RAB4A

Summary

RAB4A (RAB4A, member RAS oncogene family, HGNC:9781) is a protein-coding gene on chromosome 1q42.13, encoding Ras-related protein Rab-4A (P20338). The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes.

This gene is a member of the largest group in the Ras superfamily of small GTPases, which regulate membrane trafficking. The encoded protein is associated with early endosomes and is involved in their sorting and recycling. The protein also plays a role in regulating the recycling of receptors from endosomes to the plasma membrane. Alternatively spliced transcript variants have been observed for this gene.

Source: NCBI Gene 5867 — RefSeq curated summary.

At a glance

• GWAS associations: 6
• Clinical variants (ClinVar): 47 total
• MANE Select transcript: NM_004578

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9781
Approved symbol	RAB4A
Name	RAB4A, member RAS oncogene family
Location	1q42.13
Locus type	gene with protein product
Status	Approved
Aliases	HRES-1/RAB4
Ensembl gene	ENSG00000168118
Ensembl biotype	protein_coding
OMIM	179511
Entrez	5867

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 11 protein_coding, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000366690, ENST00000473894, ENST00000481981, ENST00000489342, ENST00000618010, ENST00000895472, ENST00000895473, ENST00000895474, ENST00000895475, ENST00000895476, ENST00000919084, ENST00000919085, ENST00000919086, ENST00000962542

RefSeq mRNA: 2 — MANE Select: NM_004578 NM_001271998, NM_004578

CCDS: CCDS31050, CCDS73046

Canonical transcript exons

ENST00000366690 — 8 exons

Exon	Start	End
ENSE00001429124	229271111	229271370
ENSE00001842622	229303806	229305894
ENSE00003509444	229288729	229288843
ENSE00003526502	229286486	229286566
ENSE00003532138	229297482	229297636
ENSE00003557935	229295848	229295910
ENSE00003581583	229298977	229299072
ENSE00003673235	229302862	229302989

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 98.47.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 43.5565 / max 293.3452, expressed in 1815 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
8975	38.8804	1815
8976	3.3699	1505
8977	0.7590	363
8974	0.5473	302

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lateral nuclear group of thalamus	UBERON:0002736	98.47	gold quality
parotid gland	UBERON:0001831	97.32	gold quality
substantia nigra pars compacta	UBERON:0001965	96.19	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	96.12	gold quality
palpebral conjunctiva	UBERON:0001812	95.78	gold quality
penis	UBERON:0000989	95.60	gold quality
heart right ventricle	UBERON:0002080	95.50	gold quality
dorsal plus ventral thalamus	UBERON:0001897	95.46	gold quality
substantia nigra pars reticulata	UBERON:0001966	95.35	gold quality
endothelial cell	CL:0000115	95.28	gold quality
calcaneal tendon	UBERON:0003701	95.27	gold quality
pons	UBERON:0000988	95.10	gold quality
amniotic fluid	UBERON:0000173	95.07	gold quality
medial globus pallidus	UBERON:0002477	94.95	gold quality
globus pallidus	UBERON:0001875	94.75	gold quality
subthalamic nucleus	UBERON:0001906	94.66	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.64	gold quality
lower esophagus	UBERON:0013473	94.61	gold quality
saliva-secreting gland	UBERON:0001044	94.51	gold quality
gingival epithelium	UBERON:0001949	94.49	gold quality
body of stomach	UBERON:0001161	94.46	gold quality
cranial nerve II	UBERON:0000941	94.39	gold quality
monocyte	CL:0000576	94.26	gold quality
esophagus squamous epithelium	UBERON:0006920	94.26	gold quality
substantia nigra	UBERON:0002038	94.22	gold quality
midbrain	UBERON:0001891	94.21	gold quality
cervix squamous epithelium	UBERON:0006922	94.16	gold quality
trachea	UBERON:0003126	94.14	gold quality
gingiva	UBERON:0001828	94.12	gold quality
ventral tegmental area	UBERON:0002691	94.09	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

100 targeting RAB4A, 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-3925-3P	100.00	69.95	1237
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-3065-5P	99.97	71.56	3281
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-3912-5P	99.95	66.11	925
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-338-5P	99.92	72.34	2951
HSA-MIR-300	99.92	71.76	2856
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-10527-5P	99.91	72.28	3754

Literature-anchored findings (GeneRIF, showing 36)

