DDX4

Summary

DDX4 (DEAD-box helicase 4, HGNC:18700) is a protein-coding gene on chromosome 5q11.2, encoding Probable ATP-dependent RNA helicase DDX4 (Q9NQI0). ATP-dependent RNA helicase required during spermatogenesis.

DEAD box proteins, characterized by the conserved motif Asp-Glu-Ala-Asp (DEAD), are putative RNA helicases. They are implicated in a number of cellular processes involving alteration of RNA secondary structure such as translation initiation, nuclear and mitochondrial splicing, and ribosome and spliceosome assembly. Based on their distribution patterns, some members of this family are believed to be involved in embryogenesis, spermatogenesis, and cellular growth and division. This gene encodes a DEAD box protein, which is a homolog of VASA proteins in Drosophila and several other species. The gene is specifically expressed in the germ cell lineage in both sexes and functions in germ cell development. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 54514 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 88 total
• MANE Select transcript: NM_024415

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18700
Approved symbol	DDX4
Name	DEAD-box helicase 4
Location	5q11.2
Locus type	gene with protein product
Status	Approved
Aliases	VASA
Ensembl gene	ENSG00000152670
Ensembl biotype	protein_coding
OMIM	605281
Entrez	54514

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 10 protein_coding, 2 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000353507, ENST00000354991, ENST00000503129, ENST00000505374, ENST00000506511, ENST00000506848, ENST00000507645, ENST00000508580, ENST00000509312, ENST00000511491, ENST00000511853, ENST00000514278, ENST00000514679, ENST00000515709

RefSeq mRNA: 4 — MANE Select: NM_024415 NM_001142549, NM_001166533, NM_001166534, NM_024415

CCDS: CCDS3969, CCDS47208, CCDS54854, CCDS54855

Canonical transcript exons

ENST00000505374 — 22 exons

Exon	Start	End
ENSE00001006534	55787846	55788000
ENSE00001006539	55785729	55785871
ENSE00001006544	55779964	55780065
ENSE00001006545	55767881	55767940
ENSE00001006548	55786518	55786670
ENSE00001006553	55790576	55790705
ENSE00001836626	55738061	55738101
ENSE00002070589	55816463	55817157
ENSE00003464336	55764014	55764064
ENSE00003466551	55746164	55746221
ENSE00003525425	55760200	55760277
ENSE00003550773	55738950	55739032
ENSE00003551088	55792641	55792807
ENSE00003594549	55815313	55815423
ENSE00003601995	55785297	55785344
ENSE00003622722	55781934	55781981
ENSE00003625502	55763175	55763252
ENSE00003649806	55785447	55785494
ENSE00003670795	55781066	55781146
ENSE00003675981	55813673	55813772
ENSE00003678676	55814901	55815171
ENSE00003789467	55798426	55798571

Expression profiles

Bgee: expression breadth ubiquitous, 113 present calls, max score 98.52.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.1994 / max 145.2494, expressed in 6 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
56472	0.1368	6
56471	0.0626	5

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	98.52	gold quality
right testis	UBERON:0004534	97.93	gold quality
sperm	CL:0000019	97.83	gold quality
left testis	UBERON:0004533	97.56	gold quality
male germ cell	CL:0000015	97.26	gold quality
oocyte	CL:0000023	96.27	gold quality
testis	UBERON:0000473	96.21	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	95.50	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	95.22	gold quality
adult organism	UBERON:0007023	89.66	gold quality
buccal mucosa cell	CL:0002336	71.36	silver quality
cranial nerve II	UBERON:0000941	52.48	silver quality
mucosa of urinary bladder	UBERON:0001259	51.90	gold quality
pancreatic ductal cell	CL:0002079	50.94	silver quality
corpus callosum	UBERON:0002336	50.22	gold quality
cortical plate	UBERON:0005343	50.22	gold quality
Brodmann (1909) area 9	UBERON:0013540	49.89	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	49.67	gold quality
epithelial cell of pancreas	CL:0000083	49.63	gold quality
right frontal lobe	UBERON:0002810	49.33	gold quality
Brodmann (1909) area 46	UBERON:0006483	49.30	gold quality
blood vessel layer	UBERON:0004797	49.29	gold quality
body of pancreas	UBERON:0001150	49.25	gold quality
cervix squamous epithelium	UBERON:0006922	49.20	gold quality
right coronary artery	UBERON:0001625	49.19	gold quality
hair follicle	UBERON:0002073	49.18	gold quality
quadriceps femoris	UBERON:0001377	48.93	gold quality
olfactory bulb	UBERON:0002264	48.92	gold quality
choroid plexus epithelium	UBERON:0003911	48.89	gold quality
putamen	UBERON:0001874	48.88	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	31.50
E-ANND-3	yes	5.53

