NS1 Mediated Effects on Host Pathways	11	25.1×	5e-11

GO biological processes:

GO term	Partners	Fold	FDR
RNA export from nucleus	7	39.5×	1e-07
NLS-bearing protein import into nucleus	8	38.7×	9e-09
nucleocytoplasmic transport	9	21.2×	1e-07
positive regulation of microtubule polymerization	5	20.3×	5e-04
protein export from nucleus	6	18.5×	2e-04
protein import into nucleus	15	13.0×	8e-10
mRNA export from nucleus	7	12.5×	3e-04
mRNA transport	7	11.1×	5e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	64
Likely benign	5
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

2669 predictions. Top by Δscore:

Variant	Effect	Δscore
22:41249326:TCAC:T	donor_loss	1.0000
22:41249327:CA:C	donor_loss	1.0000
22:41249328:A:AC	donor_gain	1.0000
22:41249328:AC:A	donor_loss	1.0000
22:41249329:C:A	donor_loss	1.0000
22:41249329:C:CC	donor_gain	1.0000
22:41249447:TCACT:T	acceptor_gain	1.0000
22:41249448:CACT:C	acceptor_gain	1.0000
22:41249448:CACTC:C	acceptor_gain	1.0000
22:41249449:ACT:A	acceptor_gain	1.0000
22:41249450:CT:C	acceptor_gain	1.0000
22:41249450:CTC:C	acceptor_gain	1.0000
22:41249451:TCT:T	acceptor_gain	1.0000
22:41249452:C:CC	acceptor_gain	1.0000
22:41249452:C:G	acceptor_gain	1.0000
22:41249462:C:CT	acceptor_gain	1.0000
22:41249465:A:T	acceptor_gain	1.0000
22:41249727:A:AG	donor_loss	1.0000
22:41249728:CCT:C	donor_loss	1.0000
22:41251006:CCTA:C	donor_gain	1.0000
22:41251009:A:AC	donor_gain	1.0000
22:41251010:C:CC	donor_gain	1.0000
22:41251015:T:TA	donor_gain	1.0000
22:41251028:T:TA	donor_gain	1.0000
22:41251105:TCAGT:T	acceptor_gain	1.0000
22:41251106:CAGT:C	acceptor_gain	1.0000
22:41251106:CAGTC:C	acceptor_gain	1.0000
22:41251107:AGT:A	acceptor_gain	1.0000
22:41251108:GT:G	acceptor_gain	1.0000
22:41251108:GTCT:G	acceptor_loss	1.0000

AlphaMissense

3827 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:41257984:G:C	N246K	1.000
22:41257984:G:T	N246K	1.000
22:41257988:T:A	D245V	1.000
22:41264686:C:T	G153D	1.000
22:41264691:G:C	N151K	1.000
22:41264691:G:T	N151K	1.000
22:41264770:C:T	G125E	1.000
22:41264778:G:C	N122K	1.000
22:41264778:G:T	N122K	1.000
22:41268124:C:A	R91S	1.000
22:41268124:C:G	R91S	1.000
22:41249399:A:G	L542P	0.999
22:41257987:G:C	D245E	0.999
22:41257987:G:T	D245E	0.999
22:41257988:T:G	D245A	0.999
22:41258068:A:C	N218K	0.999
22:41258068:A:T	N218K	0.999
22:41261489:C:G	R191P	0.999
22:41261490:G:C	R191G	0.999
22:41261490:G:T	R191S	0.999
22:41261491:G:C	N190K	0.999
22:41261491:G:T	N190K	0.999
22:41261494:T:A	R189S	0.999
22:41261494:T:G	R189S	0.999
22:41261495:C:G	R189T	0.999
22:41264671:C:T	G158D	0.999
22:41264680:C:T	G155D	0.999
22:41264761:C:T	G128D	0.999
22:41264776:G:T	A123E	0.999
22:41264782:T:A	D121V	0.999

dbSNP variants (sampled 300 via entrez): RS1000026024 (22:41292518 T>A,C), RS1000107155 (22:41272476 C>T), RS1000134488 (22:41257718 C>T), RS1000145489 (22:41289152 C>T), RS1000187188 (22:41257510 A>G), RS1000239863 (22:41295993 A>C), RS1000249806 (22:41257696 G>A), RS1000250270 (22:41293467 A>G), RS1000256056 (22:41251720 A>G), RS1000338095 (22:41299169 G>A), RS1000339979 (22:41267629 A>G), RS1000360312 (22:41289029 T>A), RS1000365212 (22:41293197 T>G), RS1000391625 (22:41288785 C>A,G,T), RS1000427655 (22:41246792 A>C,T)

Disease associations

OMIM: gene MIM:602362 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST002539_94	Schizophrenia	2.000000e-11
GCST004521_55	Autism spectrum disorder or schizophrenia	9.000000e-09
GCST004946_20	Schizophrenia	1.000000e-12
GCST005232_52	Neuroticism	3.000000e-18
GCST006803_24	Schizophrenia	6.000000e-13
GCST006979_829	Heel bone mineral density	4.000000e-23
GCST007324_131	Adventurousness	5.000000e-11
GCST007941_8	Medication use (adrenergics, inhalants)	5.000000e-12
GCST008357_39	Mood instability	7.000000e-11
GCST008521_21	Bitter beverage consumption	2.000000e-09
GCST010002_83	Refractive error	2.000000e-27
GCST010133_13	Lamb consumption	3.000000e-08
GCST011126_11	Caffeine consumption from coffee or tea	2.000000e-09
GCST011126_37	Caffeine consumption from coffee or tea	1.000000e-15
GCST90020025_1736	Waist-to-hip ratio adjusted for BMI	3.000000e-08
GCST90020027_405	Waist-hip index	3.000000e-08

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0007660	neuroticism measurement
EFO:0009270	heel bone mineral density
EFO:0008579	risk-taking behaviour
EFO:0009941	Inhalant adrenergic use measurement
EFO:0008475	mood instability measurement
EFO:0010089	bitter beverage consumption measurement
EFO:0008111	diet measurement
EFO:0006781	coffee consumption measurement
EFO:0010091	tea consumption measurement
EFO:0007788	BMI-adjusted waist-hip ratio

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects binding, increases reaction, decreases expression, increases expression	3
ON 01910	affects localization, increases phosphorylation, increases sumoylation, affects binding	3
cobaltous chloride	decreases expression, decreases reaction	2
Acetaminophen	increases expression	2
Benzo(a)pyrene	increases expression, increases methylation	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	2
Cyclosporine	increases expression	2
Aflatoxin B1	increases expression, increases methylation	2
FR900359	decreases phosphorylation	1
bisphenol F	increases expression	1
titanium dioxide	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, decreases expression, affects localization	1
oridonin	decreases expression, affects localization	1
beta-lapachone	increases expression	1
zinc chloride	decreases expression, decreases reaction	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
zinc chromate	decreases expression, increases abundance	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
aflatoxin B2	decreases methylation	1
coumarin	affects phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
chloropicrin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
14-deoxy-11,12-didehydroandrographolide	decreases expression	1
abrine	increases expression	1
2-amino-14,16-dimethyloctadecan-3-ol	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1

Clinical trials (associated diseases)

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