• Rab coupling protein (RCP), a novel Rab4 and Rab11 effector protein (PMID:11786538)
• Data suggest that abnormal membrane recycling in Niemann-Pick type A and C lipid storage disease fibroblasts results from specific inhibition of rab4 function by excess cholesterol in early endosomes. (PMID:15292453)
• In contrast to Rab11, Rab4 is not involved in exocytosis (PMID:15689494)
• Rab4 specific residue His39 modulates the nucleotide binding pocket giving rise to a reduced rate for nucleotide hydrolysis and exchange (PMID:15907487)
• critical element that regulates epithelial sodium channel (ENaC) function by GTP-GDP recycling and concomitant changes in ENaC expression at the cell surface and in intracellular pool (PMID:16389071)
• The study suggests that Rab4 regulates the channel through multiple mechanisms that include protein-protein interaction, GTP/GDP exchange, and channel protein trafficking. (PMID:16413502)
• CT229 of Chlamydia trachomatis interacts with and recruits Rab4A to the inclusion membrane and therefore may play a role in regulating the intracellular trafficking or fusogenicity of the chlamydial inclusion. (PMID:16926431)
• Regulation of CD4 expression via recycling by HRES-1/RAB4 controls susceptibility to HIV infection (PMID:16935861)
• NDRG1 specifically interacts with constitutively active Rab4aQ67L mutant protein and not with GDP-bound Rab4aS22N mutant proving NDRG1 as a novel Rab4a effector (PMID:17786215)
• Both phosphorylated and nonphosphorylated MOR internalize via Rab5-dependent pathway after agonist stimulation, and the phosphorylated and nonphosphorylated MORs recycle through distinct vesicular trafficking pathways mediated by Rab4 and Rab11. (PMID:18550774)
• Cyclic AMP-mediated phosphoinositide-3-kinase-independent activation of Rab4 facilitates Ntcp translocation in a hepatoma cell line. (PMID:18688880)
• oxytocin receptors localize in vesicles containing the Rab5 and Rab4 small GTPases (PMID:19126785)
• activation of mTOR causes the loss of TCRzeta in lupus T cells through HRES-1/Rab4-dependent lysosomal degradation. (PMID:19201859)
• conclude that a recycling pathway regulated by Rab4A is a critical effector of VEGFR1 during branching morphogenesis of the vasculature (PMID:19302266)
• Data show that within several minutes after initiating rapid endocytosis of B2ARs by the isoproterenol, bright “puffs” of locally increased surface fluorescence intensity representing discrete Rab4-dependent recycling events. (PMID:19369423)
• D-AKAP2 promotes accumulation of recycling proteins in the Rab4/Rab11-positive endocytic recycling compartment (PMID:19797056)
• Findings substantiate the notion that modulation of the temporal and spatial distribution of P-gp in cancer cells may be a valid therapeutic strategy to alleviate the MDR phenotype, and signal to Rab4 as a potential target. (PMID:20209493)
• These findings suggest that Rab14 and Rab4 act sequentially, together with RUFY1. (PMID:20534812)
• Overexpression of Rab4 regulates angiotensin II type I receptor phosphorylation and sensitization. (PMID:20943774)
• Thus down- or up-regulation of Rab4A expression or Rab4A function triggered inhibition or increase of procathepsin L secretion respectively. (PMID:21501115)
• Upregulated expression of rab4, rab5, rab7 and rab27 correlates with antemortem measures of cognitive decline in individuals with mild cognitive impairment and Alzheimer disease. (PMID:21669283)
• our findings suggest an evolutionarily conserved function of HDPTP-Rab4 in the regulation of endocytic trafficking, cell adhesion and migration. (PMID:22825871)
• TBC1D16 is a GTPase activating protein for Rab4A that regulates transferrin receptor recycling and EGFR trafficking and signaling. (PMID:23019362)
• Data indicate that Rab4 regulates ether-a-go-go-related gene (hERG) channel density via neural precursor cell-expressed developmentally down-regulated protein 4-2 (Nedd4-2). (PMID:23792956)
• HRES-1/Rab4 regulates autophagy through promoting the formation of LC3(+) autophagosomes and the preservation of mitochondria. (PMID:24404161)
• Together the findings indicate that Arl1 links Rab4-dependent formation of endosomal sorting domains with downstream assembly of adaptor protein complexes that constitute the endosomal sorting machinery. (PMID:24835460)
• The results contradict the model of feedback activation of Rab5 and instead indicate that Rbpt5 is recruited by both Rabex5 recognizing ubiquitylated cargo and by Rab4 to activate Rab5 in a feed-forward manner. (PMID:26430212)
• Rab4 expression is up-regulated by laminar shear stress, which contributed to improved vascular endothelial cell autophagy and function. (PMID:26716952)
• These findings bring attention to the effects of C-terminal carboxylmethylation on RAB GTPases and provide a rationale for targeting ICMT in the treatment of metastatic cancer (PMID:28604748)
• -type prostaglandin D synthase regulates the trafficking of the PGD2 DP1 receptor by interacting with the GTPase Rab4 (PMID:31575663)
• Complex Rab4-Mediated Regulation of Endosomal Size and EGFR Activation. (PMID:32019812)
• Agonist-activated glucagon receptors are deubiquitinated at early endosomes by two distinct deubiquitinases to facilitate Rab4a-dependent recycling. (PMID:32967969)
• RAB4A GTPase regulates epithelial-to-mesenchymal transition by modulating RAC1 activation. (PMID:36307864)
• Receptor-mediated internalization promotes increased endosome size and number in a RAB4- and RAB5-dependent manner. (PMID:37423034)
• Ras-related Protein in Brain 4A (Rab4A) is Downregulated by miR-496 to inhibit the Progression of Gastric Cancer. (PMID:38523522)
• Arf1-dependent LRBA recruitment to Rab4 endosomes is required for endolysosome homeostasis. (PMID:39325073)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	rab4a	ENSDARG00000019144
mus_musculus	Rab4a	ENSMUSG00000019478
rattus_norvegicus	Rab4a	ENSRNOG00000017467

