RUFY4

Summary

RUFY4 (RUN and FYVE domain containing 4, HGNC:24804) is a protein-coding gene on chromosome 2q35, encoding RUN and FYVE domain-containing protein 4 (Q6ZNE9). ARL8 effector that promotes the coupling of endolysosomes to dynein-dynactin for retrograde transport along microtubules.

Enables phosphatidylinositol-3-phosphate binding activity. Involved in autophagosome assembly; cellular response to interleukin-4; and positive regulation of macroautophagy. Located in autophagosome.

Source: NCBI Gene 285180 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 116 total
• MANE Select transcript: NM_198483

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:24804
Approved symbol	RUFY4
Name	RUN and FYVE domain containing 4
Location	2q35
Locus type	gene with protein product
Status	Approved
Aliases	FLJ46536, ZFYVE31
Ensembl gene	ENSG00000188282
Ensembl biotype	protein_coding
OMIM	620994
Entrez	285180

Gene structure

Transcript identifiers

Ensembl transcripts: 11 — 6 protein_coding_CDS_not_defined, 3 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000344321, ENST00000374155, ENST00000457754, ENST00000463618, ENST00000463872, ENST00000465568, ENST00000472496, ENST00000480164, ENST00000495721, ENST00000497857, ENST00000697321

RefSeq mRNA: 1 — MANE Select: NM_198483 NM_198483

Canonical transcript exons

ENST00000697321 — 13 exons

Exon	Start	End
ENSE00001386201	218070753	218070859
ENSE00001462614	218073816	218073885
ENSE00001462616	218072779	218072885
ENSE00001702335	218089952	218090584
ENSE00001709916	218069253	218069348
ENSE00002449418	218069481	218069558
ENSE00003484646	218076427	218076533
ENSE00003488695	218089252	218089362
ENSE00003498596	218072374	218072499
ENSE00003584110	218075093	218075740
ENSE00003615421	218073243	218073386
ENSE00003617790	218070500	218070651
ENSE00003683022	218083110	218083256

Expression profiles

Bgee: expression breadth ubiquitous, 120 present calls, max score 78.06.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0149 / max 4.7238, expressed in 6 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
25272	0.0149	6

Top tissues by expression

133 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	78.06	gold quality
granulocyte	CL:0000094	77.69	gold quality
monocyte	CL:0000576	75.87	gold quality
leukocyte	CL:0000738	75.17	gold quality
spleen	UBERON:0002106	66.62	gold quality
lymph node	UBERON:0000029	65.90	gold quality
blood	UBERON:0000178	65.56	gold quality
bone marrow	UBERON:0002371	65.01	gold quality
bone marrow cell	CL:0002092	64.39	gold quality
vermiform appendix	UBERON:0001154	64.17	gold quality
gall bladder	UBERON:0002110	62.05	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	61.63	gold quality
duodenum	UBERON:0002114	61.48	gold quality
tonsil	UBERON:0002372	59.73	gold quality
rectum	UBERON:0001052	58.72	gold quality
lower esophagus mucosa	UBERON:0035834	58.34	gold quality
Ammon’s horn	UBERON:0001954	57.16	gold quality
prostate gland	UBERON:0002367	56.79	gold quality
small intestine	UBERON:0002108	55.74	gold quality
small intestine Peyer’s patch	UBERON:0003454	55.36	gold quality
right uterine tube	UBERON:0001302	54.66	gold quality
urinary bladder	UBERON:0001255	54.33	gold quality
amygdala	UBERON:0001876	53.66	gold quality
temporal lobe	UBERON:0001871	53.60	gold quality
esophagus mucosa	UBERON:0002469	52.88	gold quality
right adrenal gland cortex	UBERON:0035827	52.14	gold quality
right coronary artery	UBERON:0001625	51.92	gold quality
left adrenal gland	UBERON:0001234	51.60	gold quality
mucosa of transverse colon	UBERON:0004991	51.44	gold quality
substantia nigra	UBERON:0002038	51.34	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	3.08

