ARL4D

Summary

ARL4D (ARF like GTPase 4D, HGNC:656) is a protein-coding gene on chromosome 17q21.31, encoding ADP-ribosylation factor-like protein 4D (P49703). Small GTP-binding protein which cycles between an inactive GDP-bound and an active GTP-bound form, and the rate of cycling is regulated by guanine nucleotide exchange factors (GEF) and GTPase-activating proteins (GAP). It is a selective cancer dependency (DepMap: 16.8% of cell lines).

ADP-ribosylation factor 4D is a member of the ADP-ribosylation factor family of GTP-binding proteins. ARL4D is closely similar to ARL4A and ARL4C and each has a nuclear localization signal and an unusually high guanine nucleotide exchange rate. This protein may play a role in membrane-associated intracellular trafficking.

Source: NCBI Gene 379 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 43 total
• Cancer dependency (DepMap): dependent in 16.8% of screened cell lines
• MANE Select transcript: NM_001661

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:656
Approved symbol	ARL4D
Name	ARF like GTPase 4D
Location	17q21.31
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000175906
Ensembl biotype	protein_coding
OMIM	600732
Entrez	379

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 5 protein_coding

ENST00000320033, ENST00000869170, ENST00000869171, ENST00000936185, ENST00000936186

RefSeq mRNA: 1 — MANE Select: NM_001661 NM_001661

CCDS: CCDS11463

Canonical transcript exons

ENST00000320033 — 2 exons

Exon	Start	End
ENSE00001280119	43398993	43399093
ENSE00001280129	43399661	43401137

Expression profiles

Bgee: expression breadth ubiquitous, 245 present calls, max score 95.31.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.0881 / max 125.3019, expressed in 1513 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
161081	13.0881	1513

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pharyngeal mucosa	UBERON:0000355	95.31	gold quality
lower esophagus mucosa	UBERON:0035834	94.66	gold quality
esophagus mucosa	UBERON:0002469	94.53	gold quality
vena cava	UBERON:0004087	93.52	silver quality
cervix squamous epithelium	UBERON:0006922	93.35	silver quality
oocyte	CL:0000023	92.99	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.72	gold quality
parotid gland	UBERON:0001831	92.65	gold quality
gingival epithelium	UBERON:0001949	92.24	gold quality
gingiva	UBERON:0001828	92.07	gold quality
right lobe of liver	UBERON:0001114	91.87	gold quality
tongue squamous epithelium	UBERON:0006919	91.51	silver quality
cortical plate	UBERON:0005343	91.24	gold quality
left lobe of thyroid gland	UBERON:0001120	91.18	gold quality
cervix epithelium	UBERON:0004801	91.05	gold quality
esophagus	UBERON:0001043	90.61	gold quality
nipple	UBERON:0002030	90.61	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	90.34	gold quality
right lobe of thyroid gland	UBERON:0001119	90.33	gold quality
thyroid gland	UBERON:0002046	90.12	gold quality
skin of abdomen	UBERON:0001416	89.66	gold quality
skin of leg	UBERON:0001511	89.31	gold quality
left testis	UBERON:0004533	89.26	gold quality
squamous epithelium	UBERON:0006914	89.13	gold quality
adult mammalian kidney	UBERON:0000082	89.02	gold quality
body of tongue	UBERON:0011876	88.87	silver quality
right testis	UBERON:0004534	88.77	gold quality
nasal cavity epithelium	UBERON:0005384	88.56	gold quality
penis	UBERON:0000989	88.45	gold quality
left uterine tube	UBERON:0001303	87.95	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-7316	yes	2509.70
E-GEOD-93593	yes	560.98
E-GEOD-75688	yes	191.84
E-HCAD-5	yes	26.88
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

77 targeting ARL4D, 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-8485	100.00	77.57	4731
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548J-3P	99.94	72.61	4881
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-515-5P	99.92	69.82	2343
HSA-MIR-519E-5P	99.92	69.62	2358
HSA-MIR-4728-5P	99.85	69.39	4718

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 16.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 4)

• ARF4L 15-24 and ARF4L 69-77, possessed the ability to induce HLA-A2-restricted and tumor-reactive CTLs from peripheral blood mononuclear cells of patients with brain tumors (PMID:12472661)
• Study shows that three related Arf-like GTPases Arl4a, Arl4c, and Arl4d, are able to recruit ARNO and other cytohesins to the plasma membrane by binding to their PH domains irrespective of whether they are in the diglycine or triglycine form. (PMID:17398095)
• a portion of endogenous ARL4D and the GTP-binding-defective ARL4D mutant ARL4D(T35N) reside in the mitochondria (PMID:22927989)
• Phosphorylation of Arl4A/D promotes their binding by the HYPK chaperone for their stable recruitment to the plasma membrane. (PMID:35857868)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	arl4d	ENSDARG00000045074
mus_musculus	Arl4d	ENSMUSG00000034936
rattus_norvegicus	Arl4d	ENSRNOG00000020770

