CDK5RAP3

Summary

CDK5RAP3 (CDK5 regulatory subunit associated protein 3, HGNC:18673) is a protein-coding gene on chromosome 17q21.32, encoding CDK5 regulatory subunit-associated protein 3 (Q96JB5). Substrate adapter of E3 ligase complexes mediating ufmylation, the covalent attachment of the ubiquitin-like modifier UFM1 to substrate proteins, and which is involved in various processes, such as ribosome recycling and reticulophagy (also called ER-phagy).

This gene encodes a protein that has been reported to function in signaling pathways governing transcriptional regulation and cell cycle progression. It may play a role in tumorigenesis and metastasis. A pseudogene of this gene is located on the long arm of chromosome 20. Alternative splicing results in multiple transcript variants that encode different isoforms.

Source: NCBI Gene 80279 — RefSeq curated summary.

At a glance

• GWAS associations: 4
• Clinical variants (ClinVar): 108 total
• MANE Select transcript: NM_176096

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:18673
Approved symbol	CDK5RAP3
Name	CDK5 regulatory subunit associated protein 3
Location	17q21.32
Locus type	gene with protein product
Status	Approved
Aliases	MST016, FLJ13660, C53, IC53, HSF-27, OK/SW-cl.114, LZAP
Ensembl gene	ENSG00000108465
Ensembl biotype	protein_coding
OMIM	608202
Entrez	80279

Gene structure

Transcript identifiers

Ensembl transcripts: 40 — 18 retained_intron, 10 protein_coding, 7 nonsense_mediated_decay, 5 protein_coding_CDS_not_defined

ENST00000338399, ENST00000536708, ENST00000577442, ENST00000577664, ENST00000577802, ENST00000578018, ENST00000578134, ENST00000578525, ENST00000578663, ENST00000578733, ENST00000578996, ENST00000579175, ENST00000579605, ENST00000579632, ENST00000579780, ENST00000579853, ENST00000580287, ENST00000580391, ENST00000580670, ENST00000581160, ENST00000581662, ENST00000581708, ENST00000582114, ENST00000582275, ENST00000582482, ENST00000583182, ENST00000583352, ENST00000583363, ENST00000583697, ENST00000584042, ENST00000584063, ENST00000584168, ENST00000584186, ENST00000584525, ENST00000584592, ENST00000584991, ENST00000585163, ENST00000894559, ENST00000894560, ENST00000930755

RefSeq mRNA: 5 — MANE Select: NM_176096 NM_001278197, NM_001278198, NM_001278216, NM_001278217, NM_176096

CCDS: CCDS42356, CCDS62232

Canonical transcript exons

ENST00000338399 — 14 exons

Exon	Start	End
ENSE00002705962	47971113	47971152
ENSE00003496847	47976712	47976822
ENSE00003501824	47978829	47978917
ENSE00003519862	47980593	47980798
ENSE00003542636	47971362	47971407
ENSE00003580139	47974400	47974448
ENSE00003590516	47975514	47975653
ENSE00003601192	47973931	47974031
ENSE00003604457	47981437	47981781
ENSE00003605576	47977832	47977910
ENSE00003607867	47975869	47976013
ENSE00003659768	47981163	47981334
ENSE00003665952	47973519	47973650
ENSE00003787135	47975159	47975337

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.40.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.2112 / max 377.1279, expressed in 1818 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
161395	15.2198	1799
161394	5.4901	1691
161393	3.8255	1442
161396	2.5863	1198
161398	0.0547	8
161400	0.0263	5
161397	0.0065	3
161399	0.0020	1

