RAB5A

Summary

RAB5A (RAB5A, member RAS oncogene family, HGNC:9783) is a protein-coding gene on chromosome 3p24.3, encoding Ras-related protein Rab-5A (P20339). The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes.

Enables GDP binding activity; GTP binding activity; and GTPase activity. Involved in several processes, including amyloid-beta clearance by transcytosis; early endosome to late endosome transport; and regulation of exocytosis. Located in several cellular components, including cytoplasmic side of early endosome membrane; nucleoplasm; and terminal bouton.

Source: NCBI Gene 5868 — RefSeq curated summary.

At a glance

• GWAS associations: 2
• Clinical variants (ClinVar): 32 total
• MANE Select transcript: NM_004162

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9783
Approved symbol	RAB5A
Name	RAB5A, member RAS oncogene family
Location	3p24.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000144566
Ensembl biotype	protein_coding
OMIM	179512
Entrez	5868

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 8 protein_coding, 3 retained_intron, 2 nonsense_mediated_decay

ENST00000273047, ENST00000412966, ENST00000422242, ENST00000443878, ENST00000446547, ENST00000469122, ENST00000473608, ENST00000476544, ENST00000873830, ENST00000928748, ENST00000928749, ENST00000928750, ENST00000928751

RefSeq mRNA: 2 — MANE Select: NM_004162 NM_001292048, NM_004162

CCDS: CCDS2633, CCDS77710

Canonical transcript exons

ENST00000273047 — 6 exons

Exon	Start	End
ENSE00001162720	19950806	19951061
ENSE00001368096	19983708	19985175
ENSE00001769725	19947097	19947521
ENSE00003501937	19975601	19975752
ENSE00003645041	19978310	19978403
ENSE00003674763	19976047	19976169

Expression profiles

Bgee: expression breadth ubiquitous, 300 present calls, max score 99.16.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 48.7824 / max 674.9576, expressed in 1826 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
35647	21.3031	1814
35651	10.5103	1777
35648	8.6022	1764
35650	5.9826	1736
35652	1.2366	794
35649	0.7738	444
35653	0.2759	108
202701	0.0979	31

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gingival epithelium	UBERON:0001949	99.16	gold quality
esophagus squamous epithelium	UBERON:0006920	99.10	gold quality
gingiva	UBERON:0001828	98.98	gold quality
squamous epithelium	UBERON:0006914	98.94	gold quality
epithelium of esophagus	UBERON:0001976	98.69	gold quality
endothelial cell	CL:0000115	98.64	gold quality
lower lobe of lung	UBERON:0008949	98.62	gold quality
upper leg skin	UBERON:0004262	98.56	gold quality
corpus epididymis	UBERON:0004359	98.56	gold quality
pons	UBERON:0000988	98.49	gold quality
substantia nigra pars compacta	UBERON:0001965	98.48	gold quality
penis	UBERON:0000989	98.46	gold quality
substantia nigra pars reticulata	UBERON:0001966	98.45	gold quality
medulla oblongata	UBERON:0001896	98.39	gold quality
hair follicle	UBERON:0002073	98.38	gold quality
inferior olivary complex	UBERON:0002127	98.37	gold quality
superior vestibular nucleus	UBERON:0007227	98.37	gold quality
cauda epididymis	UBERON:0004360	98.35	gold quality
tongue squamous epithelium	UBERON:0006919	98.33	gold quality
subthalamic nucleus	UBERON:0001906	98.32	gold quality
postcentral gyrus	UBERON:0002581	98.30	gold quality
skin of hip	UBERON:0001554	98.26	gold quality
CA1 field of hippocampus	UBERON:0003881	98.24	gold quality
amniotic fluid	UBERON:0000173	98.14	gold quality
palpebral conjunctiva	UBERON:0001812	98.14	gold quality
germinal epithelium of ovary	UBERON:0001304	98.13	gold quality
parotid gland	UBERON:0001831	98.13	gold quality
parietal lobe	UBERON:0001872	98.11	gold quality
seminal vesicle	UBERON:0000998	98.09	gold quality
dorsal plus ventral thalamus	UBERON:0001897	98.09	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-MTAB-8060	no	167.57
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