Paralogs (30): ARF5 (ENSG00000004059), SAR1A (ENSG00000079332), ARFRP1 (ENSG00000101246), TRIM23 (ENSG00000113595), ARL6 (ENSG00000113966), ARL1 (ENSG00000120805), ARL4A (ENSG00000122644), ARL8B (ENSG00000134108), ARF3 (ENSG00000134287), ARL3 (ENSG00000138175), ARL5C (ENSG00000141748), ARF1 (ENSG00000143761), ARL8A (ENSG00000143862), ARL11 (ENSG00000152213), SAR1B (ENSG00000152700), ARL5A (ENSG00000162980), ARF6 (ENSG00000165527), ARL5B (ENSG00000165997), ARF4 (ENSG00000168374), ARL13B (ENSG00000169379), ARL13A (ENSG00000174225), ARL10 (ENSG00000175414), ARL14 (ENSG00000179674), ARL15 (ENSG00000185305), ARL17A (ENSG00000185829), ARL4C (ENSG00000188042), ARL9 (ENSG00000196503), ARL2 (ENSG00000213465), ARL16 (ENSG00000214087), ARL17B (ENSG00000228696)

Protein

Protein identifiers

ADP-ribosylation factor-like protein 4D — P49703 (reviewed: P49703)

Alternative names: ADP-ribosylation factor-like protein 4L

All UniProt accessions (1): P49703

UniProt curated annotations — full annotation on UniProt →

Function. Small GTP-binding protein which cycles between an inactive GDP-bound and an active GTP-bound form, and the rate of cycling is regulated by guanine nucleotide exchange factors (GEF) and GTPase-activating proteins (GAP). GTP-binding protein that does not act as an allosteric activator of the cholera toxin catalytic subunit. Recruits CYTH1, CYTH2, CYTH3 and CYTH4 to the plasma membrane in GDP-bound form.

Subunit / interactions. Interacts with CYTH2; the interaction is direct and ARL4D GTP-dependent. Does not interact with ARL4D.

Subcellular location. Nucleus. Nucleolus. Cell membrane. Cytoplasm.

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

RefSeq proteins (1): NP_001652* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005225	Small_GTP-bd	Domain
IPR006689	Small_GTPase_ARF/SAR	Family
IPR024156	Small_GTPase_ARF	Family
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF00025

UniProt features (7 total): binding site 3, initiator methionine 1, chain 1, lipid moiety-binding region 1, sequence variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49703-F1	89.98	0.83

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 (3): 28–35; 76–80; 135–138

Post-translational modifications (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 152 (showing top): GSE45365_NK_CELL_VS_CD8A_DC_MCMV_INFECTION_DN, MODULE_92, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, LFA1_Q6, CREBP1_Q2, GOBP_VESICLE_MEDIATED_TRANSPORT, CREB_Q4, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, NF1_Q6_01, TCCCCAC_MIR491, MODULE_99, E4F1_Q6, GOBP_SECRETION, LINDVALL_IMMORTALIZED_BY_TERT_DN, BURTON_ADIPOGENESIS_PEAK_AT_8HR

GO Biological Process (3): intracellular protein transport (GO:0006886), protein secretion (GO:0009306), vesicle-mediated transport (GO:0016192)

GO Molecular Function (4): GTPase activity (GO:0003924), GTP binding (GO:0005525), nucleotide binding (GO:0000166), protein binding (GO:0005515)

GO Cellular Component (5): nucleolus (GO:0005730), cytoplasm (GO:0005737), plasma membrane (GO:0005886), nucleus (GO:0005634), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein transport	2
cellular anatomical structure	2
intracellular protein localization	1
intracellular transport	1
secretion by cell	1
establishment of protein localization to extracellular region	1
protein localization to extracellular region	1
transport	1
cellular process	1
ribonucleoside triphosphate phosphatase activity	1
guanyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
nuclear lumen	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
membrane	1
cell periphery	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1387 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ARL4D	CYTH2	Q99418	718
ARL4D	FLNA	P21333	468
ARL4D	CYTH3	O43739	447
ARL4D	CYTH4	Q9UIA0	428
ARL4D	CYTH1	Q15438	396
ARL4D	ARL16	Q0P5N6	374
ARL4D	SMKR1	H3BMG3	364
ARL4D	GPR176	Q14439	349
ARL4D	TMEM106A	Q96A25	311
ARL4D	MORN4	Q8NDC4	297
ARL4D	NPTX2	P47972	295
ARL4D	ZNF575	Q86XF7	290
ARL4D	FGD6	Q6ZV73	287
ARL4D	ZNF701	Q9NV72	285
ARL4D	WIPF3	A6NGB9	284

