RAB40A

Summary

RAB40A (RAB40A, member RAS oncogene family, HGNC:18283) is a protein-coding gene on chromosome Xq22.2, encoding Ras-related protein Rab-40A (Q8WXH6). RAB40A small GTPase acts as substrate-recognition component of the ECS(RAB40A) E3 ubiquitin ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.

This gene encodes a member of the Rab40 subfamily of Rab small GTP-binding proteins that contains a C-terminal suppressors of cytokine signaling box.

Source: NCBI Gene 142684 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 2 total — 1 pathogenic
• MANE Select transcript: NM_080879

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18283
Approved symbol	RAB40A
Name	RAB40A, member RAS oncogene family
Location	Xq22.2
Locus type	gene with protein product
Status	Approved
Aliases	RAR2A, Rar-2
Ensembl gene	ENSG00000172476
Ensembl biotype	protein_coding
OMIM	301065
Entrez	142684

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000304236, ENST00000372633, ENST00000905301, ENST00000905302, ENST00000942559, ENST00000942560

RefSeq mRNA: 1 — MANE Select: NM_080879 NM_080879

CCDS: CCDS35357

Canonical transcript exons

ENST00000304236 — 3 exons

Exon	Start	End
ENSE00001173849	103499130	103500826
ENSE00001183584	103517374	103517525
ENSE00001183586	103519370	103519489

Expression profiles

Bgee: expression breadth ubiquitous, 163 present calls, max score 80.25.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0738 / max 20.0952, expressed in 21 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
199996	0.0738	21

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	80.25	gold quality
corpus epididymis	UBERON:0004359	77.04	gold quality
right ovary	UBERON:0002118	75.84	gold quality
left ovary	UBERON:0002119	74.63	gold quality
stromal cell of endometrium	CL:0002255	73.33	gold quality
body of uterus	UBERON:0009853	72.59	gold quality
left uterine tube	UBERON:0001303	70.32	gold quality
mucosa of stomach	UBERON:0001199	70.17	gold quality
cauda epididymis	UBERON:0004360	70.17	gold quality
endocervix	UBERON:0000458	69.91	gold quality
caput epididymis	UBERON:0004358	69.15	gold quality
ovary	UBERON:0000992	68.59	gold quality
nucleus accumbens	UBERON:0001882	68.53	gold quality
myometrium	UBERON:0001296	68.50	gold quality
lower esophagus mucosa	UBERON:0035834	68.05	gold quality
lower esophagus muscularis layer	UBERON:0035833	68.02	gold quality
lower esophagus	UBERON:0013473	67.99	gold quality
tibial nerve	UBERON:0001323	67.33	gold quality
right adrenal gland	UBERON:0001233	67.08	gold quality
right lung	UBERON:0002167	66.88	gold quality
prostate gland	UBERON:0002367	66.74	gold quality
left coronary artery	UBERON:0001626	66.66	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	66.63	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	66.28	gold quality
esophagus	UBERON:0001043	65.96	gold quality
right adrenal gland cortex	UBERON:0035827	65.96	gold quality
right testis	UBERON:0004534	65.89	gold quality
coronary artery	UBERON:0001621	65.80	gold quality
adenohypophysis	UBERON:0002196	65.59	gold quality
cortical plate	UBERON:0005343	65.53	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.04

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

9 targeting RAB40A, 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-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-4738-3P	98.98	67.98	1846

Cross-species orthologs

0 orthologs

Paralogs (68): RAB27B (ENSG00000041353), RAB27A (ENSG00000069974), RAB7A (ENSG00000075785), RABL2B (ENSG00000079974), RAB21 (ENSG00000080371), RAB10 (ENSG00000084733), RAB18 (ENSG00000099246), RAB36 (ENSG00000100228), IFT27 (ENSG00000100360), RAB40AL (ENSG00000102128), RAB11A (ENSG00000103769), RAB2A (ENSG00000104388), RAB3D (ENSG00000105514), RAB3A (ENSG00000105649), RAB5C (ENSG00000108774), RAB34 (ENSG00000109113), RAB5B (ENSG00000111540), RAB35 (ENSG00000111737), RAB23 (ENSG00000112210), DNAJC27 (ENSG00000115137), RAB29 (ENSG00000117280), RAB32 (ENSG00000118508), RAB14 (ENSG00000119396), RAB9B (ENSG00000123570), RAB9A (ENSG00000123595), RAB38 (ENSG00000123892), RAB22A (ENSG00000124209), RAB17 (ENSG00000124839), RAB2B (ENSG00000129472), RAB25 (ENSG00000132698), RAB33A (ENSG00000134594), RAB30 (ENSG00000137502), RAB1A (ENSG00000138069), RAB20 (ENSG00000139832), RAB15 (ENSG00000139998), RAB40B (ENSG00000141542), RAB13 (ENSG00000143545), RABL2A (ENSG00000144134), RAB5A (ENSG00000144566), RAB19 (ENSG00000146955)