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

34 targeting RUFY4, 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-4481	100.00	66.42	1669
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-95-5P	99.89	72.17	3973
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-4679	99.76	69.19	1229
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-1303	99.65	69.77	1662
HSA-MIR-762	99.58	66.61	1994
HSA-MIR-6733-3P	99.54	67.80	1281
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-4498	99.47	67.42	2360
HSA-MIR-508-5P	99.41	64.25	1248
HSA-MIR-3692-5P	99.29	67.04	1421
HSA-MIR-5001-5P	99.05	66.76	1972
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-4536-5P	98.47	64.39	657
HSA-MIR-6765-3P	97.83	64.59	1165
HSA-MIR-5192	96.89	63.35	879
HSA-MIR-3126-5P	96.87	65.83	912
HSA-MIR-6875-5P	96.87	65.49	958
HSA-MIR-7847-3P	96.63	64.58	952
HSA-MIR-4515	95.70	65.73	716

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Rufy4	ENSMUSG00000061815
rattus_norvegicus	Rufy4	ENSRNOG00000032991

Paralogs (1): FYCO1 (ENSG00000163820)

Protein

Protein identifiers

RUN and FYVE domain-containing protein 4 — Q6ZNE9 (reviewed: Q6ZNE9)

All UniProt accessions (2): C9J235, Q6ZNE9

UniProt curated annotations — full annotation on UniProt →

Function. ARL8 effector that promotes the coupling of endolysosomes to dynein-dynactin for retrograde transport along microtubules. Acts by binding both GTP-bound ARL8 and dynein-dynactin. In nonneuronal cells, promotes concentration of endolysosomes in the juxtanuclear area. In hippocampal neurons, drives retrograde transport of endolysosomes from the axon to the soma. Positive regulator of macroautophagy in dendritic cells. Increases autophagic flux, probably by stimulating both autophagosome formation and facilitating tethering with lysosomes. Binds to phosphatidylinositol 3-phosphate (PtdIns3P) through its FYVE-type zinc finger. Positive regulator of osteosclast bone-resorbing activity, possibly by promoting late endosome-lysosome fusion by acting as an adapter protein between RAB7A on late endosomes and LAMP2 on primary lysosomes.

Subunit / interactions. Forms homodimers (via coiled coil domain). Interacts with RAB7A. Forms a ternary complex with RAB7A and LAMP2; the interaction with RAB7A is mediated by RUFY4 (via RUN and coiled coil domains). Interacts with GTP-, but not GDP-bound ARL8A and ARL8B. Interacts with dynactin/DCTN1 and the dynein intermediate chain DYNC1I1/2.

Subcellular location. Cytoplasmic vesicle. Autophagosome. Lysosome.

Domain organisation. The RUN domain and the FYVE-type zinc finger are essential for its function in the positive regulation of macroautophagy.

Induction. Up-regulated by IL4/interleukin-4 in monocyte-derived dendritic cells.

Miscellaneous. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Isoforms (2)

UniProt ID	Names	Canonical?
Q6ZNE9-2	1	yes
Q6ZNE9-3	2

RefSeq proteins (1): NP_940885* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004012	Run_dom	Domain
IPR011011	Znf_FYVE_PHD	Homologous_superfamily
IPR013083	Znf_RING/FYVE/PHD	Homologous_superfamily
IPR017455	Znf_FYVE-rel	Domain
IPR037213	Run_dom_sf	Homologous_superfamily
IPR042939	RUFY4	Family
IPR059036	RUFY4_dom	Domain

Pfam: PF02759, PF25366

UniProt features (16 total): binding site 8, splice variant 2, chain 1, domain 1, zinc finger region 1, region of interest 1, coiled-coil region 1, compositionally biased region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6ZNE9-F1	68.07	0.38

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): 545; 548; 559; 562; 521; 524; 537; 540

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 105 (showing top): GOBP_REGULATION_OF_AUTOPHAGY, GOBP_AXO_DENDRITIC_TRANSPORT, GOBP_LYSOSOMAL_TRANSPORT, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, GOBP_VACUOLE_ORGANIZATION, GOBP_RESPONSE_TO_INTERLEUKIN_4, GOBP_RESPONSE_TO_PEPTIDE, GOBP_VESICLE_ORGANIZATION, GOBP_ENDOSOME_TO_LYSOSOME_TRANSPORT, GOBP_MEMBRANE_FUSION, GOBP_REGULATION_OF_EXOCYTOSIS, GOBP_VACUOLAR_TRANSPORT, GOBP_VESICLE_MEDIATED_TRANSPORT, CAGCTG_AP4_Q5, GOBP_MACROAUTOPHAGY

GO Biological Process (8): autophagosome assembly (GO:0000045), positive regulation of macroautophagy (GO:0016239), positive regulation of bone resorption (GO:0045780), positive regulation of exocytosis (GO:0045921), multivesicular body-lysosome fusion (GO:0061763), cellular response to interleukin-4 (GO:0071353), positive regulation of retrograde axon cargo transport (GO:2001019), autophagy (GO:0006914)

