KPNA4

Summary

KPNA4 (karyopherin subunit alpha 4, HGNC:6397) is a protein-coding gene on chromosome 3q25.33, encoding Importin subunit alpha-3 (O00629). Functions in nuclear protein import as an adapter protein for nuclear receptor KPNB1.

The nuclear import of karyophilic proteins is directed by short amino acid sequences termed nuclear localization signals (NLSs). Karyopherins, or importins, are cytoplasmic proteins that recognize NLSs and dock NLS-containing proteins to the nuclear pore complex. The protein encoded by this gene shares the sequence similarity with Xenopus importin-alpha and Saccharomyces cerevisiae Srp1. This protein is found to interact with the NLSs of DNA helicase Q1 and SV40 T antigen.

Source: NCBI Gene 3840 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Limited, GenCC)
• GWAS associations: 14
• Clinical variants (ClinVar): 46 total
• Druggable target: yes
• MANE Select transcript: NM_002268

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6397
Approved symbol	KPNA4
Name	karyopherin subunit alpha 4
Location	3q25.33
Locus type	gene with protein product
Status	Approved
Aliases	QIP1, SRP3, IPOA3, MGC12217, MGC26703
Ensembl gene	ENSG00000186432
Ensembl biotype	protein_coding
OMIM	602970
Entrez	3840

Gene structure

Transcript identifiers

Ensembl transcripts: 19 — 13 protein_coding, 3 nonsense_mediated_decay, 3 retained_intron

ENST00000334256, ENST00000469804, ENST00000483437, ENST00000676799, ENST00000676866, ENST00000676958, ENST00000678020, ENST00000678630, ENST00000678734, ENST00000678765, ENST00000678839, ENST00000914241, ENST00000914242, ENST00000960889, ENST00000960890, ENST00000960891, ENST00000960892, ENST00000960893, ENST00000960894

RefSeq mRNA: 1 — MANE Select: NM_002268 NM_002268

CCDS: CCDS3191

Canonical transcript exons

ENST00000334256 — 17 exons

Exon	Start	End
ENSE00000968149	160536796	160536840
ENSE00000968150	160535808	160535897
ENSE00000968151	160535661	160535690
ENSE00000968152	160535513	160535565
ENSE00000968155	160527953	160528039
ENSE00000968157	160525800	160525844
ENSE00001002715	160525938	160526107
ENSE00001002719	160531462	160531557
ENSE00001076126	160521779	160521910
ENSE00001076133	160514077	160514181
ENSE00001076136	160515452	160515580
ENSE00001076137	160509800	160509871
ENSE00001076140	160508107	160508269
ENSE00001224224	160495007	160502202
ENSE00002274578	160530855	160530940
ENSE00003788410	160504958	160505052
ENSE00003908081	160565214	160565571

Expression profiles

Bgee: expression breadth ubiquitous, 289 present calls, max score 99.02.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 55.7406 / max 569.3408, expressed in 1826 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
45373	25.2075	1820
45372	23.3389	1817
45371	2.5135	1332
45374	2.3193	1361
45369	0.8156	399
45370	0.7973	457
45375	0.3766	179
45363	0.3719	149

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
biceps brachii	UBERON:0001507	99.02	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.86	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.82	gold quality
cauda epididymis	UBERON:0004360	98.41	gold quality
endothelial cell	CL:0000115	98.40	gold quality
body of tongue	UBERON:0011876	98.09	gold quality
heart right ventricle	UBERON:0002080	97.85	gold quality
corpus epididymis	UBERON:0004359	97.80	gold quality
oral cavity	UBERON:0000167	97.60	gold quality
saphenous vein	UBERON:0007318	97.50	gold quality
caput epididymis	UBERON:0004358	97.44	gold quality
gingival epithelium	UBERON:0001949	97.29	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.14	gold quality
superficial temporal artery	UBERON:0001614	97.07	gold quality
skeletal muscle tissue	UBERON:0001134	97.04	gold quality
gastrocnemius	UBERON:0001388	97.01	gold quality
muscle of leg	UBERON:0001383	96.95	gold quality
muscle organ	UBERON:0001630	96.90	gold quality
gingiva	UBERON:0001828	96.90	gold quality
tongue	UBERON:0001723	96.85	gold quality
vastus lateralis	UBERON:0001379	96.73	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.66	gold quality
ventricular zone	UBERON:0003053	96.58	gold quality
quadriceps femoris	UBERON:0001377	96.42	gold quality
seminal vesicle	UBERON:0000998	96.41	gold quality
mucosa of paranasal sinus	UBERON:0005030	96.38	gold quality
substantia nigra pars compacta	UBERON:0001965	96.35	gold quality
jejunum	UBERON:0002115	96.34	gold quality
deltoid	UBERON:0001476	96.33	gold quality
vena cava	UBERON:0004087	96.19	gold quality