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-4A — P20338 (reviewed: P20338)

All UniProt accessions (2): P20338, A0A087WYT5

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. RAB4A is involved in protein transport. Also plays a role in vesicular traffic. Mediates VEGFR2 endosomal trafficking to enhance VEGFR2 signaling. Acts as a regulator of platelet alpha-granule release during activation and aggregation of platelets.

Subunit / interactions. Interacts with SGSM1, SGSM2 and SGSM3. Interacts with RAB11FIP1, RABEP1, ZFYVE20 and RUFY1. Interacts (membrane-bound form) with NDRG1; the interaction involves NDRG1 in vesicular recycling of E-cadherin. Interacts (in GTP-bound form) with GRIPAP1 (via N-terminus). Interacts with RABEP1 and RBSN. Does not interact with HPS4. Interacts with RABEP2; this interaction may mediate VEGFR2 cell surface expression.

Subcellular location. Membrane. Cytoplasm. Early endosome membrane. Recycling endosome membrane.

Post-translational modifications. Phosphorylated by CDK1 kinase during mitosis. Serotonylation of Gln-72 by TGM2 during activation and aggregation of platelets leads to constitutive activation of GTPase activity.

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. Switch 1, switch 2 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 drives 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.

RefSeq proteins (2): NP_001258927, NP_004569* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001806	Small_GTPase	Family
IPR005225	Small_GTP-bd	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR041819	Rab4	Family
IPR050209	Rab_GTPases_membrane_traffic	Family

Pfam: PF00071

Catalyzed reactions (Rhea), 1 shown:

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

UniProt features (57 total): binding site 29, helix 8, strand 6, modified residue 4, short sequence motif 2, lipid moiety-binding region 2, mutagenesis site 2, sequence conflict 2, chain 1, turn 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
2BME	X-RAY DIFFRACTION	1.57
2BMD	X-RAY DIFFRACTION	1.8
1Z0K	X-RAY DIFFRACTION	1.92
1YU9	X-RAY DIFFRACTION	2.07

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P20338-F1	87.90	0.71

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 (29): 26; 27; 27; 27; 28; 28; 42; 44; 45; 45; 68; 71 …

Post-translational modifications (6): 72, 190, 204, 218, 216, 218

Mutagenesis-validated functional residues (2):

Position	Phenotype
51	10-fold decrease in zfyve20 binding affinity.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-1445148	Translocation of SLC2A4 (GLUT4) to the plasma membrane
R-HSA-1660499	Synthesis of PIPs at the plasma membrane
R-HSA-8854214	TBC/RABGAPs
R-HSA-8873719	RAB geranylgeranylation
R-HSA-8875656	MET receptor recycling