GO Molecular Function (5): zinc ion binding (GO:0008270), phosphatidylinositol-3-phosphate binding (GO:0032266), dynactin binding (GO:0034452), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (4): autophagosome (GO:0005776), endolysosome (GO:0036019), lysosome (GO:0005764), cytoplasmic vesicle (GO:0031410)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
Atg12 activating enzyme activity	1
protein-phosphatidylethanolamide deconjugating activity	1
Atg12 conjugating enzyme activity	1
Atg12 ligase activity	1
organelle assembly	1
Atg1/ULK1 kinase complex assembly	1
autophagosome organization	1
positive regulation of autophagy	1
macroautophagy	1
regulation of macroautophagy	1
regulation of bone resorption	1
bone resorption	1
positive regulation of multicellular organismal process	1
exocytosis	1
regulation of exocytosis	1
positive regulation of secretion by cell	1
vesicle fusion	1
endosome to lysosome transport via multivesicular body sorting pathway	1
lysosomal membrane organization	1
response to interleukin-4	1
cellular response to cytokine stimulus	1
retrograde axonal transport	1
positive regulation of intracellular transport	1
regulation of retrograde axon cargo transport	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
transition metal ion binding	1
phosphatidylinositol phosphate binding	1
cytoskeletal protein binding	1
binding	1
cation binding	1
vacuole	1
lysosome	1
endosome	1
lytic vacuole	1
cytoplasm	1
intracellular vesicle	1

Protein interactions and networks

STRING

486 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RUFY4	RUFY2	Q8WXA3	683
RUFY4	ARL5B	Q96KC2	552
RUFY4	ZNF142	P52746	532
RUFY4	TMBIM1	Q969X1	464
RUFY4	PLEKHM1	Q9Y4G2	444
RUFY4	STK36	Q9NRP7	432
RUFY4	TTLL7	Q6ZT98	419
RUFY4	RUNDC3A	Q59EK9	419
RUFY4	KRTAP10-8	P60410	418
RUFY4	TMEM44	Q2T9K0	402
RUFY4	SNRNP48	Q6IEG0	397
RUFY4	RNF175	Q8N4F7	396
RUFY4	KRTAP4-1	Q9BYQ7	392
RUFY4	RAB33A	Q14088	380
RUFY4	NAA30	Q147X3	368

IntAct

44 interactions, top by confidence:

A	B	Type	Score
NDC80	RUFY4	psi-mi:“MI:0915”(physical association)	0.830
RUFY4	NDC80	psi-mi:“MI:0915”(physical association)	0.830
RUFY4	NDC80	psi-mi:“MI:0914”(association)	0.830
RUFY4	LNX1	psi-mi:“MI:0915”(physical association)	0.720
RUFY4	MAP1LC3C	psi-mi:“MI:0915”(physical association)	0.560
CDKN2D	RUFY4	psi-mi:“MI:0915”(physical association)	0.560
RUFY4	DMWD	psi-mi:“MI:0915”(physical association)	0.560
RUFY4	GFAP	psi-mi:“MI:0915”(physical association)	0.560
LMNA	RUFY4	psi-mi:“MI:0915”(physical association)	0.560
RUFY4	NF2	psi-mi:“MI:0915”(physical association)	0.560
TSC1	RUFY4	psi-mi:“MI:0915”(physical association)	0.560
RUFY4	SPRED1	psi-mi:“MI:0915”(physical association)	0.560
HTT	RUFY4	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (21): RUFY4 (Two-hybrid), RUFY4 (Two-hybrid), TRAPPC9 (Affinity Capture-MS), TRAPPC9 (Affinity Capture-MS), RUFY4 (Two-hybrid), RUFY4 (Two-hybrid), RUFY4 (Two-hybrid), RUFY4 (Two-hybrid), MAP1LC3C (Two-hybrid), TRAPPC9 (Affinity Capture-MS), TRAPPC10 (Affinity Capture-MS), TRAPPC6B (Affinity Capture-MS), TRAPPC5 (Affinity Capture-MS), TRAPPC2 (Affinity Capture-MS), NDC80 (Affinity Capture-MS)