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pituitary gland	UBERON:0000007	99.40	gold quality
right uterine tube	UBERON:0001302	99.39	gold quality
adenohypophysis	UBERON:0002196	99.32	gold quality
right lobe of thyroid gland	UBERON:0001119	99.26	gold quality
body of pancreas	UBERON:0001150	99.26	gold quality
left lobe of thyroid gland	UBERON:0001120	99.19	gold quality
thyroid gland	UBERON:0002046	99.17	gold quality
spleen	UBERON:0002106	99.13	gold quality
right hemisphere of cerebellum	UBERON:0014890	99.08	gold quality
left testis	UBERON:0004533	99.03	gold quality
right testis	UBERON:0004534	99.02	gold quality
right ovary	UBERON:0002118	99.01	gold quality
cerebellar hemisphere	UBERON:0002245	99.00	gold quality
granulocyte	CL:0000094	98.98	gold quality
cerebellar cortex	UBERON:0002129	98.98	gold quality
left ovary	UBERON:0002119	98.97	gold quality
fundus of stomach	UBERON:0001160	98.94	gold quality
cerebellum	UBERON:0002037	98.94	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.87	gold quality
prostate gland	UBERON:0002367	98.82	gold quality
ovary	UBERON:0000992	98.81	gold quality
body of stomach	UBERON:0001161	98.80	gold quality
saliva-secreting gland	UBERON:0001044	98.75	gold quality
minor salivary gland	UBERON:0001830	98.74	gold quality
endocervix	UBERON:0000458	98.69	gold quality
metanephros cortex	UBERON:0010533	98.63	gold quality
lower esophagus mucosa	UBERON:0035834	98.58	gold quality
right lobe of liver	UBERON:0001114	98.57	gold quality
tonsil	UBERON:0002372	98.57	gold quality
tibial nerve	UBERON:0001323	98.54	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.16
E-MTAB-7606	no	821.51

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

17 targeting CDK5RAP3, 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-3667-3P	99.99	67.17	1636
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-3059-5P	99.70	69.93	2491
HSA-MIR-4516	99.61	67.78	3390
HSA-MIR-6832-5P	99.58	64.82	1132
HSA-MIR-3925-5P	99.21	67.90	1466
HSA-MIR-4477A	98.83	69.75	2952
HSA-MIR-6780A-3P	98.42	67.49	1518
HSA-MIR-6881-3P	98.04	68.24	1777
HSA-MIR-7111-3P	97.80	66.75	1467
HSA-MIR-4637	97.69	68.14	632
HSA-MIR-296-5P	97.61	64.02	851
HSA-MIR-708-3P	97.50	68.67	1082
HSA-MIR-874-5P	96.93	63.92	1014
HSA-MIR-7846-3P	96.92	65.18	51
HSA-MIR-4732-5P	90.07	64.77	412
HSA-MIR-6078	75.68	58.05	34

Literature-anchored findings (GeneRIF, showing 26)