63 targeting RAB5A, 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-5692A	100.00	74.40	6850
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-141-3P	99.94	72.79	2421
HSA-MIR-200A-3P	99.94	72.68	2420
HSA-MIR-539-5P	99.93	70.30	2855
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-3666	99.90	73.24	1833
HSA-MIR-4295	99.90	73.11	1838
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-4671-3P	99.88	72.46	1045
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4503	99.85	71.45	1869
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-494-3P	99.70	71.45	2795

Literature-anchored findings (GeneRIF, showing 40)

• Expression of a GTPase-hydrolysis-defective rab5a affects lysosome biogenesis by alteration of traffic between lysosomes and endosomes. (PMID:11792815)
• Rab5a regulates fusion between pathogen-containing phagosomes and cytoplasmic organelles in human neutrophils (PMID:11884531)
• an endocytotic catalyst, a tandem regulator of thyroid hormone production (PMID:12034881)
• effect of SARA on rab5-mediated endocytosis (PMID:12432064)
• Rab5a has a P-loop backbone amide group, which is required for catalysis (PMID:12433916)
• dynamin2 and Rab5 have roles in endocytosis of lysophosphatidic acid-coupled LPA1/EDG-2 receptors (PMID:12668728)
• In Rab5 overexpressing cells, the levels of beta-cleaved amyloid precursor protein (APP) carboxyl-terminal fragments (betaCTF), the rate-limiting proteolytic intermediate in Abeta generation, were increased (PMID:12761223)
• increase in the concentration of copper in the medium (189 microM) rapidly induces a redistribution of the MNK protein from early sorting endosomes, positive for Rab5-myc protein, to late endosomes, containing the Rab7-myc protein (PMID:14644159)
• Cell cycle was lengthened by blocking or reducing expression of RAB5A G81R mutation. (PMID:14669515)
• identification of a pathway directly linking the small GTPase Rab5, a key regulator of endocytosis, to signal transduction and mitogenesis via APPL1 and APPL2, two Rab5 effectors (PMID:15016378)
• Guanine nucleotide binding state of rab5 has no bearing on the rate of EGFR endocytosis. However, expression of dominant negative rab5 affects downstream endocytic trafficking by slowing the ligand-induced disappearance of total cellular EGFR. (PMID:15023538)
• Rab5 regulates and coordinates different endocytic mechanisms through its effector Rabankyrin-5 (PMID:15328530)
• These results suggest that amyotrophic lateral sclerosis 2 C-terminal like (ALS2CL), a novel ALS2 homologue, modulates Rab5-mediated endosome dynamics in HeLa cells. (PMID:15388334)
• Taken together, these results demonstrate that Rab5 is required for insulin receptor membrane trafficking and signaling. (PMID:16554017)
• We show that EGF relocates to the cell centre in a dynein-dependent fashion, concomitant with the sorting away of transferrin receptor, although it remains in Rab5-positive early endosomes. (PMID:17173037)
• Rab5 participates in the hepatitis C virus RNA replication machinery. (PMID:17301141)
• Rab 5 is required for the cellular entry of dengue and West Nile viruses. (PMID:17301152)
• TSH controls Rab5a activity by promoting its GTP-bound state (PMID:17473071)
• Results suggest that Rab5 and RalA regulate P-gp trafficking between the plasma membrane and an intracellular compartment. (PMID:17524504)