MSigDB gene sets: 242 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_DN, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, GOCC_SECRETORY_GRANULE, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, DITTMER_PTHLH_TARGETS_UP, MITSIADES_RESPONSE_TO_APLIDIN_DN, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, CHANDRAN_METASTASIS_DN, GOBP_REGULATION_OF_VESICLE_MEDIATED_TRANSPORT, MODULE_120, MARTINEZ_RB1_TARGETS_DN, GOBP_ANTIGEN_PROCESSING_AND_PRESENTATION, GAZDA_DIAMOND_BLACKFAN_ANEMIA_PROGENITOR_DN

GO Biological Process (8): protein transport (GO:0015031), vesicle-mediated transport (GO:0016192), antigen processing and presentation (GO:0019882), regulation of endocytosis (GO:0030100), Rab protein signal transduction (GO:0032482), neurotransmitter receptor transport postsynaptic membrane to endosome (GO:0098968), vesicle-mediated transport in synapse (GO:0099003), small GTPase-mediated signal transduction (GO:0007264)

GO Molecular Function (8): GTPase activity (GO:0003924), G protein activity (GO:0003925), GTP binding (GO:0005525), GDP binding (GO:0019003), metal ion binding (GO:0046872), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (12): cytoplasmic vesicle membrane (GO:0030659), early endosome membrane (GO:0031901), vesicle (GO:0031982), insulin-responsive compartment (GO:0032593), perinuclear region of cytoplasm (GO:0048471), recycling endosome (GO:0055037), recycling endosome membrane (GO:0055038), extracellular exosome (GO:0070062), glutamatergic synapse (GO:0098978), cytoplasm (GO:0005737), endosome (GO:0005768), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Membrane Trafficking	1
PI Metabolism	1
Rab regulation of trafficking	1
Post-translational protein modification	1
Signaling by MET	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
transport	2
vesicle-mediated transport	2
synapse	2
guanyl ribonucleotide binding	2
cytoplasmic vesicle	2
endosome membrane	2
intracellular protein localization	1
establishment of protein localization	1
cellular process	1
immune system process	1
endocytosis	1
regulation of cellular component organization	1
regulation of vesicle-mediated transport	1
small GTPase-mediated signal transduction	1
receptor localization to synapse	1
intracellular signaling cassette	1
ribonucleoside triphosphate phosphatase activity	1
GTPase activity	1
molecular function regulator activity	1
purine ribonucleoside triphosphate binding	1
anion binding	1
cation binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
vesicle membrane	1
early endosome	1
membrane-bounded organelle	1
secretory granule	1
cytoplasm	1
endosome	1
recycling endosome	1
extracellular vesicle	1
intracellular anatomical structure	1
endomembrane system	1

Protein interactions and networks

STRING

2830 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RAB4A	RBSN	Q9H1K0	991
RAB4A	RABEP1	Q15276	975
RAB4A	RAB11FIP1	Q6WKZ4	952
RAB4A	EEA1	Q15075	849
RAB4A	AKAP10	O43572	820
RAB4A	SGSM3	Q96HU1	807
RAB4A	RABGEF1	Q9UJ41	791
RAB4A	RUFY1	Q96T51	790
RAB4A	GRIPAP1	Q4V328	783
RAB4A	SGSM1	Q2NKQ1	782
RAB4A	SGSM2	O43147	758
RAB4A	TBC1D15	Q8TC07	754
RAB4A	RAB5A	P20339	719
RAB4A	RAB11FIP2	Q7L804	717
RAB4A	TFRC	P02786	715

IntAct

100 interactions, top by confidence:

A	B	Type	Score
GDI1	RAB4A	psi-mi:“MI:0914”(association)	0.820
GDI1	RAB4A	psi-mi:“MI:0915”(physical association)	0.820
GDI1	RAB4A	psi-mi:“MI:2364”(proximity)	0.820
EXOC5	RAB4A	psi-mi:“MI:0915”(physical association)	0.720
RAB4A	EXOC5	psi-mi:“MI:0915”(physical association)	0.720
RAB4A	GDI2	psi-mi:“MI:0915”(physical association)	0.690
GDI2	RAB4A	psi-mi:“MI:2364”(proximity)	0.690
VPS52	RAB4A	psi-mi:“MI:0915”(physical association)	0.670
RAB4A	GRIPAP1	psi-mi:“MI:0915”(physical association)	0.670
RAB4A	RBSN	psi-mi:“MI:2364”(proximity)	0.660
RAB4A	RBSN	psi-mi:“MI:0915”(physical association)	0.660
	RAB4A	psi-mi:“MI:0414”(enzymatic reaction)	0.620
	RAB4A	psi-mi:“MI:0883”(gtpase reaction)	0.620
KCTD7	RAB4A	psi-mi:“MI:0915”(physical association)	0.560
RAB4A	HACE1	psi-mi:“MI:0915”(physical association)	0.560
RAB4A	RABEP1	psi-mi:“MI:0915”(physical association)	0.560
RAB4A	GARIN6	psi-mi:“MI:0915”(physical association)	0.560
RAB4A	KCTD7	psi-mi:“MI:0915”(physical association)	0.560
RAB4A	RABEP2	psi-mi:“MI:0915”(physical association)	0.550
LRIG1	LRIG2	psi-mi:“MI:0914”(association)	0.530