Protein

Protein identifiers

Ras-related protein Rab-40A — Q8WXH6 (reviewed: Q8WXH6)

Alternative names: SOCS box-containing protein RAR2A

All UniProt accessions (1): Q8WXH6

UniProt curated annotations — full annotation on UniProt →

Function. RAB40A small GTPase acts as substrate-recognition component of the ECS(RAB40A) E3 ubiquitin ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. The Rab40 subfamily belongs to the Rab family that are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different sets of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. As part of the ECS(RAB40A) complex, mediates RHOU ‘Lys-48’-linked ubiquitination and degradation, thus inhibiting focal adhesion disassembly during cell migration.

Subunit / interactions. Component of the cullin-5-RING E3 ubiquitin-protein ligase complex (ECS(RAB40A) complex) composed of CUL5, Elongin BC (ELOB and ELOC), RNF7/RBX2 and RAB40A.

Subcellular location. Cell membrane.

Activity regulation. Regulated by guanine nucleotide exchange factors (GEFs) which promote the exchange of bound GDP for free GTP. Regulated by GTPase activating proteins (GAPs) which increase the GTP hydrolysis activity. Inhibited by GDP dissociation inhibitors (GDIs).

Domain organisation. The SOCS box contains two defined motifs including the BC box that recruits and binds Elongin BC complex, and the Cul box which interacts with the Cullin family of proteins to form a ECS (Elongin-Cullin-SOCS-box protein) E3 ubiquitin ligase complex. Switch I, switch II and the interswitch regions are characteristic of Rab GTPases and mediate the interactions with Rab downstream effectors. The switch regions undergo conformational changes upon nucleotide binding which drive interaction with specific sets of effector proteins, with most effectors only binding to GTP-bound Rab.

Pathway. Protein modification; protein ubiquitination.

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

RefSeq proteins (1): NP_543155* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001496	SOCS_box	Domain
IPR001806	Small_GTPase	Family
IPR005225	Small_GTP-bd	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR036036	SOCS_box-like_dom_sf	Homologous_superfamily
IPR050305	Small_GTPase_Rab	Family

Pfam: PF00071, PF07525

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (19 total): binding site 8, lipid moiety-binding region 2, sequence conflict 2, region of interest 2, chain 1, propeptide 1, modified residue 1, sequence variant 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8WXH6-F1	74.08	0.37

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 (8): 72; 126; 127; 26; 27; 28; 28; 69

Post-translational modifications (3): 274, 269, 274

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8873719	RAB geranylgeranylation

MSigDB gene sets: 73 (showing top): GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_EXOCYTOSIS, GOBP_CELL_JUNCTION_ORGANIZATION, MODULE_285, WTGAAAT_UNKNOWN, GOBP_SECRETION, GOBP_POST_TRANSLATIONAL_PROTEIN_MODIFICATION, GOBP_PROTEASOMAL_PROTEIN_CATABOLIC_PROCESS, GOBP_PROTEIN_CATABOLIC_PROCESS, GOCC_EXOCYTIC_VESICLE, GOCC_SECRETORY_VESICLE, GOCC_TRANSFERASE_COMPLEX, TAATTA_CHX10_01

GO Biological Process (5): exocytosis (GO:0006887), protein ubiquitination (GO:0016567), intracellular signal transduction (GO:0035556), proteasome-mediated ubiquitin-dependent protein catabolic process (GO:0043161), negative regulation of focal adhesion disassembly (GO:0120184)

GO Molecular Function (7): GTPase activity (GO:0003924), G protein activity (GO:0003925), GTP binding (GO:0005525), metal ion binding (GO:0046872), ubiquitin-like ligase-substrate adaptor activity (GO:1990756), nucleotide binding (GO:0000166), hydrolase activity (GO:0016787)