Single-cell (SCXA)

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

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

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

398 targeting KPNA4, 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-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-3134	100.00	66.43	777
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3924	100.00	72.09	2394
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-4692	100.00	67.32	2066
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-548AW	99.99	72.57	3559

Literature-anchored findings (GeneRIF, showing 27)

• Our results indicate that the nuclear import of RHA is mediated by the importin-alpha3/importin-beta-dependent pathway and suggest that the specificity for importin may regulate the functions of cargo proteins. (PMID:16375861)
• Daxx interacts selectively with importin alpha3 through its NLS1 and NLS2 sequences. Conversely, importin alpha3 utilizes two NLS-binding sites for Daxx interaction, suggesting that it mediates nuclear import of Daxx. (PMID:17661348)
• Expression of importin alpha3, a protein involved in p50/p65 nuclear import, was decreased in cells overexpressing PHB. (PMID:19710421)
• stress-induced accumulation of non-ubiquitinated p53 in the cytoplasm promotes interaction with importin-alpha3 and rapid import (PMID:19927155)
• The papillomavirus E2 proteins preferentially interacted with alpha importins 3 and 5, and showed very weak or no interaction with the other three widely expressed alpha importins (alpha1, alpha 4, and alpha 7). (PMID:20193720)
• Impalpha3 is an HIV integrase-interacting cofactor and is required for efficient HIV-1 nuclear import and replication. (PMID:20554775)
• Importin alpha3/Qip1 is involved in multiplication of mutant influenza virus with alanine mutation at amino acid 9 independently of nuclear transport function. (PMID:23383277)
• upon DNA damage transport adaptor importin-alpha4 imports XPA into the nucleus in an ATR-dependent manner. (PMID:23861882)
• miR-223 downregulation promotes glomerular endothelial cell activation by upregulating importin alpha4 and alpha5 in IgA nephropathy (PMID:24284509)
• Karyopherin alpha 3 and karyopherin alpha 4 proteins mediate the nuclear import of methyl-CpG binding protein 2. (PMID:26245896)
• Our results showed that miR-181 family expression was closely correlated with TCGA subtypes and patients’ overall survival, indicating that miR-181b. (PMID:26283154)
• Our results suggest a potential role of Hsa-miR-567 as a novel prognostic biomarker for BC and as regulator of KPNA4. (PMID:28000015)
• These results suggest that the Japanese encephalitis virus NS5 inhibits the induction of type I interferon by targeting KPNA3 and KPNA4. (PMID:28179530)
• Development of a pipeline for automated, high-throughput analysis of PSPC1 paraspeckle protein isoforms reveals specific roles for KPNA2, KPNA4 and KPNA6 proteins. (PMID:28240251)
• Importin alpha3 facilitates the nuclear transport of the Ran guanine nucleotide exchange factor RCC1. (PMID:29042532)
• miR-3619-5p inhibited cell proliferation and cisplatin resistance of cutaneous squamous cell carcinoma (CSCC) by regulating KPNA4 expression, suggesting that miR-3619-5p/KPNA4 pathway may represent a potential promising strategy for the treatment of patients with CSCC. (PMID:30967266)
• Disease-specific alteration of karyopherin-alpha subtype establishes feed-forward oncogenic signaling in head and neck squamous cell carcinoma. (PMID:31822798)
• STAT3-induced upregulation of circCCDC66 facilitates the progression of non-small cell lung cancer by targeting miR-33a-5p/KPNA4 axis. (PMID:32151944)
• Human importin alpha3 and its N-terminal truncated form, without the importin-beta-binding domain, are oligomeric species with a low conformational stability in solution. (PMID:32234409)
• A Phosphorylation-Induced Switch in the Nuclear Localization Sequence of the Intrinsically Disordered NUPR1 Hampers Binding to Importin. (PMID:32933064)
• KPNA4 regulated by miR-548b-3p promotes the malignant phenotypes of papillary thyroid cancer. (PMID:33188837)
• Value of KPNA4 as a diagnostic and prognostic biomarker for hepatocellular carcinoma. (PMID:33535183)
• LINC00467 facilitates osteosarcoma progression by sponging miR217 to regulate KPNA4 expression. (PMID:33537823)
• KPNA4 is involved in cataract formation via the nuclear import of p53. (PMID:33798680)
• The nuclear localization sequence of the epigenetic factor RYBP binds to human importin alpha3. (PMID:33945888)
• Ginsenoside Rg3 inhibits osteosarcoma progression by reducing circ_0003074 expression in a miR-516b-5p/KPNA4-dependent manner. (PMID:34930332)
• Circular RNA hsa_circ_0008003 promotes the progression of non-small-cell lung cancer by sponging miR-548I and regulating KPNA4 expression. (PMID:36573325)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	kpna4	ENSDARG00000023190
mus_musculus	Kpna4	ENSMUSG00000027782
rattus_norvegicus	Kpna4	ENSRNOG00000010768
drosophila_melanogaster	Kap-alpha3	FBGN0027338
drosophila_melanogaster	alphaKap4	FBGN0035657
caenorhabditis_elegans		WBGENE00002074