• IC53 is a novel gene, mainly expressed in vascular endothelial cells and mediates cell proliferation (PMID:12054757)
• results strongly indicate that in response to genotoxic stress, Cdk5 activator-binding protein C53(C53) serves as an important regulatory component of DNA damage checkpoint through modulating cyclin dependent kinase 1-cyclin B1 function (PMID:15790566)
• It is suggested that LZAP can regulate ARF biochemical and biological activity; additionally, LZAP has p53-dependent cell-cycle effects that are independent of ARF. (PMID:16173922)
• it is concluded that CDK5RAP3, CCNB2, and RAGE genes may be used as a very reliable biomarkers of lung adenocarcinoma (PMID:17549666)
• LZAP has a role in NF-kappaB regulation and tumor suppression. (PMID:17785205)
• CDK5 regulatory subunit associated protein 3 promotes checkpoint kinase 1 activation and mitotic entry in both unperturbed cell-cycle progression and DNA damage response. (PMID:19223857)
• Endothelium-specific overexpression of human IC53 downregulates endothelial nitric oxide synthase activity and elevates systolic blood pressure in mice. (PMID:19541669)
• found that C53/LZAP and DDRGK1 became more susceptible to the proteasome-mediated degradation in RCAD knockdown cells, whereas their ubiquitination was significantly attenuated by RCAD overexpression (PMID:20228063)
• the ability of LZAP to alter p38 phosphorylation depended, at least partially, on the p38 phosphatase, Wip1 (PMID:21283629)
• Findings reveal that CDK5RAP3 is widely overexpressed in hepatocellular carcinoma and that overexpression of CDK5RAP3 promotes HCC metastasis through PAK4 activation. (PMID:21385901)
• Data indicate that IC53 is a positive mediator for colon cancer progression, and IC53-rs2737 may serve as protection from the onset of colorectal cancer. (PMID:21394385)
• Nuclear gamma-tubulin interacts with tumor suppressor protein C53 that is involved in regulation of DNA damage (PMID:21465471)
• our results strongly suggest that the binding of hepatitis viral pre-S2 LHBs with C53 is a novel negative regulator of the checkpoint response (PMID:21971960)
• LZAP may play an important role in hepatocellular carcinoma progression (PMID:22028922)
• our findings provide the new evidence that overexpression of CDK5RAP3 promotes HCC metastasis via downregulation of p14(ARF). (PMID:22860085)
• C53/LZAP protein bound indirectly to the microtubule (MT), and expression of the C53/LZAP cleavage product caused abnormal MT bundling and NE rupture. (PMID:23478299)
• CDK5RAP3 negatively regulates the beta-catenin signaling pathway by repressing GSK-3beta phosphorylation in gastric neoplasms. (PMID:27793695)
• Our results demonstrated that CDK5RAP3 negatively regulates the Wnt/beta-catenin signaling pathway by repressing AKT phosphorylation, which leads to better survival of patients with gastric cancer. (PMID:29540196)
• Prognostic analysis showed that the co-expression of CDK5RAP3 and DDRGK1 was an independent prognostic factor correlating with the overall survival of gastric cancer patients. (PMID:30228783)
• Study demonstrated that CDK5RAP3/C53 isoform d (IC53d) was upregulated in gastric cancer tissues and was associated with tumor Tstage. Furthermore, overexpression of IC53d promoted the proliferation, colony formation and G1/S phase transition of gastric cancer cells, leading to enhancement of tumorigenesis in vitro and in vivo. (PMID:30864700)
• The current findings advance innovation in drug discovery and highlight C53 as a novel pGC-B activator with sustained in vivo activity and anti-fibrotic actions in vitro. (PMID:30954448)
• CDK5RAP3 is associated with autophagy and down-regulated in renal cancer. (PMID:31061682)
• CDK5RAP3 acts as a putative tumor inhibitor in papillary thyroid carcinoma via modulation of Akt/GSK-3beta/Wnt/beta-catenin signaling. (PMID:35219640)
• CDK5RAP3 acts as a tumour suppressor in gastric cancer through the infiltration and polarization of tumour-associated macrophages. (PMID:35999359)
• CDK5RAP3 is a novel super-enhancer-driven gene activated by master TFs and regulates ER-Phagy in neuroblastoma. (PMID:38636893)
• TSPAN6 reinforces the malignant progression of glioblastoma via interacting with CDK5RAP3 and regulating STAT3 signaling pathway. (PMID:38725860)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	cdk5rap3	ENSDARG00000045092
mus_musculus	Cdk5rap3	ENSMUSG00000018669
rattus_norvegicus	Cdk5rap3	ENSRNOG00000048747
drosophila_melanogaster	CG30291	FBGN0050291
caenorhabditis_elegans		WBGENE00013765

Protein

Protein identifiers

CDK5 regulatory subunit-associated protein 3 — Q96JB5 (reviewed: Q96JB5)

Alternative names: CDK5 activator-binding protein C53, LXXLL/leucine-zipper-containing ARF-binding protein, Protein HSF-27

All UniProt accessions (13): Q96JB5, J3KRI2, J3KRK4, J3KS63, J3KSD0, J3KTA5, J3QL86, J3QL95, J3QQS7, J3QQY1, J3QRM1, J3QRX0, J3QS62