GO Cellular Component (8): endosome (GO:0005768), plasma membrane (GO:0005886), synaptic vesicle (GO:0008021), Cul5-RING ubiquitin ligase complex (GO:0031466), cytoplasm (GO:0005737), Golgi apparatus (GO:0005794), lipid droplet (GO:0005811), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Post-translational protein modification	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular anatomical structure	2
endomembrane system	2
cellular anatomical structure	2
vesicle-mediated transport	1
secretion by cell	1
vesicle fusion to plasma membrane	1
protein modification by small protein conjugation	1
signal transduction	1
ubiquitin-dependent protein catabolic process	1
proteasomal protein catabolic process	1
focal adhesion disassembly	1
regulation of focal adhesion disassembly	1
negative regulation of cell-substrate junction organization	1
ribonucleoside triphosphate phosphatase activity	1
GTPase activity	1
molecular function regulator activity	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
cation binding	1
enzyme-substrate adaptor activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
catalytic activity	1
cytoplasmic vesicle	1
membrane	1
cell periphery	1
exocytic vesicle	1
presynapse	1
cullin-RING ubiquitin ligase complex	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

716 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RAB40A	TCEAL3	Q969E4	466
RAB40A	BEX5	Q5H9J7	431
RAB40A	CUL5	Q93034	422
RAB40A	TCEAL4	Q96EI5	392
RAB40A	TCEAL5	Q5H9L2	392
RAB40A	WSB2	Q9NYS7	375
RAB40A	RILPL2	Q969X0	372
RAB40A	LRRC41	Q15345	370
RAB40A	ELOB	Q15370	342
RAB40A	TCEAL2	Q9H3H9	321
RAB40A	TMEM151B	Q8IW70	311
RAB40A	ASB12	Q8WXK4	308
RAB40A	PCMTD2	Q9NV79	307
RAB40A	LSM6	P62312	296
RAB40A	MORF4L2	Q15014	289

IntAct

19 interactions, top by confidence:

A	B	Type	Score
RAB40A	RAB40AL	psi-mi:“MI:0914”(association)	0.530
HSP90AB1	RAB40A	psi-mi:“MI:0915”(physical association)	0.400
RAB40A	Bicdl2	psi-mi:“MI:0915”(physical association)	0.400
RAB40A	ARIH2	psi-mi:“MI:0914”(association)	0.350
AKT1	RAB40A	psi-mi:“MI:2364”(proximity)	0.270
BRAF	RAB40A	psi-mi:“MI:2364”(proximity)	0.270
FBXW7	RAB40A	psi-mi:“MI:2364”(proximity)	0.270
SMAD4	RAB40A	psi-mi:“MI:2364”(proximity)	0.270
SMARCA4	RAB40A	psi-mi:“MI:2364”(proximity)	0.270
SPOP	RAB40A	psi-mi:“MI:2364”(proximity)	0.270
RAB40A	SPOP	psi-mi:“MI:2364”(proximity)	0.270
RAB40A	EGFR	psi-mi:“MI:2364”(proximity)	0.270
RAB40A	PTPN11	psi-mi:“MI:2364”(proximity)	0.270
RAB40A	TP53	psi-mi:“MI:2364”(proximity)	0.270
RAB40A	PTEN	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (33): TCEB1 (Affinity Capture-MS), CUL5 (Affinity Capture-MS), COPS6 (Affinity Capture-MS), RAB40AL (Affinity Capture-MS), ISCA1 (Affinity Capture-MS), LYRM7 (Affinity Capture-MS), FAM192A (Affinity Capture-MS), PSME3 (Affinity Capture-MS), ARIH2 (Affinity Capture-MS), RAB40A (Two-hybrid), RAB40A (Reconstituted Complex), RAB40A (Affinity Capture-MS), RAB40AL (Affinity Capture-MS), ISCA1 (Affinity Capture-MS), CUL5 (Affinity Capture-MS)

ESM2 similar proteins: A1DZY4, A6QP66, O35626, O35929, O88910, O88954, P0C0E4, P35295, P51157, P51158, P53667, P53668, P53669, P55040, P55041, P55043, P63032, P63033, Q06AU5, Q12829, Q13368, Q13637, Q3SWY9, Q5E9J3, Q5FVY2, Q5R541, Q5RFI2, Q6DGN0, Q6IMA3, Q6IMA7, Q6IMB1, Q6P0U3, Q6T310, Q8AVS6, Q8IYK8, Q8QFP8, Q8VEL9, Q8VHP8, Q8VHQ4, Q8WXH6

Diamond homologs: A4FV54, C4YL11, F1PTE3, O01803, O24466, O35509, P01123, P0C0E4, P0CY30, P0CY31, P10536, P11620, P16976, P17609, P20790, P20791, P22125, P22127, P22128, P22129, P24409, P28186, P28188, P31584, P33723, P34140, P35280, P35281, P35286, P35289, P36861, P40392, P41924, P46638, P51153, P55258, P59190, P61006, P61007, P61026