Paralogs (6): KPNA6 (ENSG00000025800), KPNA3 (ENSG00000102753), KPNA1 (ENSG00000114030), KPNA2 (ENSG00000182481), KPNA7 (ENSG00000185467), KPNA5 (ENSG00000196911)

Protein

Protein identifiers

Importin subunit alpha-3 — O00629 (reviewed: O00629)

Alternative names: Importin alpha Q1, Karyopherin subunit alpha-4

All UniProt accessions (6): A0A7I2V333, A0A7I2V340, A0A7I2V5X0, A0A7I2YQ95, O00629, H7C4F6

UniProt curated annotations — full annotation on UniProt →

Function. Functions in nuclear protein import as an adapter protein for nuclear receptor KPNB1. Binds specifically and directly to substrates containing either a simple or bipartite NLS motif. Docking of the importin/substrate complex to the nuclear pore complex (NPC) is mediated by KPNB1 through binding to nucleoporin FxFG repeats and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to importin-beta and the three components separate and importin-alpha and -beta are re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran from importin. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. Mediates nuclear import of AARS1, MRTFA and RANBP3. (Microbial infection) In vitro, mediates the nuclear import of human cytomegalovirus UL84 by recognizing a non-classical NLS. In vitro, mediates the nuclear import of human cytomegalovirus UL84 by recognizing a non-classical NLS.

Subunit / interactions. Forms a complex with importin subunit beta-1 (KPNB1). Interacts with SNAI1. Interacts with TALDO1 isoform 1. Interacts with CYB1. (Microbial infection) Interacts with MERS virus protein OF4b; this interaction prevents the translocation of NF-kappa-B complex to the nucleus. (Microbial infection) Interacts with human adenovirus 5 E1A protein; this interaction allows E1A import into the host nucleus. (Microbial infection) Interacts with Chikungunya virus capsid protein; this interaction allows the nuclear import of the viral capsid protein.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Highly expressed in testis, ovary, small intestine, heart, skeletal muscle, lung and pancreas, but barely detectable in kidney, thymus, colon and peripheral blood leukocytes.