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

60 targeting DDX4, 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-656-3P	100.00	72.15	2788
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-23C	99.95	73.92	3192
HSA-MIR-23A-3P	99.95	74.24	3163
HSA-MIR-23B-3P	99.95	74.24	3163
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-552-5P	99.93	68.56	1583
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-6809-3P	99.91	71.45	3814
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-1323	99.83	69.89	2471
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-548O-3P	99.74	69.30	2228

Literature-anchored findings (GeneRIF, showing 22)

• marker for normal and malignant germ cells (PMID:11850529)
• The expression of VASA mRNA and protein was significantly decreased in the sperm of oligozoospermic men. (PMID:17486274)
• VASA showed a differential pattern of expression throughout the differentiation and proliferative phase and prophase I to finally associate with Balbiani’s body in primordial and primary follicles. (PMID:18534994)
• Over-expression of VASA abrogates the G2 checkpoint, induced by DNA damage, by down-regulating the expression of 14-3-3sigma. Results suggest that VASA may play a role in the progression of ovarian cancer or serve as a valuable marker of tumorigenesis. (PMID:18805576)
• Highly methylated regions of the VASA gene are associated with maturation arrest phenotype in the testis. (PMID:19629140)
• Report the generation/characterization of embryonic stem cell lines carrying a VASA-pEGFP-1 reporter construct that expresses GFP in a population of differentiating cells showing expression of characteristic markers of primordial germ cells. (PMID:19937754)
• overexpression of VASA and or DAZL, in both embryonic and induced pluripotent stem cells promoted differentiation into primordial germ cells, and maturation and progression through meiosis was enhanced. (PMID:22162380)
• Vasa/Ddx4 gene can be involved in regulation of ground and primed states of pluripotency (PMID:22288104)
• Data suggest that VASA shows differential expression in ovary; in resting primordial follicle reserve in childhood/pre-puberty, VASA is associated with Balbiani’s body space in germ cell; once follicle enters growing pool, VASA is undetectable. (PMID:23315064)
• this study reports the first analysis and comparison of the expression patterns and colocalization of DDX4 and CD133 in 59 ovarian cancer patients via tissue microarray and immunofluorescence analysis to identify the expression patterns and relationship of those two markers in ovarian cancer cells. (PMID:24727449)
• Data show that intrinsically disordered N terminus of DEAD-box RNA helicase Ddx4 forms organelles in HeLa cells and in vitro. (PMID:25747659)
• DDX4 cell-free seminal mRNA was absent in 44% of Sertoli cell-only syndrome cases diagnosed by testicular histopathology, but present in all patients presenting with maturation arrest or hypospermatogenesis (PMID:27211570)
• The 20-mer peptide (residues 228-247) of human DDX-4, an ATP-dependent RNA helicase known to regulate germ cell development, binds to a unique shallow binding surface on RanBPM formed by highly conserved loops on the surface of the beta-sheet with two aspartates on one end, a positive patch on the opposite end, and a tryptophan lining at the bottom of the surface. (PMID:27622290)
• positivity for DDX4 gene was detected in 17 of 39 males with nonobstructive azoospermia which was due to maturation arrest in 35.3% of cases, due to incomplete Sertoli cell only in 23.5% and due to complete Sertoli cell only in 41.2%. (PMID:28000927)
• Four sterility-related genes, including BOLL, DDX4, HORMAD1, and MAEL, were found to have increased methylation at CpGs of the promoter regions and decreased mRNA expressions in nonobstructive azoospermia and hypospermatogenesis (HS) testis and are believed to be associated with HS. (PMID:28342926)
• Results suggest that DDX4 positively regulates cell cycle progression of diverse somatic-derived blood cancer cells, implying its broad contributions to the cancer cell phenotype. (PMID:28612512)
• Described are adult ovarian cell populations. A fluorescence-activated cell sorting technique incorporating dual-detection of DDX4 with aldehyde dehydrogenase 1 (ALDH1) demonstrates the existence of two sub-populations of small DDX4-positive cells (approx. 7 microm diameter) with ALDH1 activity, distinguished by expression of differentially spliced DDX4 transcripts and of DAZL, a major regulator of germ cell differenti… (PMID:29725036)
• This study clearly demonstrates that the C-terminus of DDX4 can be expressed on the cell surface despite its lack of a conventional membrane-targeting or secretory sequence. (PMID:31212843)
• DEAD-Box Helicase 4 (Ddx4)(+) Stem Cells Sustain Tumor Progression in Non-Serous Ovarian Cancers. (PMID:32847044)
• VASA protein and gene expression analysis of human non-obstructive azoospermia and normal by immunohistochemistry, immunocytochemistry, and bioinformatics analysis. (PMID:36241908)
• Discriminating activities of DEAD-Box Helicase 41 from myeloid malignancy-associated germline variants by genetic rescue. (PMID:36347925)
• The germline factor DDX4 contributes to the chemoresistance of small cell lung cancer cells. (PMID:36653474)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	ddx4	ENSDARG00000014373
mus_musculus	Ddx4	ENSMUSG00000021758
rattus_norvegicus	Ddx4	ENSRNOG00000026686
drosophila_melanogaster	vas	FBGN0283442
caenorhabditis_elegans	glh-1	WBGENE00001598
caenorhabditis_elegans	glh-2	WBGENE00001599
caenorhabditis_elegans	glh-3	WBGENE00001600