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 14 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
protein ubiquitination	5	15.9×	8e-04
negative regulation of apoptotic process	5	13.4×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	1
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
564878	GRCh37/hg19 Xq22.2(chrX:102767250-103236332)x2	Pathogenic

SpliceAI

545 predictions. Top by Δscore:

Variant	Effect	Δscore
X:103519347:A:AC	donor_gain	1.0000
X:103519348:C:CC	donor_gain	1.0000
X:103500839:T:TC	acceptor_gain	0.9900
X:103500844:A:C	acceptor_gain	0.9900
X:103500851:A:C	acceptor_gain	0.9900
X:103517524:CA:C	acceptor_gain	0.9900
X:103517526:C:CC	acceptor_gain	0.9900
X:103500831:T:C	acceptor_gain	0.9800
X:103500843:CA:C	acceptor_gain	0.9800
X:103517372:ACC:A	donor_gain	0.9800
X:103517373:CCC:C	donor_gain	0.9800
X:103517522:CACA:C	acceptor_gain	0.9800
X:103500844:A:AC	acceptor_gain	0.9700
X:103517369:CTCA:C	donor_loss	0.9700
X:103517370:TCA:T	donor_loss	0.9700
X:103517371:CACCC:C	donor_loss	0.9700
X:103517373:C:G	donor_loss	0.9700
X:103517366:AGACT:A	donor_loss	0.9600
X:103517367:GACT:G	donor_loss	0.9600
X:103517368:ACTC:A	donor_loss	0.9600
X:103517372:AC:A	donor_gain	0.9600
X:103517373:CC:C	donor_gain	0.9600
X:103500825:TTCTT:T	acceptor_gain	0.9500
X:103500827:CTT:C	acceptor_gain	0.9500
X:103500831:T:TC	acceptor_gain	0.9500
X:103517420:T:C	donor_gain	0.9500
X:103500830:C:CC	acceptor_gain	0.9400
X:103500850:C:CT	acceptor_gain	0.9300
X:103501223:CATTT:C	acceptor_gain	0.9300
X:103517365:GAGAC:G	donor_loss	0.9300

AlphaMissense

1821 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:103500289:G:C	S156R	0.993
X:103500289:G:T	S156R	0.993
X:103500291:T:G	S156R	0.993
X:103500323:G:T	A145D	0.970
X:103500384:C:A	G125W	0.955
X:103500451:G:C	F102L	0.954
X:103500451:G:T	F102L	0.954
X:103500453:A:G	F102L	0.954
X:103500245:G:T	A171D	0.949
X:103500274:G:C	F161L	0.945
X:103500274:G:T	F161L	0.945
X:103500276:A:G	F161L	0.945
X:103500377:C:G	R127P	0.943
X:103500477:A:C	Y94D	0.942
X:103500386:A:T	V124E	0.940
X:103500473:T:A	D95V	0.940
X:103500361:G:C	F132L	0.939
X:103500361:G:T	F132L	0.939
X:103500363:A:G	F132L	0.939
X:103500479:A:T	V93D	0.939
X:103500324:C:G	A145P	0.938
X:103500379:A:C	N126K	0.933
X:103500379:A:T	N126K	0.933
X:103500355:C:A	R134S	0.929
X:103500355:C:G	R134S	0.929
X:103500383:C:T	G125E	0.928
X:103500455:G:A	S101F	0.928
X:103500563:A:G	L65P	0.928
X:103500668:A:G	I30T	0.928
X:103500695:C:A	G21V	0.926

dbSNP variants (sampled 300 via entrez): RS1000261749 (X:103507010 T>C), RS1000473719 (X:103495781 T>C), RS1000604147 (X:103504725 T>C), RS1000845895 (X:103495170 A>G), RS1000899254 (X:103495991 A>C), RS1000932654 (X:103503187 A>G), RS1001021319 (X:103516612 T>C), RS1001071405 (X:103504286 A>G), RS1001185436 (X:103496535 G>A), RS1001296091 (X:103507044 C>A), RS1001299284 (X:103513809 G>A), RS1001454373 (X:103505475 G>A), RS1001526411 (X:103505868 T>C), RS1001829321 (X:103503354 G>A), RS1001838784 (X:103516702 T>C)

Disease associations

OMIM: gene MIM:301065 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002388_277	Lymphocyte count	1.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004587	lymphocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

8 total (human), top 8 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
CGP 52608	affects binding, increases reaction	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	affects methylation	1
Copper	affects binding, decreases expression	1
Disulfiram	affects binding, decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Valproic Acid	decreases methylation	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

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