UniProt curated annotations — full annotation on UniProt →

Function. Substrate adapter of E3 ligase complexes mediating ufmylation, the covalent attachment of the ubiquitin-like modifier UFM1 to substrate proteins, and which is involved in various processes, such as ribosome recycling and reticulophagy (also called ER-phagy). As part of the UREL complex, plays a key role in ribosome recycling by promoting mono-ufmylation of RPL26/uL24 subunit of the 60S ribosome. Ufmylation of RPL26/uL24 occurs on free 60S ribosomes following ribosome dissociation: it weakens the junction between post-termination 60S subunits and SEC61 translocons, promoting release and recycling of the large ribosomal subunit from the endoplasmic reticulum membrane. Ufmylation of RPL26/uL24 and subsequent 60S ribosome recycling either take place after normal termination of translation or after ribosome stalling during cotranslational translocation at the endoplasmic reticulum. Within the UREL complex, CDK5RAP3 acts as a substrate adapter that constrains UFL1 ligase activity to mono-ufmylate RPL26/uL24 at ‘Lys-134’. The UREL complex is also involved in reticulophagy in response to endoplasmic reticulum stress by promoting ufmylation of proteins such as CYB5R3, thereby promoting lysosomal degradation of ufmylated proteins. Also acts as a regulator of transcription: negatively regulates NF-kappa-B-mediated gene transcription through the control of RELA phosphorylation. Also regulates mitotic G2/M transition checkpoint and mitotic G2 DNA damage checkpoint. Through its interaction with CDKN2A/ARF and MDM2 may induce MDM2-dependent p53/TP53 ubiquitination, stabilization and activation in the nucleus, thereby promoting G1 cell cycle arrest and inhibition of cell proliferation. May also play a role in the rupture of the nuclear envelope during apoptosis. May regulate MAPK14 activity by regulating its dephosphorylation by PPM1D/WIP1. Required for liver development. (Microbial infection) May be negatively regulated by hepatitis B virus large envelope protein mutant pre-s2 to promote mitotic entry.

Subunit / interactions. Substrate adapter component of the UFM1 ribosome E3 ligase (UREL) complex, composed of UFL1, DDRGK1 and CDK5RAP3. Interaction with UFL1 anchors CDK5RAP3 in the cytoplasm, preventing its translocation to the nucleus which allows expression of the CCND1 cyclin and progression of cells through the G1/S transition. Interacts with ATG8 family proteins MAP1LC3A, MAP1LC3B, GABARAP, GABARAPL1 and GABARAPL2. Interacts with CDK5R1; competes with CDK5RAP1 and CDK5RAP2. Interacts with RELA. Interacts with CHEK1; may negatively regulate CHEK1 and thereby stimulate entry into mitosis. Interacts with CDKN2A/ARF and MDM2; forms a ternary complex involved in regulation of p53/TP53. Interacts with MAPK14. Interacts with CCNB1. Interacts with TUBG1; may regulate CDK5RAP3 in mitotic G2/M transition checkpoint. (Microbial infection) Interacts with hepatitis B virus large envelope protein mutant pre-s2; promotes mitotic entry.

Subcellular location. Endoplasmic reticulum membrane. Cytoplasm. Nucleus. Cytoskeleton. Microtubule organizing center. Centrosome.

Tissue specificity. Ubiquitously expressed. Expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas. Isoform 3 is expressed in kidney, liver, skeletal muscle and placenta.

Post-translational modifications. May be phosphorylated by CDK5. Ubiquitinated. Probably triggers proteasomal degradation and is negatively regulated by UFL1. May be ufmylated. Cleaved by caspases early during apoptosis, the resulting peptides may play a role in rupture of the nuclear envelope.

Domain organisation. The shuffled ATG8-binding motifs mediate interaction with both ATG8 family protein and UFM1. The RPL10a-binding domain (RBD) anchors the UREL complex onto the ribosome via association with RPL10a/ul1.

Miscellaneous. Due to an intron retention. Due to intron retention.

Similarity. Belongs to the CDK5RAP3 family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q96JB5-1	1	yes
Q96JB5-2	2, IC53
Q96JB5-3	3, IC53-2
Q96JB5-4	4

RefSeq proteins (5): NP_001265126, NP_001265127, NP_001265145, NP_001265146, NP_788276* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008491	CDK5RAP3	Family

Pfam: PF05600

UniProt features (52 total): helix 19, mutagenesis site 11, sequence conflict 5, splice variant 4, short sequence motif 3, turn 3, region of interest 2, strand 2, chain 1, sequence variant 1, cross-link 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
8OJ5	ELECTRON MICROSCOPY	2.9
9GY4	ELECTRON MICROSCOPY	3
8OHD	ELECTRON MICROSCOPY	3.1
8QFC	ELECTRON MICROSCOPY	3.2
8OJ0	ELECTRON MICROSCOPY	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96JB5-F1	83.29	0.63

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (1): 450

Mutagenesis-validated functional residues (11):