ESM2 similar proteins: A1L443, A2IDD5, A4IFI1, A6NJZ7, A6NNL0, A6NNM3, A8MT33, B1AL46, D3Z5T1, O95153, Q2M3G4, Q2T9R2, Q3TVI4, Q3TYX8, Q49AM3, Q4KLY2, Q569K6, Q5JTD0, Q5JXC2, Q5SSQ6, Q5SW24, Q5VT03, Q5VZR2, Q6ZNE9, Q7TN08, Q7TNF8, Q7Z591, Q80VJ8, Q810H6, Q811T9, Q86SX3, Q8C963, Q8CB62, Q8CII8, Q8IVF1, Q8IXR5, Q8N0S2, Q8N137, Q8N205, Q8N6L0

Diamond homologs: Q3TYX8, Q6NXD8, Q6ZNE9, Q6ZUT9, Q8VDC1, Q9BQS8, A2RSQ0, A7YDW0, O08576, Q08DX0, Q08E29, Q0V9V7, Q17QK1, Q3B7K9, Q4R7B9, Q59EK9, Q5FVJ0, Q5NVC2, Q5R4V2, Q5R565, Q5R5R4, Q5U3W3, Q6PDC0, Q7L099, Q8BIJ7, Q8R4C2, Q8TEQ0, Q8WXA3, Q96NL0, Q96T51, Q9D394, A8QCE4, A8XJZ8, B0G126, B4JHI7, D3ZVP7, O14964, O17907, O59722, O76054

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	95
Likely benign	15
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1898 predictions. Top by Δscore:

Variant	Effect	Δscore
2:218070648:AGAGG:A	donor_loss	1.0000
2:218070649:GAG:G	donor_gain	1.0000
2:218070649:GAGGT:G	donor_loss	1.0000
2:218070652:GTG:G	donor_loss	1.0000
2:218070653:T:G	donor_loss	1.0000
2:218072365:T:A	acceptor_gain	1.0000
2:218072370:CTAGT:C	acceptor_loss	1.0000
2:218072372:A:AG	acceptor_gain	1.0000
2:218072372:AGTTT:A	acceptor_gain	1.0000
2:218072373:G:GA	acceptor_gain	1.0000
2:218072373:GT:G	acceptor_gain	1.0000
2:218072373:GTT:G	acceptor_gain	1.0000
2:218072373:GTTT:G	acceptor_gain	1.0000
2:218072373:GTTTG:G	acceptor_gain	1.0000
2:218073385:GA:G	donor_gain	1.0000
2:218073387:G:GG	donor_gain	1.0000
2:218083257:G:GG	donor_gain	1.0000
2:218070652:G:GG	donor_gain	0.9900
2:218071830:G:GT	donor_gain	0.9900
2:218072361:ATTTT:A	acceptor_gain	0.9900
2:218072366:G:A	acceptor_gain	0.9900
2:218072499:GGTA:G	donor_loss	0.9900
2:218072777:A:AG	acceptor_gain	0.9900
2:218072778:G:GG	acceptor_gain	0.9900
2:218073239:ACAG:A	acceptor_gain	0.9900
2:218073391:G:GG	donor_gain	0.9900
2:218073946:T:G	donor_gain	0.9900
2:218077583:T:TA	acceptor_gain	0.9900
2:218083262:G:GT	donor_gain	0.9900
2:218070650:AG:A	donor_gain	0.9800

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000026092 (2:218063616 A>T), RS1000085395 (2:218072321 C>A,T), RS1000120793 (2:218077085 G>A,T), RS1000165553 (2:218047208 C>A), RS1000207270 (2:218088066 T>C), RS1000244996 (2:218067284 C>A,T), RS1000297101 (2:218056342 T>C), RS1000323641 (2:218034501 G>A,T), RS1000372454 (2:218053306 T>A), RS1000447057 (2:218059590 A>G,T), RS1000487610 (2:218077998 G>A), RS1000502820 (2:218050193 G>A), RS1000503540 (2:218048331 A>G), RS1000603992 (2:218055095 A>G), RS1000611208 (2:218081898 CAT>C)

Disease associations

OMIM: gene MIM:620994 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST004131_76	Inflammatory bowel disease	2.000000e-07
GCST004618_56	White blood cell count (basophil)	8.000000e-10
GCST008163_577	Height	3.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005090	basophil count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

6 total (human), top 6 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
ethyl-p-hydroxybenzoate	decreases expression	1
bisphenol S	decreases methylation	1
Benzo(a)pyrene	increases methylation	1
Cadmium	decreases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	decreases methylation	1

Clinical trials (associated diseases)

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