IntAct

25 interactions, top by confidence:

A	B	Type	Score
ARL4C	RGS12	psi-mi:“MI:0914”(association)	0.640
CCDC102B	ARL4D	psi-mi:“MI:0915”(physical association)	0.610
ARL4D	CCDC102B	psi-mi:“MI:0915”(physical association)	0.610
ARL4D	IFI30	psi-mi:“MI:0914”(association)	0.530
ARL4D	HNRNPA2B1	psi-mi:“MI:0915”(physical association)	0.400
ARL4D	rep	psi-mi:“MI:0915”(physical association)	0.370
ARL4D		psi-mi:“MI:0914”(association)	0.350
ARL4D	APAF1	psi-mi:“MI:0914”(association)	0.350
ARL4D	EIF2B1	psi-mi:“MI:0915”(physical association)	0.000
ARL4D	TLE1	psi-mi:“MI:0915”(physical association)	0.000
ARL4D	UBR1	psi-mi:“MI:0915”(physical association)	0.000
ARL4D	UNC119	psi-mi:“MI:0915”(physical association)	0.000
ARL4D	SNRPN	psi-mi:“MI:0915”(physical association)	0.000
ARL4D	EPRS1	psi-mi:“MI:0915”(physical association)	0.000
ARL4D	DNAJA1	psi-mi:“MI:0915”(physical association)	0.000
ARL4D	EML4	psi-mi:“MI:0915”(physical association)	0.000
ARL4D	MAPK8IP3	psi-mi:“MI:0915”(physical association)	0.000
ARL4D	NDRG1	psi-mi:“MI:0915”(physical association)	0.000
ARL4D	PGAM1	psi-mi:“MI:0915”(physical association)	0.000
ARL4D	PRKCSH	psi-mi:“MI:0915”(physical association)	0.000
ARL4D	CNPY4	psi-mi:“MI:0915”(physical association)	0.000
TMEM230	ARL4D	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (145): CCDC102B (Two-hybrid), ARL4D (Reconstituted Complex), TERF2 (Affinity Capture-MS), TUBA3C (Affinity Capture-MS), TERF2IP (Affinity Capture-MS), IFI30 (Affinity Capture-MS), ARL4D (Affinity Capture-Western), ARL4D (Two-hybrid), ARL4D (Reconstituted Complex), CYTH2 (Co-localization), ARF6 (Co-localization), ARL4D (Two-hybrid), DNAJA1 (Two-hybrid), EML4 (Two-hybrid), MAPK8IP3 (Two-hybrid)

ESM2 similar proteins: A8ISN6, B5FYQ0, E2RQ15, O48649, P0CM16, P0CM17, P0DH91, P11076, P26991, P36405, P37996, P40617, P40940, P46629, P49702, P49703, P51821, P51824, P56559, P57735, P61208, P61213, P61214, P84083, P84084, P84085, Q0VC18, Q10943, Q13795, Q19705, Q1MTE5, Q20758, Q2TBW6, Q3T0M9, Q52NJ4, Q58DI9, Q58DW6, Q5BK71, Q5R579, Q5REU3

Diamond homologs: A1CRG9, A1D4D1, A3LTA2, A8INQ0, A8ISN6, B5FYQ0, H2L0N8, O04266, O04267, O04834, O08697, O45379, P0C950, P0C951, P0CM16, P0CM17, P0CR30, P0CR31, P20606, P22274, P25160, P36404, P36405, P36536, P37996, P49703, P52885, P56559, P61208, Q01474, Q01475, Q02804, Q06849, Q09767, Q0CUN7, Q0VC18, Q10943, Q13795, Q19705, Q1MTE5

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	37
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

222 predictions. Top by Δscore:

Variant	Effect	Δscore
17:43399091:GAG:G	donor_gain	1.0000
17:43399091:GAGGT:G	donor_loss	1.0000
17:43399094:GTAA:G	donor_loss	1.0000
17:43399095:T:A	donor_loss	1.0000
17:43399642:T:TA	acceptor_gain	1.0000
17:43399653:T:A	acceptor_gain	1.0000
17:43399659:A:AG	acceptor_gain	1.0000
17:43399660:G:GG	acceptor_gain	1.0000
17:43399089:GAGAG:G	donor_gain	0.9900
17:43399184:A:T	donor_gain	0.9900
17:43399641:AT:A	acceptor_gain	0.9900
17:43399642:T:G	acceptor_gain	0.9900
17:43399654:G:A	acceptor_gain	0.9900
17:43399657:TCA:T	acceptor_loss	0.9900
17:43399659:AGAT:A	acceptor_loss	0.9900
17:43399660:G:A	acceptor_loss	0.9900
17:43399660:GA:G	acceptor_gain	0.9900
17:43399660:GAT:G	acceptor_gain	0.9900
17:43399660:GATA:G	acceptor_gain	0.9900
17:43399075:A:T	donor_gain	0.9800
17:43399091:G:GT	donor_gain	0.9800
17:43399094:G:GG	donor_gain	0.9800
17:43399660:GATAA:G	acceptor_gain	0.9800
17:43399167:G:GT	donor_gain	0.9700
17:43399641:A:AG	acceptor_gain	0.9700
17:43399657:TCAGA:T	acceptor_gain	0.9600
17:43399658:CAGAT:C	acceptor_gain	0.9600
17:43399659:AGATA:A	acceptor_gain	0.9600
17:43399655:GTTCA:G	acceptor_gain	0.9500
17:43399656:TTCAG:T	acceptor_gain	0.9500

AlphaMissense

1279 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:43399836:C:T	T35I	0.999
17:43399895:T:C	F55L	0.999
17:43399897:C:A	F55L	0.999
17:43399897:C:G	F55L	0.999
17:43399815:G:A	G28E	0.998
17:43399832:A:C	K34Q	0.998
17:43399833:A:T	K34M	0.998
17:43399834:G:C	K34N	0.998
17:43399834:G:T	K34N	0.998
17:43399991:T:A	W87R	0.998
17:43399991:T:C	W87R	0.998
17:43400124:T:C	L131P	0.998
17:43399830:G:A	G33E	0.997
17:43399955:T:A	W75R	0.997
17:43399955:T:C	W75R	0.997
17:43399958:G:C	D76H	0.997
17:43399959:A:C	D76A	0.997
17:43399993:G:C	W87C	0.997
17:43399993:G:T	W87C	0.997
17:43400019:G:A	G96D	0.997
17:43400028:T:C	F99S	0.997
17:43400140:G:C	K136N	0.997
17:43400140:G:T	K136N	0.997
17:43399803:T:A	V24D	0.996
17:43399814:G:A	G28R	0.996
17:43399814:G:C	G28R	0.996
17:43399814:G:T	G28W	0.996
17:43399830:G:T	G33V	0.996
17:43399832:A:G	K34E	0.996
17:43399833:A:C	K34T	0.996

dbSNP variants (sampled 300 via entrez): RS1001571192 (17:43397145 C>T), RS1002576957 (17:43400217 T>C), RS1003500315 (17:43398278 C>A), RS1003582316 (17:43398959 G>A), RS1004125418 (17:43397890 T>C), RS1004326320 (17:43398678 G>A), RS1005739484 (17:43399267 G>A), RS1005767050 (17:43401561 T>C), RS1007412793 (17:43401051 C>G), RS1008068552 (17:43397238 G>A,T), RS1008430456 (17:43397388 C>T), RS1009229368 (17:43398038 C>G), RS1010834450 (17:43399089 G>T), RS1011137199 (17:43398982 G>A), RS1011318405 (17:43397174 G>A)

Disease associations

OMIM: gene MIM:600732 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Acetaminophen	decreases expression, increases expression	3
Estradiol	decreases expression, increases expression	3
Cadmium Chloride	decreases expression, increases abundance, increases expression	3
sodium arsenite	increases expression, decreases expression, affects cotreatment, increases abundance	2
Tobacco Smoke Pollution	decreases expression, increases expression	2
Cyclosporine	decreases expression, decreases methylation	2
aristolochic acid I	increases expression	1
bisphenol A	increases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
trichostatin A	affects expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
cobaltous chloride	decreases expression	1
butyraldehyde	increases expression	1
tobacco tar	decreases expression	1
doxifluridine	decreases response to substance	1
manganese chloride	affects cotreatment, increases abundance, increases expression	1
cupric chloride	decreases expression	1
azoxystrobin	decreases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	decreases expression	1
abrine	increases expression	1
licochalcone B	increases expression	1
MT19c compound	decreases expression	1
NSC668394	increases expression	1
Capecitabine	decreases response to substance	1
Decitabine	increases expression	1
Antimycin A	increases expression	1
Arsenic	increases abundance, increases expression, affects cotreatment	1
Benzo(a)pyrene	affects methylation	1

Clinical trials (associated diseases)

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