• The crystal structures of human APPL1 N-terminal BAR-PH domain motif, is reported. (PMID:17581628)
• Rab5 activation via amyloid precursor protein signal pathway mediates neuronal apoptosis. (PMID:17611268)
• B coxsackievirus entry depends on occludin and require the activity of Rab34, Ras, and Rab5, GTPases known to regulate macropinocytosis. (PMID:18005733)
• SopB mediates PI(3)P production on the SCV indirectly through recruitment of Rab5 and its effector Vps34. (PMID:18725540)
• Rab5 is a critical regulator of syndecan-1 shedding that serves as an on-off molecular switch through its alternation between the GDP-bound and GTP-bound forms. (PMID:18957427)
• caspase 8 has a role as a modulator of p85alpha Rab5-GAP activity and endosomal trafficking (PMID:18974049)
• AdipoR1 is internalized through a clathrin- and Rab5-dependent pathway and that endocytosis may play a role in the regulation of adiponectin signaling. (PMID:18982021)
• Specific residues of RIN1 are required for its interaction with Rab5, binding to the endosomal membranes and subsequent regulation of the fusion reaction. (PMID:19032933)
• Mutations in the Vps9 domain of Rin1 lead to a loss-of-function phenotype, indicating a specific structure-function relationship between Rab5 and Rin1. (PMID:19118546)
• oxytocin receptors localize in vesicles containing the Rab5 and Rab4 small GTPases (PMID:19126785)
• Rab GTPase regulation of VEGFR2 trafficking and signaling in endothelial cells; Endothelial cell migration was increased by Rab5a depletion but decreased by Rab7a depletion (PMID:19372461)
• Borna Disease Virus cell entry was Rab5 dependent and exhibited rapid fusion kinetics. (PMID:19656886)
• suppression of Rab5A or 5B hampered the degradation of EGFR (PMID:19723633)
• Data report the identification of Rab22 as a binding site on early endosomes for direct recruitment of Rabex-5 and activation of Rab5, establishing a Rab22-Rab5 signaling relay to promote early endosome fusion. (PMID:19759177)
• The objective of the current study was to perform a detailed examination of the structural flexibility of the phosphate-binding loop (P-loop) as well as the switch I and II regions of human Rab5a upon its binding with GTP. (PMID:19819222)
• The Rab5(Q79L) not only induces formation of enlarged early endosomes but also causes enlargement of later endocytic profiles. (PMID:19830447)
• These studies identify Rab5 as a key integrator of caspase-8-mediated signal transduction downstream of integrins, regulating cell survival and migration in vivo and in vitro. (PMID:19923319)
• Rab5(Q79L) interacts with the carboxyl terminus of RUFY3 (PMID:20376209)
• Rab5a promoted proliferation of ovarian cancer cells, which may be associated with the APPL1-related epidermal growth factor signaling pathway. (PMID:20412119)
• Data demonstrate a key role of Rab and Arf family small GTPases and intracellular trafficking in mTORC1 activation. (PMID:20457610)
• Rab5 and Rab7, were associated with the pathway of autophagosome formation and the fate of intracellular group A streptococcus. (PMID:20472552)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rab5ab	ENSDARG00000007257
danio_rerio	rab5aa	ENSDARG00000018602
mus_musculus	Rab5a	ENSMUSG00000017831
rattus_norvegicus	Rab5al1	ENSRNOG00000057056
rattus_norvegicus	Rab5a	ENSRNOG00000062595