Paralogs (38): DDX20 (ENSG00000064703), DDX3Y (ENSG00000067048), DDX1 (ENSG00000079785), DDX43 (ENSG00000080007), DDX18 (ENSG00000088205), DDX24 (ENSG00000089737), DDX17 (ENSG00000100201), DDX49 (ENSG00000105671), DDX50 (ENSG00000107625), DDX5 (ENSG00000108654), DDX25 (ENSG00000109832), DDX6 (ENSG00000110367), DDX55 (ENSG00000111364), DDX59 (ENSG00000118197), DDX54 (ENSG00000123064), DDX39A (ENSG00000123136), DDX27 (ENSG00000124228), DDX31 (ENSG00000125485), DDX56 (ENSG00000136271), EIF4A3 (ENSG00000141543), DDX46 (ENSG00000145833), EIF4A2 (ENSG00000156976), DDX19B (ENSG00000157349), EIF4A1 (ENSG00000161960), DDX21 (ENSG00000165732), DDX19A (ENSG00000168872), TDRD12 (ENSG00000173809), DDX23 (ENSG00000174243), DDX10 (ENSG00000178105), DDX28 (ENSG00000182810), DDX41 (ENSG00000183258), DDX53 (ENSG00000184735), DDX51 (ENSG00000185163), DDX42 (ENSG00000198231), DDX39B (ENSG00000198563), DDX47 (ENSG00000213782), DDX3X (ENSG00000215301), DDX52 (ENSG00000278053)

Protein

Protein identifiers

Probable ATP-dependent RNA helicase DDX4 — Q9NQI0 (reviewed: Q9NQI0)

Alternative names: DEAD box protein 4, Vasa homolog

All UniProt accessions (8): Q9NQI0, D6RAF5, D6RAT7, D6RBL3, D6RCM4, D6RIB2, H0Y960, H0YBW0

UniProt curated annotations — full annotation on UniProt →

Function. ATP-dependent RNA helicase required during spermatogenesis. Required to repress transposable elements and preventing their mobilization, which is essential for the germline integrity. Acts via the piRNA metabolic process, which mediates the repression of transposable elements during meiosis by forming complexes composed of piRNAs and Piwi proteins and governs the methylation and subsequent repression of transposons. Involved in the secondary piRNAs metabolic process, the production of piRNAs in fetal male germ cells through a ping-pong amplification cycle. Required for PIWIL2 slicing-triggered piRNA biogenesis: helicase activity enables utilization of one of the slice cleavage fragments generated by PIWIL2 and processing these pre-piRNAs into piRNAs.