Position	Phenotype
217	abolished interaction with ufl1; when associated with a-355, a-359, a-373 and a-432.
268	alters cleavage by casp3 in vitro. prevents apoptosis-induced cleavage in vivo; when associated with e-282 and e-311.
269	abolished interaction with atg8 family proteins; when associated with a-294 and a-312.
282	alters cleavage by casp3 in vitro. prevents apoptosis-induced cleavage in vivo; when associated with e-268 and e-311.
294	abolished interaction with atg8 family proteins; when associated with a-269 and a-312.
311	alters cleavage by casp3 in vitro. prevents apoptosis-induced cleavage in vivo; when associated with e-268 and e-282.
312	abolished interaction with atg8 family proteins; when associated with a-269 and a-294.
355	abolished interaction with ufl1; when associated with a-355, a-359, a-373 and a-432.
359	abolished interaction with ufl1; when associated with a-217, a-355, a-373 and a-432.
373	abolished interaction with ufl1; when associated with a-217, a-355, a-359 and a-432.
432	abolished interaction with ufl1; when associated with a-217, a-355, a-359 and a-373.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 270 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_MAP_KINASE_ACTIVITY, GOBP_HEPATICOBILIARY_SYSTEM_DEVELOPMENT, GOBP_REGULATION_OF_AUTOPHAGY, WANG_CLIM2_TARGETS_UP, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_NEGATIVE_REGULATION_OF_KINASE_ACTIVITY, GOBP_REGULATION_OF_PHOSPHATASE_ACTIVITY, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_ERYTHROCYTE_HOMEOSTASIS, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_REGULATION_OF_TRANSFERASE_ACTIVITY

GO Biological Process (29): regulation of cyclin-dependent protein serine/threonine kinase activity (GO:0000079), liver development (GO:0001889), negative regulation of protein phosphorylation (GO:0001933), mitotic G2 DNA damage checkpoint signaling (GO:0007095), regulation of mitotic cell cycle (GO:0007346), brain development (GO:0007420), cell population proliferation (GO:0008283), regulation of phosphatase activity (GO:0010921), apoptotic nuclear changes (GO:0030262), endoplasmic reticulum unfolded protein response (GO:0030968), positive regulation of protein ubiquitination (GO:0031398), obsolete negative regulation of NF-kappaB transcription factor activity (GO:0032088), ribosome disassembly (GO:0032790), response to endoplasmic reticulum stress (GO:0034976), negative regulation of protein catabolic process (GO:0042177), negative regulation of MAP kinase activity (GO:0043407), negative regulation of protein kinase activity by regulation of protein phosphorylation (GO:0044387), mitotic G2/M transition checkpoint (GO:0044818), regulation of neuron differentiation (GO:0045664), positive regulation of transcription by RNA polymerase II (GO:0045944), definitive erythrocyte differentiation (GO:0060318), protein ufmylation (GO:0071569), negative regulation of protein serine/threonine kinase activity (GO:0071901), rescue of stalled cytosolic ribosome (GO:0072344), positive regulation of reticulophagy (GO:0140501), positive regulation of protein localization to nucleus (GO:1900182), positive regulation of signal transduction by p53 class mediator (GO:1901798), blood circulation (GO:0008015), obsolete positive regulation of proteolysis involved in protein catabolic process (GO:1903052)

GO Molecular Function (8): protein kinase binding (GO:0019901), cyclin binding (GO:0030332), ubiquitin-like protein ligase binding (GO:0044389), mitogen-activated protein kinase binding (GO:0051019), NF-kappaB binding (GO:0051059), MDM2/MDM4 family protein binding (GO:0097371), ubiquitin-like ligase-substrate adaptor activity (GO:1990756), protein binding (GO:0005515)