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), RAB19 (ENSG00000146955), RAB41 (ENSG00000147127)

Protein

Protein identifiers

Ras-related protein Rab-5A — P20339 (reviewed: P20339)

All UniProt accessions (4): P20339, C9J3X8, F8WCY6, F8WD79

UniProt curated annotations — full annotation on UniProt →

Function. The small GTPases Rab 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. RAB5A is required for the fusion of plasma membranes and early endosomes and involved in early endocytic trafficking. Required for EEA1 recruitment to early endosomes. Recruits FERRY complex to early endosomes, where FERRY links early endosomes with a subgroup of mRNAs to enable mRNA intracellular distribution. Recruits RABEP1/Rabaptin-5 effector to early endosomes, thereby promoting endocytic membrane fusion. Required for EGF and transferrin endocytosis and trafficking through early endosomes. Contributes to the regulation of filopodia extension. Required for the exosomal release of SDCBP, CD63, PDCD6IP and syndecan. Regulates maturation of apoptotic cell-containing phagosomes, probably downstream of DYN2 and PIK3C3.

Subunit / interactions. Interacts (GTP-bound) with SGSM3; SGSM3 acts as a GAP. Interacts with SGSM1. Interacts with GDI1; this promotes dissociation from membranes; phosphorylation at Ser-84 disrupts this interaction. Interacts with GDI2; phosphorylation at Ser-84 disrupts the interaction. Interacts (GTP-bound) with EEA1; EEA1 acts as a RAB5A effector. Interacts with RABEP1; one RABEP1 homodimer binds two RAB5A chains, but at opposite sides of the dimer; RABEP1 acts as RAB5A effector. Interacts with RABEP1-RABGEF1 complex; interaction stimulates RABGEF1-mediated GEF activity on RAB5A and the complex acts as RAB5A effector. Interacts with RINL; RINL acts as a GEF. Interacts with RIN1 and GAPVD1, which regulate its pathway, probably by acting as a GEF. Interacts with ALS2CL, SUN2, ZFYVE20 and RUFY1. Interacts (GTP-bound) with PPP1R21; mediates the recruitment of FERRY complex by RAB5A onto early endosomes. Interacts with PIK3CB. Interacts with OCRL. Interacts with INPP5F. May be a component of a complex composed of RAB5A, DYN2 and PIK3C3. Interacts with CLN5. Interacts with APPL2. Interacts with F8A1/F8A2/F8A3. Found in a complex with F8A1/F8A2/F8A3, HTT and RAB5A; mediates the recruitment of HTT by RAB5A onto early endosomes. Interacts with ATP9A. Does not interact with BLOC-3 complex (heterodimer of HPS1 and HPS4). Interacts with CCDC158.

Subcellular location. Cell membrane. Early endosome membrane. Melanosome. Cytoplasmic vesicle. Cell projection. Ruffle. Membrane. Cytoplasm. Cytosol. Phagosome membrane. Endosome membrane.

Post-translational modifications. Phosphorylation of Ser-84 in the switch II region by LRRK2 prevents the association of RAB regulatory proteins, including RAB GDP dissociation inhibitors GDI1 and GDI2. (Microbial infection) Glycosylated on arginine residues by S.typhimurium protein Ssek3.

Activity regulation. Regulated by guanine nucleotide exchange factors (GEFs) including RINL and RABGEF1, which promote the exchange of bound GDP for free GTP. Regulated by GTPase activating proteins (GAPs) including SGSM3, which increase the GTP hydrolysis activity. Inhibited by GDP dissociation inhibitors (GDIs).

Domain organisation. 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.

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

Isoforms (2)

UniProt ID	Names	Canonical?
P20339-1	1	yes
P20339-2	2

RefSeq proteins (2): NP_001278977, NP_004153* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001806	Small_GTPase	Family
IPR005225	Small_GTP-bd	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF00071

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (57 total): binding site 18, mutagenesis site 12, strand 7, helix 7, region of interest 3, lipid moiety-binding region 2, sequence conflict 2, chain 1, modified residue 1, glycosylation site 1, splice variant 1, compositionally biased region 1, turn 1

Structure

Experimental structures (PDB)

20 structures.

PDB	Method	Resolution (Å)
1R2Q	X-RAY DIFFRACTION	1.05
1N6H	X-RAY DIFFRACTION	1.51
1N6P	X-RAY DIFFRACTION	1.54
1N6K	X-RAY DIFFRACTION	1.55
1N6R	X-RAY DIFFRACTION	1.55
1N6I	X-RAY DIFFRACTION	1.6
1N6L	X-RAY DIFFRACTION	1.6
1N6N	X-RAY DIFFRACTION	1.6
1N6O	X-RAY DIFFRACTION	1.8
3MJH	X-RAY DIFFRACTION	2.03
1TU4	X-RAY DIFFRACTION	2.2
1TU3	X-RAY DIFFRACTION	2.31
9RX5	ELECTRON MICROSCOPY	3.15
9RX6	ELECTRON MICROSCOPY	3.52
9RX9	ELECTRON MICROSCOPY	3.99
9RXA	ELECTRON MICROSCOPY	4
9RXB	ELECTRON MICROSCOPY	4.03
4Q9U	X-RAY DIFFRACTION	4.62
7BL1	ELECTRON MICROSCOPY	9.8
9S47	ELECTRON MICROSCOPY	9.88