Subunit / interactions. Found in a mRNP complex, at least composed of TDRD1, TDRD6, TDRD7 and DDX4. Interacts with RANBP9. Interacts with RANBP10. Interacts with PIWIL2 and MAEL. Interacts with BMAL1 and CLOCK. Interacts with Tex19.1 and, probably, Tex19.2. Interacts with RBM46.

Subcellular location. Cytoplasm. Perinuclear region.

Tissue specificity. Expressed only in ovary and testis. Expressed in migratory primordial germ cells in the region of the gonadal ridge in both sexes.

Similarity. Belongs to the DEAD box helicase family. DDX4/VASA subfamily.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9NQI0-1	1	yes
Q9NQI0-2	2
Q9NQI0-3	3
Q9NQI0-4	4

RefSeq proteins (4): NP_001136021, NP_001160005, NP_001160006, NP_077726* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000629	RNA-helicase_DEAD-box_CS	Conserved_site
IPR001650	Helicase_C-like	Domain
IPR011545	DEAD/DEAH_box_helicase_dom	Domain
IPR014001	Helicase_ATP-bd	Domain
IPR014014	RNA_helicase_DEAD_Q_motif	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF00270, PF00271

Enzyme classification (BRENDA):

• EC 3.6.4.13 — RNA helicase (BRENDA: 3 organisms, 3 substrates, 0 inhibitors, 0 Km, 0 kcat entries)

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (27 total): compositionally biased region 5, splice variant 4, sequence conflict 4, modified residue 3, region of interest 3, domain 2, sequence variant 2, short sequence motif 2, chain 1, binding site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NQI0-F1	69.06	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 (1): 332–339

Post-translational modifications (3): 222, 226, 722

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-5601884	PIWI-interacting RNA (piRNA) biogenesis
R-HSA-9696264	RND3 GTPase cycle

MSigDB gene sets: 178 (showing top): GOBP_MALE_GAMETE_GENERATION, AAAYRNCTG_UNKNOWN, GOBP_NEGATIVE_REGULATION_OF_GENE_EXPRESSION_EPIGENETIC, GOBP_DNA_METHYLATION_DEPENDENT_CONSTITUTIVE_HETEROCHROMATIN_FORMATION, GOBP_ORGANELLE_FISSION, GOBP_CILIUM_MOVEMENT, GOBP_CILIUM_OR_FLAGELLUM_DEPENDENT_CELL_MOTILITY, GOBP_MALE_MEIOSIS_I, GOBP_CELLULAR_PROCESS_INVOLVED_IN_REPRODUCTION_IN_MULTICELLULAR_ORGANISM, HIF1_Q3, HELLER_HDAC_TARGETS_SILENCED_BY_METHYLATION_UP, GOBP_PIRNA_PROCESSING, GOBP_DEVELOPMENTAL_PROCESS_INVOLVED_IN_REPRODUCTION, GOBP_MEIOTIC_CELL_CYCLE_PROCESS, CONRAD_GERMLINE_STEM_CELL

GO Biological Process (12): male meiotic nuclear division (GO:0007140), male meiosis I (GO:0007141), gamete generation (GO:0007276), germ cell development (GO:0007281), spermatogenesis (GO:0007283), cell differentiation (GO:0030154), flagellated sperm motility (GO:0030317), piRNA processing (GO:0034587), transposable element silencing by piRNA-mediated heterochromatin formation (GO:0141006), transposable element silencing by piRNA-mediated DNA methylation (GO:0141196), regulatory ncRNA-mediated gene silencing (GO:0031047), meiotic cell cycle (GO:0051321)