Domain organisation. Consists of an N-terminal hydrophilic region, a hydrophobic central region composed of 10 repeats, and a short hydrophilic C-terminus. The N-terminal hydrophilic region contains the importin beta binding domain (IBB domain), which is sufficient for binding importin beta and essential for nuclear protein import. The IBB domain is thought to act as an intrasteric autoregulatory sequence by interacting with the internal autoinhibitory NLS. Binding of KPNB1 probably overlaps the internal NLS and contributes to a high affinity for cytoplasmic NLS-containing cargo substrates. After dissociation of the importin/substrate complex in the nucleus the internal autohibitory NLS contributes to a low affinity for nuclear NLS-containing proteins. The major and minor NLS binding sites are mainly involved in recognition of simple or bipartite NLS motifs. Structurally located within in a helical surface groove they contain several conserved Trp and Asn residues of the corresponding third helices (H3) of ARM repeats which mainly contribute to binding.

Similarity. Belongs to the importin alpha family.

RefSeq proteins (1): NP_002259* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000225	Armadillo	Repeat
IPR002652	Importin-a_IBB	Domain
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR024931	Importin_alpha	Family
IPR032413	Arm_3	Repeat
IPR036975	Importin-a_IBB_sf	Homologous_superfamily

Pfam: PF00514, PF01749, PF16186

UniProt features (57 total): helix 31, repeat 10, strand 4, turn 3, region of interest 2, modified residue 2, initiator methionine 1, chain 1, short sequence motif 1, sequence conflict 1, domain 1

Structure

Experimental structures (PDB)

17 structures.

PDB	Method	Resolution (Å)
6BW9	X-RAY DIFFRACTION	1.6
8HKW	X-RAY DIFFRACTION	1.9
7LFC	X-RAY DIFFRACTION	2.1
7RG5	X-RAY DIFFRACTION	2.15
6BWA	X-RAY DIFFRACTION	2.2
6BVV	X-RAY DIFFRACTION	2.3
6BVZ	X-RAY DIFFRACTION	2.3
6BWB	X-RAY DIFFRACTION	2.3
6WX8	X-RAY DIFFRACTION	2.3
7RFY	X-RAY DIFFRACTION	2.5
7JJL	X-RAY DIFFRACTION	2.6
4UAE	X-RAY DIFFRACTION	2.7
8FUB	X-RAY DIFFRACTION	2.75
7LF4	X-RAY DIFFRACTION	2.85
5XZX	X-RAY DIFFRACTION	3
8FZM	X-RAY DIFFRACTION	3
5TBK	X-RAY DIFFRACTION	3.45

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00629-F1	85.67	0.75

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 (2): 2, 60

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-1169408	ISG15 antiviral mechanism
R-HSA-168276	NS1 Mediated Effects on Host Pathways
R-HSA-9918432	Maturation of DENV proteins
R-HSA-1169410	Antimicrobial mechanism of IFN-stimulated genes
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1643685	Disease
R-HSA-168255	Influenza Infection
R-HSA-168256	Immune System
R-HSA-5663205	Infectious disease
R-HSA-913531	Interferon Signaling
R-HSA-9824446	Viral Infection Pathways

MSigDB gene sets: 0 (showing top):

GO Biological Process (7): protein import into nucleus (GO:0006606), NLS-bearing protein import into nucleus (GO:0006607), response to hydrogen peroxide (GO:0042542), gene expression (GO:0010467), dopamine secretion (GO:0014046), protein transport (GO:0015031), positive regulation of hippo signaling (GO:0035332)

GO Molecular Function (3): nuclear localization sequence binding (GO:0008139), nuclear import signal receptor activity (GO:0061608), protein binding (GO:0005515)