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P20339-F1	85.62	0.70

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 (18): 34; 35; 46; 47; 52; 52; 75; 78; 133; 134; 136; 164 …

Post-translational modifications (3): 84, 212, 213

Glycosylation sites (1): 120

Mutagenesis-validated functional residues (12):

Position	Phenotype
34	constitutively inactive (gdp-bound) mutant. increased interaction wih atp9a. loss of eea1 targeting to early endosomes.
54	strongly decreases zfyve20 binding affinity.
56	strongly decreases zfyve20 binding affinity.
57	strongly decreases rabep1 and zfyve20 binding affinity.
74	strongly decreases rabep1 binding affinity.
79	constitutively active (gtp-bound) mutant. loss of gtpase activity. does not inhibit filopodia formation. increased eea1
82	strongly decreases rabep1 binding affinity. impairs endosome fusion.
84	loss of phosphorylation. no effect on gdi1 and gdi2 binding.
84	phosphomimetic mutant. loss of gdi1 and gdi2 binding.
89	strongly decreases rabep1 binding affinity.
116	no effect on rabep1 binding affinity.
120	no effect on rabep1 binding affinity.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-1660499	Synthesis of PIPs at the plasma membrane
R-HSA-8854214	TBC/RABGAPs
R-HSA-8856828	Clathrin-mediated endocytosis
R-HSA-8873719	RAB geranylgeranylation
R-HSA-8876198	RAB GEFs exchange GTP for GDP on RABs
R-HSA-9636383	Prevention of phagosomal-lysosomal fusion
R-HSA-9820960	Respiratory syncytial virus (RSV) attachment and entry
R-HSA-983231	Factors involved in megakaryocyte development and platelet production

MSigDB gene sets: 347 (showing top): MORF_MBD4, GOBP_VACUOLE_ORGANIZATION, MORF_RAB5A, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, BROWNE_HCMV_INFECTION_8HR_UP, GOBP_REGULATION_OF_NEURONAL_SYNAPTIC_PLASTICITY, ENK_UV_RESPONSE_KERATINOCYTE_UP, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, GOBP_REGULATION_OF_EXOCYTOSIS, GOBP_NEUROTRANSMITTER_TRANSPORT, CAFFAREL_RESPONSE_TO_THC_UP, GOBP_MODULATION_OF_PROCESS_OF_ANOTHER_ORGANISM, BROWNE_HCMV_INFECTION_16HR_UP, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_VACUOLE_ORGANIZATION

GO Biological Process (20): intracellular protein transport (GO:0006886), endocytosis (GO:0006897), phagocytosis (GO:0006909), endosomal transport (GO:0016197), receptor internalization (GO:0031623), synaptic vesicle recycling (GO:0036465), host-mediated perturbation of viral process (GO:0044788), early endosome to late endosome transport (GO:0045022), positive regulation of exocytosis (GO:0045921), regulation of long-term neuronal synaptic plasticity (GO:0048169), plasma membrane to endosome transport (GO:0048227), regulation of endosome size (GO:0051036), regulation of filopodium assembly (GO:0051489), canonical Wnt signaling pathway (GO:0060070), amyloid-beta clearance by transcytosis (GO:0150093), protein localization to early endosome (GO:1902946), regulation of synaptic vesicle exocytosis (GO:2000300), regulation of autophagosome assembly (GO:2000785), protein transport (GO:0015031), membrane fusion (GO:0061025)

GO Molecular Function (8): GTPase activity (GO:0003924), G protein activity (GO:0003925), GTP binding (GO:0005525), GDP binding (GO:0019003), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787), guanyl nucleotide binding (GO:0019001)