GO Molecular Function (9): RNA helicase activity (GO:0003724), mRNA binding (GO:0003729), ATP binding (GO:0005524), ATP hydrolysis activity (GO:0016887), molecular condensate scaffold activity (GO:0140693), nucleotide binding (GO:0000166), nucleic acid binding (GO:0003676), helicase activity (GO:0004386), hydrolase activity (GO:0016787)

GO Cellular Component (6): nucleus (GO:0005634), cytoplasm (GO:0005737), P granule (GO:0043186), perinuclear region of cytoplasm (GO:0048471), pi-body (GO:0071546), piP-body (GO:0071547)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Gene Silencing by RNA	1
RHO GTPase cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
male gamete generation	3
meiotic cell cycle	2
meiotic nuclear division	2
sexual reproduction	2
developmental process involved in reproduction	2
transposable element silencing by heterochromatin formation	2
ATP-dependent activity	2
cellular anatomical structure	2
P granule	2
meiosis I	1
male meiotic nuclear division	1
multicellular organismal reproductive process	1
gamete generation	1
cellular process involved in reproduction in multicellular organism	1
cell development	1
cellular developmental process	1
cilium-dependent cell motility	1
cilium movement involved in cell motility	1
sperm motility	1
regulatory ncRNA processing	1
piRNA-mediated heterochromatin formation	1
gene silencing by piRNA-directed DNA methylation	1
negative regulation of gene expression	1
cell cycle	1
reproductive process	1
helicase activity	1
ATP-dependent activity, acting on RNA	1
catalytic activity, acting on RNA	1
RNA binding	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
ribonucleoside triphosphate phosphatase activity	1
protein-macromolecule adaptor activity	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
binding	1
nucleic acid conformation isomerase activity	1
catalytic activity, acting on a nucleic acid	1
catalytic activity	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

3437 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DDX4	DAZL	Q92904	905
DDX4	MAEL	Q96JY0	834
DDX4	PPP1CC	P36873	831
DDX4	TOP1	P11387	770
DDX4	SYCP3	Q8IZU3	769
DDX4	CENPC	Q03188	762
DDX4	BOLL	Q8N9W6	759
DDX4	DAZ1	Q9NQZ3	724
DDX4	IL31RA	Q8NI17	722
DDX4	STRA8	Q7Z7C7	711
DDX4	H2AX	P16104	703
DDX4	PIWIL2	Q8TC59	680
DDX4	NANOS3	P60323	679
DDX4	TDRD1	Q9BXT4	635
DDX4	DPPA3	Q6W0C5	630

IntAct

9 interactions, top by confidence:

A	B	Type	Score
USE1	NBAS	psi-mi:“MI:0914”(association)	0.640
DDX4	SRC	psi-mi:“MI:0915”(physical association)	0.400
CAND1	GTPBP10	psi-mi:“MI:0914”(association)	0.350
DCUN1D1	RGSL1	psi-mi:“MI:0914”(association)	0.350
CUL3	PXDNL	psi-mi:“MI:0914”(association)	0.350
N		psi-mi:“MI:0914”(association)	0.350
STK38L	SH3PXD2B	psi-mi:“MI:2364”(proximity)	0.270
STK38L	CCDC187	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (26): DDX4 (Affinity Capture-MS), DDX4 (Reconstituted Complex), DDX4 (Affinity Capture-MS), DDX4 (Affinity Capture-MS), DDX4 (Affinity Capture-MS), DDX4 (Proximity Label-MS), DDX4 (Affinity Capture-MS), DDX4 (Affinity Capture-MS), DDX4 (Affinity Capture-MS), DDX4 (Affinity Capture-MS), DDX4 (Proximity Label-MS), DDX4 (Affinity Capture-MS), DDX4 (Affinity Capture-MS), DDX4 (Proximity Label-MS), DDX4 (Affinity Capture-MS)