BioGRID (601): VPS52 (Two-hybrid), EXOC5 (Two-hybrid), RAB4A (Affinity Capture-MS), RAB4A (Affinity Capture-MS), RAB4A (Affinity Capture-Western), RAB4A (Two-hybrid), RAB4A (Affinity Capture-MS), RABEP1 (Reconstituted Complex), RAB4A (Affinity Capture-MS), RAB4A (Affinity Capture-MS), RAB4A (Affinity Capture-MS), RAB4A (Affinity Capture-MS), RAB4A (Affinity Capture-MS), RAB4A (Affinity Capture-MS), RAB4A (Affinity Capture-MS)

ESM2 similar proteins: A4D1S5, O13876, O80501, P05714, P10948, P10949, P20337, P20338, P34213, P35289, P35293, P35294, P51152, P51159, P56371, P62823, P90726, Q05976, Q0IIG8, Q15771, Q17QB7, Q18969, Q1HE58, Q28IZ3, Q2TBH7, Q32NQ0, Q3ZC27, Q53B90, Q54E92, Q55FK2, Q5EB77, Q5KTJ7, Q5M7U5, Q5R5H5, Q63941, Q68EK7, Q6DHC1, Q6PHI9, Q8CG50, Q923S9

Diamond homologs: A5D7F5, F1PTE3, H9BW96, O18333, O23561, O24461, P05712, P05714, P10536, P16976, P17609, P20338, P20791, P22125, P24409, P31022, P31584, P34140, P35282, P35286, P36409, P36410, P36411, P36861, P36862, P36863, P36864, P41924, P49103, P49104, P51146, P51153, P53994, P55745, P56371, P59279, P61017, P61018, P61019, P61026

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
NDRG1	up-regulates	RAB4A	binding
RAB4A	“form complex”	“Early Endosome”	binding
RAB4A	“up-regulates activity”	RUFY1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 85 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
Cargo recognition for clathrin-mediated endocytosis	6	11.2×	5e-03
RAB GEFs exchange GTP for GDP on RABs	5	11.1×	7e-03
Clathrin-mediated endocytosis	6	9.1×	5e-03

GO biological processes:

GO term	Partners	Fold	FDR
vesicle-mediated transport	8	10.0×	5e-04
protein transport	11	6.3×	5e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	33
Likely benign	1
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1036 predictions. Top by Δscore:

Variant	Effect	Δscore
1:229271368:ACGGT:A	donor_loss	1.0000
1:229271369:CGG:C	donor_loss	1.0000
1:229271371:G:GC	donor_loss	1.0000
1:229271371:G:GG	donor_gain	1.0000
1:229286562:AAAAT:A	donor_gain	1.0000
1:229286563:AAAT:A	donor_gain	1.0000
1:229286567:G:GG	donor_gain	1.0000
1:229288727:A:AG	acceptor_gain	1.0000
1:229288728:G:GA	acceptor_gain	1.0000
1:229297641:G:GG	donor_gain	1.0000
1:229298972:TTTA:T	acceptor_loss	1.0000
1:229298974:TA:T	acceptor_loss	1.0000
1:229298975:A:AG	acceptor_gain	1.0000
1:229298976:G:GA	acceptor_gain	1.0000
1:229298976:GA:G	acceptor_gain	1.0000
1:229298976:GAGC:G	acceptor_gain	1.0000
1:229298976:GAGCT:G	acceptor_gain	1.0000
1:229299068:ATCAG:A	donor_loss	1.0000
1:229299069:TCAG:T	donor_loss	1.0000
1:229299070:CAGGT:C	donor_loss	1.0000
1:229299071:AG:A	donor_loss	1.0000
1:229299072:GGTAA:G	donor_loss	1.0000
1:229299073:G:A	donor_loss	1.0000
1:229299074:T:A	donor_loss	1.0000
1:229271366:CTACG:C	donor_gain	0.9900
1:229271367:TACG:T	donor_gain	0.9900
1:229271368:ACG:A	donor_gain	0.9900
1:229286564:AAT:A	donor_gain	0.9900
1:229286564:AATG:A	donor_loss	0.9900
1:229286565:AT:A	donor_gain	0.9900