GO Cellular Component (31): ruffle (GO:0001726), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), endosome (GO:0005768), early endosome (GO:0005769), cytosol (GO:0005829), plasma membrane (GO:0005886), synaptic vesicle (GO:0008021), endosome membrane (GO:0010008), endomembrane system (GO:0012505), actin cytoskeleton (GO:0015629), endocytic vesicle (GO:0030139), axon (GO:0030424), dendrite (GO:0030425), clathrin-coated endocytic vesicle membrane (GO:0030669), phagocytic vesicle membrane (GO:0030670), synaptic vesicle membrane (GO:0030672), early endosome membrane (GO:0031901), early phagosome (GO:0032009), somatodendritic compartment (GO:0036477), melanosome (GO:0042470), neuronal cell body (GO:0043025), terminal bouton (GO:0043195), axon terminus (GO:0043679), membrane raft (GO:0045121), phagocytic vesicle (GO:0045335), extracellular exosome (GO:0070062), cytoplasmic side of early endosome membrane (GO:0098559), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410), cell projection (GO:0042995)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Rab regulation of trafficking	2
PI Metabolism	1
Membrane Trafficking	1
Post-translational protein modification	1
Suppression of phagosomal maturation	1
Respiratory Syncytial Virus Infection Pathway	1
Hemostasis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
vesicle-mediated transport	3
intracellular protein localization	2
intracellular transport	2
transport	2
cytoplasm	2
guanyl ribonucleotide binding	2
cytoplasmic vesicle	2
endosome	2
neuron projection	2
endocytic vesicle membrane	2
phagocytic vesicle	2
protein transport	1
vesicle budding from membrane	1
membrane invagination	1
import into cell	1
endocytosis	1
receptor-mediated endocytosis	1
establishment of localization in cell	1
synaptic vesicle cycle	1
host-mediated perturbation of symbiont process	1
vesicle-mediated transport between endosomal compartments	1
exocytosis	1
regulation of exocytosis	1
positive regulation of secretion by cell	1
regulation of neuronal synaptic plasticity	1
regulation of vesicle size	1
filopodium assembly	1
regulation of plasma membrane bounded cell projection assembly	1
Wnt signaling pathway	1
transcytosis	1
amyloid-beta clearance	1
protein localization to endosome	1
synaptic vesicle exocytosis	1
regulation of neurotransmitter secretion	1
regulation of regulated secretory pathway	1
autophagosome assembly	1
regulation of vacuole organization	1
regulation of organelle assembly	1
establishment of protein localization	1

Protein interactions and networks

STRING

4412 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RAB5A	EEA1	Q15075	999
RAB5A	RABEP1	Q15276	998
RAB5A	RABGEF1	Q9UJ41	998
RAB5A	APPL1	Q9UKG1	997
RAB5A	PIK3C3	Q8NEB9	995
RAB5A	RBSN	Q9H1K0	993
RAB5A	MON1A	Q86VX9	967
RAB5A	BECN1	Q14457	960
RAB5A	ANKFY1	Q9P2R3	958
RAB5A	F8A2	P23610	953
RAB5A	PIK3CB	P42338	947
RAB5A	RIN2	Q8WYP3	938
RAB5A	TFRC	P02786	930
RAB5A	CCZ1B	P86790	918
RAB5A	OCRL	Q01968	914

IntAct

216 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
APPL1	RAB5A	psi-mi:“MI:0915”(physical association)	0.840
APPL1	RAB5A	psi-mi:“MI:0403”(colocalization)	0.840
RAB5A	APPL1	psi-mi:“MI:0915”(physical association)	0.840
SUN2	RAB5A	psi-mi:“MI:0915”(physical association)	0.840
RAB5A	APPL1	psi-mi:“MI:0407”(direct interaction)	0.840
APPL1	RAB5A	psi-mi:“MI:0407”(direct interaction)	0.840
RAB5A	EEA1	psi-mi:“MI:0915”(physical association)	0.830
EEA1	RAB5A	psi-mi:“MI:0915”(physical association)	0.830
RAB5A	GDI1	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710

BioGRID (860): RAB5A (Affinity Capture-Western), KDR (Affinity Capture-Western), RAB5A (Reconstituted Complex), ANKFY1 (Affinity Capture-Western), EEA1 (Co-crystal Structure), EEA1 (Reconstituted Complex), RBSN (Reconstituted Complex), RAB5A (Reconstituted Complex), RAB5A (Affinity Capture-MS), RAB5A (Affinity Capture-MS), RAB5A (Affinity Capture-MS), RAB5A (Affinity Capture-MS), RAB5A (Affinity Capture-MS), RAB5A (Affinity Capture-RNA), RAB11B (Co-fractionation)