ESM2 similar proteins: A2SW84, A6PVI3, A8Y1R8, B0W939, B1WC40, B3LYP1, B3P0D7, B4GLK8, B4IBA4, B4JUT1, B4KCD5, B4LZ88, B4M205, B4NB54, B4PL68, B4QV17, B5G279, B7P877, C0H859, C1BY64, P34541, P40565, P52298, P52299, Q05AT9, Q08920, Q16560, Q177H0, Q1HE01, Q1LZH0, Q293V6, Q3ZBJ1, Q4QQV1, Q4R5S7, Q54KR9, Q5ZKR5, Q6DES0, Q754W7, Q7QCB6, Q84L14

Diamond homologs: A1C6C4, A1CH78, A1CXK7, A1DGZ7, A2QC74, A2QI25, A3LQ01, A3LQW7, A4QSS5, A4RHF1, A5DL80, A5DQS0, A5DS77, A5DZE6, A6R3L3, A6RGE3, A6SEH9, A6SFW7, A6ZP47, A6ZRX0, A6ZWD3, A7E449, A7EJY3, A7TKR8, C8V8H4, D0PV95, G0SFM2, O00571, O01836, O13370, O15523, P06634, P09052, P0CQ74, P0CQ75, P0CQ76, P0CQ77, P16381, P19109, P24346

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	73
Likely benign	3
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

3223 predictions. Top by Δscore:

Variant	Effect	Δscore
5:55738942:A:AG	acceptor_gain	1.0000
5:55738942:AT:A	acceptor_gain	1.0000
5:55738943:T:G	acceptor_gain	1.0000
5:55738943:T:TA	acceptor_gain	1.0000
5:55738946:ATAG:A	acceptor_loss	1.0000
5:55738947:TA:T	acceptor_loss	1.0000
5:55738948:A:AG	acceptor_gain	1.0000
5:55738948:A:T	acceptor_loss	1.0000
5:55738949:G:GC	acceptor_gain	1.0000
5:55738949:G:GT	acceptor_loss	1.0000
5:55738949:GA:G	acceptor_gain	1.0000
5:55738949:GAA:G	acceptor_gain	1.0000
5:55738949:GAAC:G	acceptor_gain	1.0000
5:55739028:AGAAG:A	donor_loss	1.0000
5:55739030:AAG:A	donor_loss	1.0000
5:55739031:AGGT:A	donor_loss	1.0000
5:55739032:GGTAA:G	donor_loss	1.0000
5:55739033:G:GA	donor_loss	1.0000
5:55739034:T:G	donor_loss	1.0000
5:55746159:CACA:C	acceptor_loss	1.0000
5:55746160:ACAG:A	acceptor_gain	1.0000
5:55746161:CA:C	acceptor_loss	1.0000
5:55746162:A:AG	acceptor_gain	1.0000
5:55746162:AG:A	acceptor_gain	1.0000
5:55746163:G:GT	acceptor_gain	1.0000
5:55746163:GG:G	acceptor_gain	1.0000
5:55746163:GGAT:G	acceptor_gain	1.0000
5:55746163:GGATA:G	acceptor_gain	1.0000
5:55746221:GG:G	donor_loss	1.0000
5:55756184:C:CA	acceptor_gain	1.0000

AlphaMissense

4760 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:55814906:G:C	R574P	1.000
5:55815065:G:C	R627P	1.000
5:55786662:G:T	G337W	0.999
5:55786663:G:A	G337E	0.999
5:55790605:G:A	G401E	0.999
5:55790680:T:C	L426P	0.999
5:55792678:A:C	E447A	0.999
5:55792678:A:T	E447V	0.999
5:55792679:A:C	E447D	0.999
5:55792679:A:T	E447D	0.999
5:55792683:G:C	D449H	0.999
5:55792684:A:C	D449A	0.999
5:55792684:A:T	D449V	0.999
5:55792687:G:C	R450P	0.999
5:55792704:T:C	F456L	0.999
5:55792706:T:A	F456L	0.999
5:55792706:T:G	F456L	0.999
5:55792779:A:C	S481R	0.999
5:55792781:T:A	S481R	0.999
5:55792781:T:G	S481R	0.999
5:55813691:T:A	V545D	0.999
5:55813693:T:C	F546L	0.999
5:55813695:T:A	F546L	0.999
5:55813695:T:G	F546L	0.999
5:55813714:G:C	A553P	0.999
5:55813762:A:C	S569R	0.999
5:55813764:T:A	S569R	0.999
5:55813764:T:G	S569R	0.999
5:55813772:G:A	G572D	0.999
5:55814913:G:C	Q576H	0.999