AlphaMissense

1419 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:229286512:G:A	G20R	1.000
1:229286512:G:C	G20R	1.000
1:229286513:G:A	G20E	1.000
1:229286513:G:T	G20V	1.000
1:229286528:G:A	G25D	1.000
1:229286531:A:T	K26I	1.000
1:229286534:C:T	S27F	1.000
1:229288753:T:A	I46K	1.000
1:229288755:G:A	G47R	1.000
1:229288755:G:C	G47R	1.000
1:229288756:G:A	G47E	1.000
1:229288764:T:C	F50L	1.000
1:229288765:T:C	F50S	1.000
1:229288766:T:A	F50L	1.000
1:229288766:T:G	F50L	1.000
1:229288813:T:A	I66K	1.000
1:229288815:T:A	W67R	1.000
1:229288815:T:C	W67R	1.000
1:229288817:G:C	W67C	1.000
1:229288817:G:T	W67C	1.000
1:229288818:G:C	D68H	1.000
1:229288818:G:T	D68Y	1.000
1:229288819:A:C	D68A	1.000
1:229288819:A:G	D68G	1.000
1:229288819:A:T	D68V	1.000
1:229288820:T:A	D68E	1.000
1:229288820:T:G	D68E	1.000
1:229288827:G:A	G71R	1.000
1:229288827:G:C	G71R	1.000
1:229288828:G:A	G71E	1.000

dbSNP variants (sampled 300 via entrez): RS1000000052 (1:229295311 C>A), RS1000249294 (1:229288968 A>G), RS1000269996 (1:229289740 C>T), RS1000551134 (1:229294624 G>A), RS1000553794 (1:229290763 A>G), RS1000561943 (1:229276661 A>G), RS1000583550 (1:229290290 G>A,T), RS1000692419 (1:229277908 A>G), RS1000723294 (1:229277678 G>A), RS1000761902 (1:229284405 A>G), RS1000824703 (1:229283101 A>G), RS1000886964 (1:229282765 A>T), RS1000944942 (1:229269772 A>C), RS1001103613 (1:229293863 G>A), RS1001219480 (1:229287723 T>G)

Disease associations

OMIM: gene MIM:179511 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001599_8	Aging	5.000000e-06
GCST002308_2	Mean arterial pressure (alcohol consumption interaction)	7.000000e-07
GCST002927_14	Mercury levels	4.000000e-08
GCST003803_3	Response to antidepressants in depression	1.000000e-06
GCST010676_2	Leukoderma in response to rhododendrol	8.000000e-06
GCST012489_105	Heel bone mineral density x serum urate levels interaction	2.000000e-08

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0022597	aging
EFO:0004329	alcohol drinking
EFO:0006340	mean arterial pressure
EFO:0004531	urate measurement
EFO:0009270	heel bone mineral density

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases methylation	3
arsenite	affects binding, increases reaction, increases methylation	2
Air Pollutants	decreases expression, increases abundance	2
Tretinoin	affects cotreatment, increases expression, decreases expression	2
Valproic Acid	decreases expression, decreases methylation	2
selenomethylselenocysteine	increases expression	1
triphenyl phosphate	affects expression	1
terbufos	increases methylation	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
sodium arsenite	affects cotreatment, increases expression	1
tamibarotene	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
abrine	decreases expression	1
bisphenol S	affects cotreatment, decreases methylation	1
Sunitinib	increases expression	1
Fulvestrant	decreases methylation, affects cotreatment	1
Benzo(a)pyrene	affects methylation	1
Caffeine	decreases phosphorylation	1
Copper	affects binding, increases expression	1
Fonofos	increases methylation	1
Ivermectin	decreases expression	1
Parathion	increases methylation	1
Smoke	decreases expression, increases abundance	1
Dihydrotestosterone	increases expression	1
Thiosemicarbazones	affects binding, increases expression	1
Tobacco Smoke Pollution	decreases methylation	1
1-Methyl-4-phenylpyridinium	increases expression	1
Tacrolimus	increases expression	1

Cellosaurus cell lines

2 cell lines: 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_TI18	HAP1 RAB4A (-) 1	Cancer cell line	Male
CVCL_TI19	HAP1 RAB4A (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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