ESM2 similar proteins: C8VQY7, G4MYS1, H9BW96, I1RMF2, M0RC99, O01803, O04157, O04486, O24461, O76742, O94655, O97572, P09527, P17610, P18066, P18067, P20339, P24408, P28185, P31022, P32939, P36411, P36864, P51149, P51150, P51151, P61271, P93267, Q06AU6, Q0IIG7, Q17QU4, Q39573, Q3T0F5, Q40523, Q40787, Q41640, Q43463, Q54QR3, Q5R9Y4, Q8BHC1

Diamond homologs: A4FV54, A6QR46, M0RC99, O18333, O18334, O80501, P05712, P11023, P16976, P17608, P18066, P20336, P20339, P20340, P22127, P22128, P24409, P25228, P29687, P31582, P31583, P34213, P35276, P35278, P35279, P35280, P35292, P36017, P36586, P36863, P49103, P49104, P51147, P51148, P53994, P55258, P61006, P61007, P61019, P61020

SIGNOR signaling

14 interactions.

A	Effect	B	Mechanism
RABEP1	up-regulates	RAB5A	binding
RABGEF1	up-regulates	RAB5A	binding
RAB5A	“form complex”	“Early Endosome”	binding
SUN2	“up-regulates activity”	RAB5A	binding
RAB5A	“up-regulates activity”	COMMD5	binding
RABGGTA	“up-regulates activity”	RAB5A	lipidation
RABGGTB	“up-regulates activity”	RAB5A	lipidation
RAB5A	“up-regulates activity”	INPP5B	binding
RAB5A	“up-regulates activity”	OCRL	binding
ALS2	“up-regulates activity”	RAB5A	binding
RAB5A	“down-regulates activity”	RAB7A	binding
RABGEF1	“up-regulates activity”	RAB5A	“guanine nucleotide exchange factor”
RAB5A	“up-regulates activity”	PIK3R4	binding
LYST	“down-regulates activity”	RAB5A	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 141 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
Defective CFTR causes cystic fibrosis	5	12.3×	8e-03
RAB GEFs exchange GTP for GDP on RABs	7	9.8×	2e-03
RAB geranylgeranylation	5	9.7×	9e-03
Clathrin-mediated endocytosis	7	6.7×	9e-03
Neutrophil degranulation	15	3.9×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
endocytosis	13	10.5×	3e-07
exocytosis	7	9.0×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	22
Likely benign	0
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1408 predictions. Top by Δscore:

Variant	Effect	Δscore
3:19950804:A:AG	acceptor_gain	1.0000
3:19950805:G:GG	acceptor_gain	1.0000
3:19950805:GGTTT:G	acceptor_gain	1.0000
3:19951047:A:T	donor_gain	1.0000
3:19975599:A:AG	acceptor_gain	1.0000
3:19975600:G:GG	acceptor_gain	1.0000
3:19975600:GCT:G	acceptor_gain	1.0000
3:19975642:GTAAA:G	acceptor_gain	1.0000
3:19975748:ATGAG:A	donor_gain	1.0000
3:19975749:TGAG:T	donor_gain	1.0000
3:19975750:GAG:G	donor_gain	1.0000
3:19975750:GAGG:G	donor_gain	1.0000
3:19975751:AG:A	donor_gain	1.0000
3:19975752:GG:G	donor_gain	1.0000
3:19975753:G:GG	donor_gain	1.0000
3:19976045:A:AG	acceptor_gain	1.0000
3:19976045:A:G	acceptor_loss	1.0000
3:19976046:G:GC	acceptor_loss	1.0000
3:19976046:G:GG	acceptor_gain	1.0000
3:19976046:GGA:G	acceptor_gain	1.0000
3:19976166:CCAGG:C	donor_loss	1.0000
3:19976168:AGG:A	donor_loss	1.0000
3:19976170:GT:G	donor_loss	1.0000
3:19976171:T:G	donor_loss	1.0000
3:19978301:T:TA	acceptor_gain	1.0000
3:19978304:A:AG	acceptor_gain	1.0000
3:19978305:A:G	acceptor_gain	1.0000
3:19978308:A:AG	acceptor_gain	1.0000
3:19978308:AG:A	acceptor_gain	1.0000
3:19978309:G:A	acceptor_loss	1.0000