dbSNP variants (sampled 300 via entrez): RS1000085745 (5:55789489 C>A), RS1000087669 (5:55748259 C>T), RS1000104609 (5:55756476 A>G), RS1000154219 (5:55740580 A>G), RS1000160268 (5:55753244 C>T), RS1000231356 (5:55753395 G>A,C), RS1000295266 (5:55774641 A>G), RS1000339403 (5:55807398 A>T), RS1000365149 (5:55780311 A>G), RS1000392035 (5:55774128 A>T), RS1000396123 (5:55801778 A>C,G,T), RS1000417010 (5:55748435 A>G), RS1000422171 (5:55780585 A>G), RS1000454788 (5:55800638 A>G), RS1000489276 (5:55747379 A>G)

Disease associations

OMIM: gene MIM:605281 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): male infertility (MONDO:0005372)

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST008399_7	Cocaine dependence	8.000000e-06

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D007248	Infertility, Male	C12.100.500.430; C12.100.750.700; C12.200.294.430

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

9 total (human), top 9 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
alpha-naphthoflavone	decreases expression, decreases reaction	1
CGP 52608	increases reaction, affects binding	1
Resveratrol	affects cotreatment, decreases expression	1
Benzo(a)pyrene	increases methylation	1
Cadmium	decreases expression	1
Copper	affects cotreatment, decreases expression	1
Valproic Acid	decreases methylation	1
9,10-Dimethyl-1,2-benzanthracene	decreases reaction, decreases expression, affects reaction	1
Aflatoxin B1	increases methylation	1