GO Cellular Component (12): nucleus (GO:0005634), nucleolus (GO:0005730), cytoplasm (GO:0005737), endoplasmic reticulum membrane (GO:0005789), centrosome (GO:0005813), cytosol (GO:0005829), endomembrane system (GO:0012505), membrane (GO:0016020), protein-containing complex (GO:0032991), endoplasmic reticulum (GO:0005783), cytoskeleton (GO:0005856), microtubule (GO:0005874)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
protein binding	2
intracellular membrane-bounded organelle	2
intracellular membraneless organelle	2
cytoplasm	2
cyclin-dependent protein serine/threonine kinase activity	1
regulation of protein serine/threonine kinase activity	1
gland development	1
hepaticobiliary system development	1
regulation of protein phosphorylation	1
protein phosphorylation	1
negative regulation of protein modification process	1
negative regulation of phosphorylation	1
mitotic G2 phase	1
mitotic DNA damage checkpoint signaling	1
mitotic G2/M transition checkpoint	1
mitotic cell cycle	1
regulation of cell cycle	1
central nervous system development	1
animal organ development	1
head development	1
cellular process	1
phosphatase activity	1
regulation of dephosphorylation	1
regulation of hydrolase activity	1
cellular component disassembly involved in execution phase of apoptosis	1
cellular response to unfolded protein	1
response to endoplasmic reticulum stress	1
intracellular signal transduction	1
protein ubiquitination	1
regulation of protein ubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
organelle disassembly	1
cellular response to stress	1
negative regulation of catabolic process	1
protein catabolic process	1
regulation of protein catabolic process	1
negative regulation of protein metabolic process	1
MAP kinase activity	1
regulation of MAP kinase activity	1

Protein interactions and networks

STRING

738 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CDK5RAP3	UFL1	O94874	999
CDK5RAP3	DDRGK1	Q96HY6	909
CDK5RAP3	CDK5	Q00535	840
CDK5RAP3	UFSP2	Q9NUQ7	800
CDK5RAP3	CDK5R1	Q15078	759
CDK5RAP3	UBA5	Q9GZZ9	711
CDK5RAP3	UFM1	P61960	711
CDK5RAP3	UFC1	Q9Y3C8	688
CDK5RAP3	MMP9	P14780	596
CDK5RAP3	RELA	Q04206	592
CDK5RAP3	UFSP1	Q6NVU6	586
CDK5RAP3	SNX11	Q9Y5W9	521
CDK5RAP3	CDK5RAP1	Q96SZ6	488
CDK5RAP3	OR2F2	O95006	445
CDK5RAP3	PAK4	O96013	438

IntAct

152 interactions, top by confidence:

A	B	Type	Score
UFL1	CDK5RAP3	psi-mi:“MI:0915”(physical association)	0.870
CDK5RAP3	UFL1	psi-mi:“MI:0407”(direct interaction)	0.870
CDK5RAP3	UFL1	psi-mi:“MI:0914”(association)	0.870
UFL1	CDK5RAP3	psi-mi:“MI:0914”(association)	0.870
CDK5RAP3	FKBP6	psi-mi:“MI:0915”(physical association)	0.860
FKBP6	CDK5RAP3	psi-mi:“MI:0915”(physical association)	0.860
UFC1	CDK5RAP3	psi-mi:“MI:0915”(physical association)	0.760
CDK5RAP3	UFC1	psi-mi:“MI:0407”(direct interaction)	0.760
TSPYL4	CDK5RAP3	psi-mi:“MI:0915”(physical association)	0.720
CDK5RAP3	TSPYL4	psi-mi:“MI:0915”(physical association)	0.720
UFC1	UFL1	psi-mi:“MI:0914”(association)	0.720
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
UFL1	DDRGK1	psi-mi:“MI:0914”(association)	0.710
DDRGK1	UFL1	psi-mi:“MI:0914”(association)	0.710

BioGRID (260): CDK5RAP3 (Two-hybrid), CDK5RAP3 (Two-hybrid), CDK5RAP3 (Affinity Capture-MS), CDK5RAP3 (Affinity Capture-MS), CDK5RAP3 (Affinity Capture-MS), CDK5RAP3 (Two-hybrid), CDK5RAP3 (Affinity Capture-MS), CDK5RAP3 (Two-hybrid), CDK5RAP3 (Affinity Capture-MS), UFL1 (Affinity Capture-MS), CDK5RAP3 (Affinity Capture-MS), CDK5RAP3 (Affinity Capture-MS), TMED4 (Affinity Capture-MS), PLD2 (Affinity Capture-MS), TMED1 (Affinity Capture-MS)

ESM2 similar proteins: A0A5G2QD80, A8E5U3, A9ULY7, O75934, Q13503, Q13561, Q16891, Q1HQF2, Q28DG8, Q28HX4, Q28Y46, Q2TBU8, Q3ZCF0, Q4R6N3, Q4V909, Q5EA95, Q5FW42, Q5PPY2, Q5R561, Q5RAX7, Q5RE46, Q5REX6, Q5RKQ0, Q5U1Z0, Q5ZKJ4, Q66J30, Q6AYH5, Q6DF11, Q6DFL5, Q6IRB3, Q6IVW0, Q6NY52, Q6PBE2, Q6TA25, Q7K2D2, Q7PZ25, Q7T3H1, Q7ZXA8, Q8BMG7, Q8BXG3

Diamond homologs: Q5REX6, Q95SK3, Q96JB5, Q99LM2, Q9JLH7, Q9U2Y2, Q9FG23, A0A2K3E7S8

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 137 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
Constitutive Signaling by Aberrant PI3K in Cancer	7	9.8×	2e-03
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	8	8.5×	2e-03

GO biological processes:

GO term	Partners	Fold	FDR
cell surface receptor protein tyrosine kinase signaling pathway	8	11.8×	1e-04
response to endoplasmic reticulum stress	7	9.9×	1e-03
positive regulation of MAPK cascade	14	9.6×	2e-07
positive regulation of cell migration	10	5.2×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	79
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2412 predictions. Top by Δscore:

Variant	Effect	Δscore
17:47973514:T:G	acceptor_gain	1.0000
17:47973515:GTAG:G	acceptor_loss	1.0000
17:47973516:TA:T	acceptor_loss	1.0000
17:47973517:A:AG	acceptor_gain	1.0000
17:47973517:A:AT	acceptor_loss	1.0000
17:47973517:AGATT:A	acceptor_gain	1.0000
17:47973518:G:GA	acceptor_gain	1.0000
17:47973518:GA:G	acceptor_gain	1.0000
17:47973518:GAT:G	acceptor_gain	1.0000
17:47973518:GATT:G	acceptor_gain	1.0000
17:47973518:GATTG:G	acceptor_gain	1.0000
17:47973646:GTCCT:G	donor_gain	1.0000
17:47973650:TGTG:T	donor_loss	1.0000
17:47973651:G:GG	donor_gain	1.0000
17:47973651:GTG:G	donor_loss	1.0000
17:47973652:T:A	donor_loss	1.0000
17:47973653:GAGT:G	donor_loss	1.0000
17:47973927:CTA:C	acceptor_loss	1.0000
17:47973929:A:AC	acceptor_loss	1.0000
17:47973929:A:AG	acceptor_gain	1.0000
17:47973930:G:GG	acceptor_gain	1.0000
17:47973930:GAC:G	acceptor_gain	1.0000
17:47974397:CA:C	acceptor_loss	1.0000
17:47974398:AGG:A	acceptor_loss	1.0000
17:47974399:G:A	acceptor_loss	1.0000
17:47975322:GCA:G	donor_gain	1.0000
17:47975325:G:GG	donor_gain	1.0000
17:47975607:G:GT	donor_gain	1.0000
17:47975607:G:T	donor_gain	1.0000
17:47976011:GCG:G	donor_gain	1.0000

AlphaMissense

3286 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:47974403:T:A	W97R	0.999
17:47974403:T:C	W97R	0.999
17:47973534:G:C	R23T	0.998
17:47973535:A:C	R23S	0.998
17:47973535:A:T	R23S	0.998
17:47973521:T:A	W19R	0.996
17:47973521:T:C	W19R	0.996
17:47973534:G:T	R23I	0.996
17:47973596:G:C	A44P	0.996
17:47973950:C:G	C68W	0.996
17:47973970:T:C	L75P	0.996
17:47974003:T:C	F86S	0.996
17:47971402:T:C	L16P	0.994
17:47973525:T:C	L20P	0.994
17:47973537:G:C	R24T	0.994
17:47973579:G:C	R38P	0.994
17:47973948:T:C	C68R	0.994
17:47974006:G:A	G87D	0.994
17:47974404:G:C	W97S	0.994
17:47974405:G:C	W97C	0.994
17:47974405:G:T	W97C	0.994
17:47978910:T:C	L357P	0.994
17:47971387:T:A	I11N	0.993
17:47973597:C:A	A44D	0.993
17:47974011:T:G	Y89D	0.993
17:47980594:T:C	L360P	0.993
17:47981477:T:A	V499E	0.993
17:47971381:T:A	I9N	0.992
17:47973533:A:G	R23G	0.992
17:47973970:T:A	L75H	0.992

dbSNP variants (sampled 300 via entrez): RS1000356865 (17:47977250 G>A), RS1000358301 (17:47978731 G>T), RS1000642657 (17:47971753 T>C), RS1000680018 (17:47980085 T>C), RS1000904795 (17:47972935 A>T), RS1000907755 (17:47974693 G>A), RS1001979087 (17:47977450 T>C), RS1002171775 (17:47979433 G>A), RS1002404923 (17:47967196 G>A), RS1002646692 (17:47975347 G>A), RS1002652077 (17:47981056 C>T), RS1002683150 (17:47981348 G>C), RS1002841586 (17:47976603 A>G), RS1003013048 (17:47969489 A>G), RS1003114694 (17:47969144 A>G)

Disease associations

OMIM: gene MIM:608202 | disease phenotypes:

GenCC curated gene-disease

Mondo (1): pulmonary hypoplasia (MONDO:0800133)

Orphanet (0):

HPO phenotypes

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

GWAS associations

4 associations (top):

Study	Trait	p-value
GCST001662_4	Generalized epilepsy	9.000000e-09
GCST002118_5	Metabolite levels (Pyroglutamine)	6.000000e-06
GCST005951_17	Body mass index	3.000000e-09
GCST010988_61	Adult body size	9.000000e-11

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005408	pyroglutamine measurement
EFO:0004340	body mass index

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects cotreatment, increases abundance, increases expression, decreases expression	4
Air Pollutants	decreases expression, affects cotreatment, affects expression, affects oxidation, increases abundance (+1 more)	4
Ozone	affects cotreatment, affects expression, affects oxidation, increases abundance	2
Smoke	increases abundance, increases expression, decreases expression	2
Particulate Matter	affects cotreatment, increases abundance, increases expression, decreases expression	2
aristolochic acid I	decreases expression	1
bisphenol F	affects cotreatment, decreases expression	1
dicrotophos	decreases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, affects expression, affects oxidation	1
lead acetate	decreases expression	1
sodium arsenate	increases expression	1
decabromobiphenyl ether	decreases expression	1
tetrabromobisphenol A	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
cupric chloride	decreases expression	1
coumarin	decreases phosphorylation	1
methacrylaldehyde	affects cotreatment, affects expression, affects oxidation, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol S	increases expression	1
jinfukang	increases expression, affects cotreatment	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT07187206	PHASE3	RECRUITING	Safety and Efficacy of FETO in CDH Phase III
NCT02875860	PHASE2	COMPLETED	‘TOTAL’ (Tracheal Occlusion To Accelerate Lung Growth) Trial
NCT02951130	PHASE2	COMPLETED	Milrinone in Congenital Diaphragmatic Hernia
NCT03101891	PHASE1	ACTIVE_NOT_RECRUITING	Renal Anhydramnios Fetal Therapy
NCT01240057	PHASE2/PHASE3	COMPLETED	Tracheal Occlusion To Accelerate Lung Growth (TOTAL) Trial for Severe Pulmonary Hypoplasia
NCT00763737	Not specified	COMPLETED	Fetal Surgery for Moderate Left Sided Congenital Diaphragmatic Hernia.
NCT02549820	Not specified	ACTIVE_NOT_RECRUITING	Fetoscopic Endoluminal Tracheal Occlusion in Severe Left Congenital Diaphragmatic Hernia
NCT02986087	Not specified	RECRUITING	Feto-Endoscopic Tracheal Occlusion (FETO) for Severe Congenital Diaphragmatic Hernia
NCT03138863	Not specified	RECRUITING	Fetal Endoscopic Tracheal Occlusion for Congenital Diaphragmatic Hernia (FETO)
NCT06728228	Not specified	RECRUITING	Amnioinfusion for Fetal Renal Failure
NCT06884423	Not specified	RECRUITING	Safety and Efficacy of FETO in CDH: A Phase III Trial