AlphaMissense

1415 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:19950964:A:C	K22N	1.000
3:19950964:A:T	K22N	1.000
3:19950966:T:C	L23P	1.000
3:19950977:G:A	G27R	1.000
3:19950977:G:C	G27R	1.000
3:19950978:G:A	G27E	1.000
3:19950978:G:T	G27V	1.000
3:19950992:G:C	G32R	1.000
3:19950992:G:T	G32C	1.000
3:19950993:G:A	G32D	1.000
3:19950993:G:T	G32V	1.000
3:19950995:A:C	K33Q	1.000
3:19950995:A:G	K33E	1.000
3:19950996:A:T	K33I	1.000
3:19950997:A:C	K33N	1.000
3:19950997:A:T	K33N	1.000
3:19951031:T:C	F45L	1.000
3:19951033:T:A	F45L	1.000
3:19951033:T:G	F45L	1.000
3:19951053:C:T	T52I	1.000
3:19951058:G:A	G54R	1.000
3:19951058:G:C	G54R	1.000
3:19951059:G:A	G54E	1.000
3:19975601:C:A	A55D	1.000
3:19975606:T:C	F57L	1.000
3:19975607:T:C	F57S	1.000
3:19975608:T:A	F57L	1.000
3:19975608:T:G	F57L	1.000
3:19975610:T:C	L58P	1.000
3:19975655:T:A	I73K	1.000

dbSNP variants (sampled 300 via entrez): RS1000008923 (3:19972896 G>T), RS1000059690 (3:19953463 A>G), RS1000064398 (3:19972680 G>T), RS1000094463 (3:19972674 A>T), RS1000135263 (3:19958880 A>G), RS1000244800 (3:19967242 A>T), RS1000336497 (3:19956119 C>T), RS1000357944 (3:19947822 G>C,T), RS1000366976 (3:19962371 C>G), RS1000427845 (3:19969812 CT>C,CTT), RS1000486062 (3:19958662 G>A,T), RS1000612387 (3:19954849 C>G), RS1000750379 (3:19951636 A>T), RS1000756550 (3:19970157 C>G), RS1000807687 (3:19965959 C>G,T)

Disease associations

OMIM: gene MIM:179512 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST006979_52	Heel bone mineral density	9.000000e-11
GCST007743_42	Iris color (L* coordinate)	5.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0009270	heel bone mineral density
EFO:0009764	eye colour measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases expression	3
bisphenol A	increases expression, affects expression	2
Air Pollutants	increases expression, decreases expression, increases abundance	2
Tobacco Smoke Pollution	affects expression, increases expression	2
Valproic Acid	affects expression, decreases methylation	2
beauvericin	affects cotreatment, increases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression	1
trichostatin A	increases expression	1
beta-lapachone	increases expression	1
zinc chromate	increases abundance, increases expression	1
tamibarotene	affects expression	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	increases abundance, increases expression	1
enniatins	affects cotreatment, increases expression	1
ICG 001	increases expression	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
asparanin A	decreases expression	1
bisphenol S	increases expression	1
jinfukang	decreases expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Bortezomib	decreases expression	1
Arsenic Trioxide	increases expression	1
Benzo(a)pyrene	affects methylation	1
Caffeine	increases phosphorylation	1
Catechin	increases expression, affects cotreatment	1
Cuprizone	affects cotreatment, increases expression	1

Cellosaurus cell lines

5 cell lines: 5 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1YP	Abcam A-549 RAB5A KO	Cancer cell line	Male
CVCL_D2CT	Abcam HCT 116 RAB5A KO	Cancer cell line	Male
CVCL_D2P0	Abcam THP-1 RAB5A KO	Cancer cell line	Male
CVCL_TI20	HAP1 RAB5A (-) 1	Cancer cell line	Male
CVCL_TI21	HAP1 RAB5A (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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