Cellosaurus cell lines

3 cell lines: 3 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B8EM	Abcam HCT 116 DDX4 KO	Cancer cell line	Male
CVCL_B9GW	Abcam A-549 DDX4 KO	Cancer cell line	Male
CVCL_D2ET	Abcam MCF-7 DDX4 KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT02202382	PHASE4	COMPLETED	Effects of Korean Red Ginseng on Male Infertility
NCT02204826	PHASE4	COMPLETED	Effects of Korean Red Ginseng on Semen Parameters in Male Infertility Patients: a Randomized, Placebo-controlled, Double-blind Clinical Study
NCT03802864	PHASE4	COMPLETED	Post-operative Pain Control of Testicular Sperm Extraction Using Liposomal Bupivacaine
NCT06100432	PHASE4	ACTIVE_NOT_RECRUITING	Effect of Eurycoma Longifolia (DLBS5055) and Multivitamins (Vitamin C+Vitamin E+ β-carotene) for Infertile Males
NCT07523022	PHASE4	ENROLLING_BY_INVITATION	Comparison of the Effect of Gonadotropin and Clomiphene Citrate Treatment on Sperm Parameters and the Outcome of Assisted Reproductive Procedures in Subfertile Men Based on the APHRODITE Groups
NCT00975117	PHASE3	COMPLETED	Spermotrend in the Treatment of Male Infertility
NCT01407432	PHASE3	COMPLETED	Impact of Folates in the Care of the Male Infertility
NCT01895816	PHASE3	COMPLETED	Herbal Tonic Fertile Supplement(ZO2C5)
NCT02605070	PHASE3	TERMINATED	Pilot Study on the Effects of FSH Treatment on the Epigenetic Characteristics of Spermatozoa in Infertile Patients With Severe Oligozoospermia
NCT07402759	PHASE3	ACTIVE_NOT_RECRUITING	Impact of tdrd9 Gene Mutations in the Therapeutic Response to L-carnitine in Oligoasthenozoospermic Men
NCT01880086	PHASE2	COMPLETED	Clomiphene Citrate for the Treatment of Low Testosterone Associated With Chronic Opioid Pain Medication Administration
NCT02061384	PHASE2	COMPLETED	RA-2 13-cis Retinoic Acid (Isotretinoin)
NCT02421887	PHASE2	COMPLETED	Males, Antioxidants, and Infertility Trial
NCT05200663	PHASE2	UNKNOWN	Efficacy Comparison of Tamoxifen and Tamoxifen With Antioxidants on Semen Quality of Male With Idiopathic Infertility
NCT05290558	PHASE2	ACTIVE_NOT_RECRUITING	The Therapeutic Effects of Bu Shen Yi Jing Pill on Semen Quality in Sub Fertile Males: a Randomized Controlled Trial
NCT06091969	PHASE2	NOT_YET_RECRUITING	Supplementation for Male Subfertility
NCT01595308	PHASE1	COMPLETED	A Pilot Study to Evaluate the Effect of Pomegranate Juice on Semen Parameters in Healthy Male Volunteers
NCT02122211	PHASE1	COMPLETED	Choline Dehydrogenase and Sperm Function: Effects of Betaine
NCT02575924	PHASE1	UNKNOWN	Influence of Culture Media on Clinical Outcomes in Poor Responders or Severe Male Infertility
NCT01304927	PHASE2/PHASE3	COMPLETED	Vitamin D Supplementation and Male Infertility: The CBG-study a Randomized Clinical Trial
NCT02349945	PHASE2/PHASE3	COMPLETED	FSH Receptor Polymorphism p.N680S and Efficacy of FSH Therapy
NCT05222841	PHASE2/PHASE3	COMPLETED	The Effectiveness of Spermotrend Food Supplement in the Treatment of Male Infertility
NCT05616598	PHASE2/PHASE3	COMPLETED	Effect of New Oral Treatment for Hepatitis C Virus on Seminal Parameters
NCT02025270	PHASE1/PHASE2	COMPLETED	MSCs For Treatment of Azoospermic Patients
NCT04541459	EARLY_PHASE1	UNKNOWN	Validation of New Devices Against Ambient Electromagnetic Radiation
NCT05792813	EARLY_PHASE1	UNKNOWN	Efficacy and Safety of Linggui Yangyuan Paste in Patients With Male Infertility
NCT06188936	EARLY_PHASE1	COMPLETED	Home Semen Analysis Tests As a Screening Tool for Fertility Patients
NCT00012480	Not specified	COMPLETED	Effect of Environmental Exposures on the Egg Fertilizing Ability of Human Sperm
NCT00044369	Not specified	COMPLETED	Role of the Toxic Metal Cadmium in the Mechanism Producing Infertility With a Varicocele
NCT00119925	Not specified	UNKNOWN	‘SPRING’-Study: Subfertility Guidelines: Patient Related Implementation in the Netherlands Among Gynaecologists
NCT00178516	Not specified	COMPLETED	Vitamin E and Male Infertility
NCT00315029	Not specified	COMPLETED	Patient-Centered Implementation Trial for Single Embryo Transfer
NCT00341120	Not specified	COMPLETED	Genetic Causes of Male Infertility
NCT00481403	Not specified	COMPLETED	Study of Sperm Molecular Factors Implicated in Male Fertility
NCT00548977	Not specified	COMPLETED	Genetic Studies Spermatogenic Failure
NCT00596739	Not specified	COMPLETED	A Study of the Pre- and Post-operative Semen Analyses and Reproductive Hormone Levels of Men Undergoing Weight-reduction Surgery
NCT00756561	Not specified	COMPLETED	HOP-2A - Intratesticular Hormone Levels
NCT00961558	Not specified	TERMINATED	Canadian Varicocelectomy Initiative (CVI): Effects on Male Fertility and Testicular Function of Varicocelectomy
NCT01075334	Not specified	UNKNOWN	Is a Carnitine Based Food Supplement (PorimoreTM) for Infertile Men Superior to Folate and Zinc With Regard to Pregnancy Rates in Intrauterine Insemination Cycles?
NCT01178463	Not specified	UNKNOWN	Spermatogonial Stem Cells in Azoospermic Patients: a Comparison Between Obstructive and Non-obstructive Azoospermia