GO Cellular Component (8): male germ cell nucleus (GO:0001673), nucleus (GO:0005634), nuclear pore (GO:0005643), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), nuclear membrane (GO:0031965), NLS-dependent protein nuclear import complex (GO:0042564)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Antimicrobial mechanism of IFN-stimulated genes	1
Influenza Infection	1
Dengue Virus Genome Translation and Replication	1
Interferon Signaling	1
Immune System	1
Viral Infection Pathways	1
Disease	1
Cytokine Signaling in Immune system	1
Infectious disease	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
import into nucleus	2
nuclear envelope	2
intracellular protein transport	1
protein localization to nucleus	1
establishment of protein localization to organelle	1
protein import into nucleus	1
response to reactive oxygen species	1
macromolecule biosynthetic process	1
signal release	1
catecholamine secretion	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
hippo signaling	1
regulation of hippo signaling	1
positive regulation of intracellular signal transduction	1
signal sequence receptor activity	1
nucleocytoplasmic carrier activity	1
binding	1
germ cell nucleus	1
intracellular membrane-bounded organelle	1
nuclear protein-containing complex	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
nucleus	1
organelle membrane	1
nucleocytoplasmic transport complex	1

Protein interactions and networks

STRING

3456 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KPNA4	RCC1	P18754	939
KPNA4	KPNB1	Q14974	886
KPNA4	PHGDH	O43175	849
KPNA4	HNRNPK	P61978	819
KPNA4	CSE1L	P55060	727
KPNA4	RECQL	P46063	714
KPNA4	STAT3	P40763	697
KPNA4	RANGAP1	P46060	643
KPNA4	NUPR1	O60356	642
KPNA4	NUP50	Q9UKX7	637
KPNA4	XPO1	O14980	593
KPNA4	TNPO1	Q92973	583
KPNA4	STAT1	P42224	552
KPNA4	TNPO3	Q9Y5L0	548
KPNA4	TNP2	Q05952	548

IntAct

305 interactions, top by confidence:

A	B	Type	Score
KPNA4	HNRNPC	psi-mi:“MI:0915”(physical association)	0.830
NUP50	KPNA4	psi-mi:“MI:0915”(physical association)	0.830
KPNA4	NUP50	psi-mi:“MI:0915”(physical association)	0.830
HNRNPC	KPNA4	psi-mi:“MI:0915”(physical association)	0.830
KPNB1	KPNA4	psi-mi:“MI:0407”(direct interaction)	0.800
KPNA4	MYC	psi-mi:“MI:0407”(direct interaction)	0.780
KPNA4	MYC	psi-mi:“MI:0915”(physical association)	0.780
KPNA4	NCBP3	psi-mi:“MI:0915”(physical association)	0.740
KPNA4	NCOR2	psi-mi:“MI:0407”(direct interaction)	0.740

BioGRID (324): KPNA4 (Two-hybrid), PLAA (Two-hybrid), NUP50 (Two-hybrid), MAT2B (Two-hybrid), CYHR1 (Two-hybrid), KPNA4 (Affinity Capture-MS), KPNA4 (Affinity Capture-MS), KPNA4 (Affinity Capture-MS), KPNA4 (Affinity Capture-MS), KPNA4 (Affinity Capture-MS), KPNA4 (Affinity Capture-RNA), ACTR1A (Co-fractionation), ACTR1B (Co-fractionation), CANX (Co-fractionation), CLGN (Co-fractionation)

ESM2 similar proteins: A2BFL2, A9QM74, B6HJ92, B8ARW2, B9FDR3, C0LLJ0, C1JZ66, C6K7I2, F4JL11, G5EB89, O00505, O00629, O04294, O14063, O14089, O22478, O35343, O35344, O43747, O60518, O75843, O80480, O88512, O94374, P22892, P52170, P52171, P52292, P52293, P52295, P91276, Q02821, Q19969, Q23924, Q557F4, Q5R5M2, Q5RAG3, Q6DGR4, Q71VM4, Q76P29

Diamond homologs: A2VE08, A9QM74, B6HJ92, C0LLJ0, C1JZ66, C6K7I2, F4JL11, G5EB89, O00505, O00629, O04294, O14063, O15131, O22478, O35343, O35344, O35345, O60684, O80480, O94374, P52170, P52171, P52292, P52293, P52294, P52295, P83953, P91276, Q02821, Q0V7M0, Q19969, Q503E9, Q557F4, Q56R16, Q5R909, Q5RBV0, Q5ZML1, Q60960, Q71VM4, Q76P29

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
KPNA4	up-regulates	NOTCH1	relocalization
KPNA4	up-regulates	NOTCH	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 120 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
Nuclear import of Rev protein	8	37.9×	2e-08
Transport of the SLBP independent Mature mRNA	6	27.6×	8e-06
Transport of the SLBP Dependant Mature mRNA	6	26.8×	8e-06
Rev-mediated nuclear export of HIV RNA	6	26.8×	8e-06
Transport of Ribonucleoproteins into the Host Nucleus	5	25.1×	8e-05
NEP/NS2 Interacts with the Cellular Export Machinery	5	24.4×	8e-05
NS1 Mediated Effects on Host Pathways	6	24.1×	1e-05
Transport of Mature mRNA Derived from an Intronless Transcript	6	23.0×	1e-05

GO biological processes:

GO term	Partners	Fold	FDR
protein import into nucleus	11	17.0×	5e-08
mRNA export from nucleus	5	15.9×	2e-03
positive regulation of miRNA transcription	5	15.6×	2e-03
mRNA transport	5	14.2×	2e-03
RNA splicing	10	9.5×	4e-05
mRNA splicing, via spliceosome	8	7.9×	1e-03
chromatin organization	6	6.4×	1e-02
chromatin remodeling	8	6.3×	3e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	19
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2228 predictions. Top by Δscore:

Variant	Effect	Δscore
3:160502086:AACTT:A	donor_gain	1.0000
3:160502087:A:C	donor_gain	1.0000
3:160502090:T:TA	donor_gain	1.0000
3:160502199:CAAT:C	acceptor_gain	1.0000
3:160502200:AATC:A	acceptor_loss	1.0000
3:160502201:ATC:A	acceptor_loss	1.0000
3:160502202:TCT:T	acceptor_loss	1.0000
3:160502203:C:CA	acceptor_loss	1.0000
3:160502204:T:A	acceptor_loss	1.0000
3:160504956:A:AC	donor_gain	1.0000
3:160504957:C:CC	donor_gain	1.0000
3:160504957:CAT:C	donor_gain	1.0000
3:160504959:T:TA	donor_gain	1.0000
3:160504962:T:C	donor_gain	1.0000
3:160505049:AGCCC:A	acceptor_loss	1.0000
3:160505053:CTGCA:C	acceptor_loss	1.0000
3:160505054:T:A	acceptor_loss	1.0000
3:160508102:CTTA:C	donor_loss	1.0000
3:160508103:TTACC:T	donor_loss	1.0000
3:160508104:TACCT:T	donor_loss	1.0000
3:160508105:A:AC	donor_gain	1.0000
3:160508105:AC:A	donor_gain	1.0000
3:160508105:ACCT:A	donor_gain	1.0000
3:160508105:ACCTC:A	donor_gain	1.0000
3:160508106:C:CG	donor_gain	1.0000
3:160508106:CC:C	donor_gain	1.0000
3:160508106:CCT:C	donor_gain	1.0000
3:160508106:CCTC:C	donor_gain	1.0000
3:160508106:CCTCC:C	donor_gain	1.0000
3:160508265:GCCAC:G	acceptor_gain	1.0000

AlphaMissense

3464 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:160504995:G:T	A477D	1.000
3:160504996:C:G	A477P	1.000
3:160505031:A:G	L465P	1.000
3:160505052:C:T	G458E	1.000
3:160508107:C:A	G458W	1.000
3:160508107:C:G	G458R	1.000
3:160508107:C:T	G458R	1.000
3:160508175:A:G	L435P	1.000
3:160508178:C:T	G434E	1.000
3:160508179:C:G	G434R	1.000
3:160508179:C:T	G434R	1.000
3:160508184:A:G	L432P	1.000
3:160508184:A:T	L432H	1.000
3:160508220:A:G	L420P	1.000
3:160508228:G:C	C417W	1.000
3:160509813:C:T	G399E	1.000
3:160509827:G:C	N394K	1.000
3:160509827:G:T	N394K	1.000
3:160509828:T:A	N394I	1.000
3:160509829:T:C	N394D	1.000
3:160509830:A:C	S393R	1.000
3:160509830:A:T	S393R	1.000
3:160509832:T:G	S393R	1.000
3:160509834:A:T	I392K	1.000
3:160509837:G:T	A391D	1.000
3:160509838:C:G	A391P	1.000
3:160509839:C:A	W390C	1.000
3:160509839:C:G	W390C	1.000
3:160509841:A:G	W390R	1.000
3:160509841:A:T	W390R	1.000

dbSNP variants (sampled 300 via entrez): RS1000050200 (3:160555712 T>A,G), RS1000078123 (3:160545774 A>C,G), RS1000082153 (3:160555434 T>A,C), RS1000135434 (3:160529093 T>G), RS1000168920 (3:160548658 C>T), RS1000220915 (3:160548966 T>C,G), RS1000232016 (3:160498451 A>G), RS1000295577 (3:160526284 A>G), RS1000340991 (3:160499380 G>A,C), RS1000435584 (3:160499175 G>A,C), RS1000437795 (3:160525713 G>C,T), RS1000466920 (3:160532384 T>C), RS1000499484 (3:160532041 C>T), RS1000565821 (3:160506216 T>A), RS1000649865 (3:160525619 T>C)

Disease associations

OMIM: gene MIM:602970 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder	Limited	Autosomal dominant

Mondo (1): neurodevelopmental disorder (MONDO:0700092)

Orphanet (0):

HPO phenotypes

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

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST002358_13	Pit-and-Fissure caries	2.000000e-09
GCST002361_21	Smooth-surface caries	3.000000e-06
GCST003262_521	Post bronchodilator FEV1	6.000000e-07
GCST003264_501	Post bronchodilator FEV1/FVC ratio	3.000000e-06
GCST006614_129	Total cholesterol levels	7.000000e-14
GCST006716_3	Alcohol use disorder (total score)	2.000000e-08
GCST008103_105	Bipolar disorder	4.000000e-06
GCST010291_4	Attention deficit hyperactivity disorder	5.000000e-08
GCST010725_1	Malaria	3.000000e-09
GCST010725_57	Malaria	2.000000e-08
GCST010725_87	Malaria	3.000000e-09
GCST90000032_3	Myeloproliferative neoplasms	4.000000e-10
GCST90011898_155	Alanine aminotransferase levels	8.000000e-14
GCST90011899_119	Aspartate aminotransferase levels	2.000000e-09

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004314	forced expiratory volume
EFO:0004713	FEV/FVC ratio
EFO:0004574	total cholesterol measurement
EFO:0009458	alcohol use disorder measurement
EFO:0004251	myeloproliferative disorder
EFO:0004736	aspartate aminotransferase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067058 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.57	Kd	27.04	nM	CHEMBL5653589
7.51	ED50	31	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148727: Binding affinity to human KPNA4 incubated for 45 mins by Kinobead based pull down assay	kd	0.0270	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression	2
Acetaminophen	increases expression	2
Calcitriol	decreases expression	2
Ivermectin	affects binding, decreases reaction, decreases expression	2
Nickel	increases expression	2
Valproic Acid	decreases expression, increases methylation	2
1-Methyl-4-phenylpyridinium	decreases reaction, increases phosphorylation, affects reaction, decreases expression, increases cleavage (+2 more)	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
FR900359	increases phosphorylation	1
triphenyl phosphate	affects expression	1
deoxynivalenol	increases expression	1
lead acetate	increases expression	1
decabromobiphenyl ether	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
nickel chloride	increases expression	1
ferrous chloride	increases expression	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, decreases expression	1
cupric chloride	increases expression	1
microcystin RR	increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
dimethylarsinous acid	increases expression	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
(4-amino-1,4-dihydro-3-(2-pyridyl)-5-thioxo-1,2,4-triazole)copper(II)	increases expression	1
hexabrominated diphenyl ether 153	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651769	Binding	Binding affinity to human KPNA4 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice