KPNA1

Summary

KPNA1 (karyopherin subunit alpha 1, HGNC:6394) is a protein-coding gene on chromosome 3q21.1, encoding Importin subunit alpha-5 (P52294). Functions in nuclear protein import as an adapter protein for nuclear receptor KPNB1.

The transport of molecules between the nucleus and the cytoplasm in eukaryotic cells is mediated by the nuclear pore complex (NPC), which consists of 60-100 proteins. Small molecules (up to 70 kD) can pass through the nuclear pore by nonselective diffusion while larger molecules are transported by an active process. The protein encoded by this gene belongs to the importin alpha family, and is involved in nuclear protein import. This protein interacts with the recombination activating gene 1 (RAG1) protein and is a putative substrate of the RAG1 ubiquitin ligase. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 3836 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 56 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002264

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6394
Approved symbol	KPNA1
Name	karyopherin subunit alpha 1
Location	3q21.1
Locus type	gene with protein product
Status	Approved
Aliases	SRP1, RCH2, NPI-1, IPOA5
Ensembl gene	ENSG00000114030
Ensembl biotype	protein_coding
OMIM	600686
Entrez	3836

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 12 protein_coding, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000344337, ENST00000464940, ENST00000465882, ENST00000466923, ENST00000470904, ENST00000476916, ENST00000482287, ENST00000485027, ENST00000493510, ENST00000494339, ENST00000896477, ENST00000896478, ENST00000911570, ENST00000911571, ENST00000962533, ENST00000962534, ENST00000962535

RefSeq mRNA: 1 — MANE Select: NM_002264 NM_002264

CCDS: CCDS3013

Canonical transcript exons

ENST00000344337 — 14 exons

Exon	Start	End
ENSE00001078786	122467322	122467429
ENSE00001154752	122421902	122427172
ENSE00001370231	122496437	122496570
ENSE00001856631	122514757	122514939
ENSE00003474517	122449574	122449737
ENSE00003477753	122437170	122437295
ENSE00003499936	122451534	122451633
ENSE00003530538	122427538	122427716
ENSE00003536212	122442038	122442116
ENSE00003601880	122433661	122433788
ENSE00003670810	122451976	122452064
ENSE00003678133	122461224	122461318
ENSE00003680015	122453870	122454001
ENSE00003690289	122463942	122464041

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 97.60.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 64.2900 / max 558.2466, expressed in 1828 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
44131	63.8958	1828
44130	0.3942	171

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
gluteal muscle	UBERON:0002000	97.60	gold quality
biceps brachii	UBERON:0001507	96.30	gold quality
sural nerve	UBERON:0015488	96.06	gold quality
deltoid	UBERON:0001476	95.75	gold quality
gastrocnemius	UBERON:0001388	95.58	gold quality
endothelial cell	CL:0000115	95.55	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	95.53	gold quality
skeletal muscle tissue	UBERON:0001134	95.38	gold quality
muscle of leg	UBERON:0001383	95.31	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	95.19	gold quality
muscle organ	UBERON:0001630	94.86	gold quality
triceps brachii	UBERON:0001509	94.79	gold quality
tibialis anterior	UBERON:0001385	94.45	gold quality
muscle tissue	UBERON:0002385	94.43	gold quality
islet of Langerhans	UBERON:0000006	94.30	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.79	gold quality
diaphragm	UBERON:0001103	93.78	silver quality
adrenal tissue	UBERON:0018303	93.77	gold quality
colonic epithelium	UBERON:0000397	93.71	gold quality
vastus lateralis	UBERON:0001379	92.83	gold quality
heart right ventricle	UBERON:0002080	92.15	gold quality
quadriceps femoris	UBERON:0001377	92.08	gold quality
cortical plate	UBERON:0005343	91.92	gold quality
smooth muscle tissue	UBERON:0001135	91.61	gold quality
monocyte	CL:0000576	91.32	gold quality
pancreatic ductal cell	CL:0002079	91.20	gold quality
stromal cell of endometrium	CL:0002255	91.16	gold quality
mononuclear cell	CL:0000842	90.86	gold quality
leukocyte	CL:0000738	90.73	gold quality
left ventricle myocardium	UBERON:0006566	90.33	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.25

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): SRF

miRNA regulators (miRDB)

322 targeting KPNA1, 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-3613-3P	100.00	76.36	7965
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-1193	100.00	65.93	529
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-12136	99.98	72.81	5713
HSA-LET-7A-5P	99.98	72.29	1790

Literature-anchored findings (GeneRIF, showing 35)

• arginine/lysine-rich nuclear localization signals mediate interactions between dimeric STATs and importin alpha 5 (PMID:12048190)
• one importin alpha molecule is able to use either its N- or C-terminal arm repeats for binding various NLS containing proteins (PMID:12740372)
• Importin alpha5 and alpha7 bind to Stat3 upon cytokine stimulation. (PMID:16298512)
• the karyopherin alpha NPI-1, a nuclear import adaptor, bound more strongly to Epstein-Barr virus nuclear antigen 1 Ser385-phosphorylated nuclear localization signal than to any other phosphorylated or nonphosphorylated forms (PMID:16439554)
• Here, VP24 is demonstrated to interact with endogenous karyopherin alpha1 and inhibits its interaction with STAT1. (PMID:17928350)
• importins alpha5 and beta1 associate with Nrf2, an interaction that was blocked by the nuclear import inhibitor SN50 (PMID:18238777)
• NPI-1 subfamily accumulates in the nucleus in response to oxidative stress, like importin alpha1/Rch1. (PMID:18707546)
• significant KPNA1-, NLRP1- and NLRP3-gene expression phenotypes associated with human genotypes of Crohn’s disease, Huntington’s disease and rheumatoid arthritis (PMID:19001869)
• PB2 interaction with alpha-importins is required for virus RNA replication. (PMID:19066626)
• Karyopherin alpha 1 is a putative substrate of the RAG1 ubiquitin ligase. (PMID:19118899)
• The VP24 IFN antagonist function of ebolavirus requires the ability of VP24 to interact with KPNalpha. (PMID:19889762)
• 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)
• Study identified the sequences KKKRR, KKKRK, and KKRKK as the optimal sequences for binding to this site for mouse importin-alpha2, human importin-alpha1, and human importin-alpha5, respectively. (PMID:20406804)
• Impalpha5 acts as a chaperone until Influenza a virus nucleoprotein (NP) is delivered in the nucleus for viral RNA encapsidation. (PMID:20974480)
• The mammalian E1 subunits can be imported separately, identify nuclear localization signals (NLSs) in Aos1 and in Uba2, and demonstrate that their import is mediated by importin alpha/beta in vitro and in intact cells. (PMID:21209321)
• This study reports the identification and classification of importin alpha 5 -interacting proteins in brain cells. (PMID:21307607)
• The ability of hnRNP C1/C2 to bind KPNA1 is diminished in the presence of VP24, and cells transiently expressing VP24 redistribute hnRNP C1/C2 from the nucleus to the cytoplasm. (PMID:21987768)
• the requirement for and the regulation of CAS in the functioning of the Vpr-Impalpha complex (PMID:22110766)
• Nucleoporin Nup50 stabilizes closed conformation of armadillo repeat 10 in importin alpha5. (PMID:22130666)
• LRRC59 facilitates transport of cytosolic FGF1 through nuclear pores by interaction with Kpns and movement of LRRC59 along the ER and NE membranes (PMID:22321063)
• mTOR and protein phosphatase 2A catalytically control the constitutive nuclear import of latent STAT1 by KPNA1, which are key modulators of STAT1 expression and apoptosis. (PMID:22399302)
• This supports the notion that de novo mutations KPNA1 in are extremely rare in schizophrenia (PMID:23425335)
• Results indicate CTNNBL1 as a unique selective nuclear localization signals (NLSs)-binding protein with striking differences from karyopherin-alphas. (PMID:24269683)
• miR-223 downregulation promotes glomerular endothelial cell activation by upregulating importin alpha4 and alpha5 in IgA nephropathy (PMID:24284509)
• Bel1 fragment with residues 215-223, which bears the NLS, interacts with KPNA1, KPNA6, and KPNA7. (PMID:25272585)
• BIG3 may block the KPNAs (KPNA1, KPNA5, and KPNA6) binding region(s) of PHB2. (PMID:26052702)
• Data show that cytoskeleton associated protein 5 (chTOG) only weakly promotes importin-regulated microtubule nucleation, but acts synergistically with TPX2 protein. (PMID:26414402)
• Data suggest that EV71 infection in enterocytes does not inhibit phosphorylation of STAT1/2 induced by IFN-beta, but p-STAT1/2 transport into the nucleus is significantly blocked; EV71 infection in enterocytes down-regulates expression of KPNA1 and induces degradation of cellular KPNA1 via caspase-3. [EV17 = Enterovirus 71] (PMID:28455446)
• Karyoppherins constitute integral constituents of the nuclear pore complex whose barrier, transport, and cargo release functionalities establish a continuum under a mechanism of Kap-centric control. (PMID:28864541)
• Importin alpha1 is specifically required for the nuclear localization of several important HSV1 proteins, capsid assembly, and capsid egress into the cytoplasm, and may become rate limiting in situ upon infection at low multiplicity or in terminally differentiated cells such as neurons. (PMID:29304174)
• Antivirals that target the host IMPalpha/beta1-virus interface. (PMID:33439253)
• Structural and calorimetric studies reveal specific determinants for the binding of a high-affinity NLS to mammalian importin-alpha. (PMID:34195786)
• KPNA1 regulates nuclear import of NCOR2 splice variant BQ323636.1 to confer tamoxifen resistance in breast cancer. (PMID:34709749)
• Decreased Expression of Karyopherin-alpha 1 is Related to the Malignant Degree of Cervical Cancer and is Critical for the Proliferation of Hela Cells. (PMID:35991835)
• Karyopherin Subunit Alpha 1 Enhances the Malignant Behaviors of Colon Cancer Cells via Promoting Nuclear Factor-kappaB p65 Nuclear Translocation. (PMID:37038032)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	kpna1	ENSDARG00000016360
mus_musculus	Kpna1	ENSMUSG00000022905
rattus_norvegicus	Kpna1	ENSRNOG00000051711
drosophila_melanogaster	Kap-alpha1	FBGN0024889

Paralogs (6): KPNA6 (ENSG00000025800), KPNA3 (ENSG00000102753), KPNA2 (ENSG00000182481), KPNA7 (ENSG00000185467), KPNA4 (ENSG00000186432), KPNA5 (ENSG00000196911)

Protein

Protein identifiers

Importin subunit alpha-5 — P52294 (reviewed: P52294)

Alternative names: Karyopherin subunit alpha-1, Nucleoprotein interactor 1, RAG cohort protein 2, SRP1-beta

All UniProt accessions (6): C9J352, C9J4U1, C9JWD9, P52294, C9JYI4, F2Z3G4

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. Mediator of PR-DUB complex component BAP1 nuclear import; acts redundantly with KPNA2 and Transportin-1/TNPO1. (Microbial infection) In vitro, mediates the nuclear import of human cytomegalovirus UL84 by recognizing a non-classical NLS.

Subunit / interactions. Heterodimer; with KPNB1. Interacts with ANP32E. Interacts with ZIC3. Interacts with NSMF; the interaction occurs in a calcium-independent manner after synaptic NMDA receptor stimulation and is required for nuclear import of NSMF but is competed by CABP1. Interacts with APEX1. Interacts with RAG1. Interacts with CTNNBL1 (via its N-terminal). Interacts with AICDA (via its NLS). Interacts with SNAI1 (via zinc fingers). Interacts with DCAF8. Interacts with ITSN1 isoform 2. Interacts with TALDO1 isoform 1. Interacts with the AMPK-mediated ‘Ser-659’ phosphorylated form of ACSS2; this interaction results in nuclear translocation of ACSS2. Interacts with BAP1 (via C-terminus); the interaction contributes to BAP1 nuclear localization. (Microbial infection) Interacts with human cytomegalovirus/HCMV UL84. (Microbial infection) Interacts with HIV-1 Vpr. (Microbial infection) Interacts with ebolavirus protein VP24. (Microbial infection) Interacts with the venezuelan equine encephalitis virus protease nsP2; this interaction probably allows the active transport of protease nsP2 into the host nucleus. (Microbial infection) Interacts with Epstein-Barr virus EBNA1; this interaction allows the nuclear import of EBNA1. (Microbial infection) Interacts with human parainfluenza virus type 2 proteins P and V.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Expressed ubiquitously.

Post-translational modifications. Polyubiquitinated in the presence of RAG1 (in vitro).

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_002255* (*=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 (64 total): helix 31, repeat 10, region of interest 4, modified residue 4, strand 4, chain 2, sequence conflict 2, turn 2, initiator methionine 1, short sequence motif 1, compositionally biased region 1, sequence variant 1, domain 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
2JDQ	X-RAY DIFFRACTION	2.2
4B18	X-RAY DIFFRACTION	2.52
3TJ3	X-RAY DIFFRACTION	2.7
6WX9	X-RAY DIFFRACTION	2.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P52294-F1	85.95	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 (4): 1, 2, 3, 63

Function

Pathways and Gene Ontology

Reactome pathways

33 pathways

ID	Pathway
R-HSA-1169408	ISG15 antiviral mechanism
R-HSA-140342	Apoptosis induced DNA fragmentation
R-HSA-162592	Integration of provirus
R-HSA-168271	Transport of Ribonucleoproteins into the Host Nucleus
R-HSA-168276	NS1 Mediated Effects on Host Pathways
R-HSA-180910	Vpr-mediated nuclear import of PICs
R-HSA-68616	Assembly of the ORC complex at the origin of replication
R-HSA-909733	Interferon alpha/beta signaling
R-HSA-9636249	Inhibition of nitric oxide production
R-HSA-9918432	Maturation of DENV proteins
R-HSA-109581	Apoptosis
R-HSA-1169410	Antimicrobial mechanism of IFN-stimulated genes
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-162587	HIV Life Cycle
R-HSA-162594	Early Phase of HIV Life Cycle
R-HSA-162906	HIV Infection
R-HSA-162909	Host Interactions of HIV factors
R-HSA-1643685	Disease
R-HSA-168255	Influenza Infection
R-HSA-168256	Immune System
R-HSA-176033	Interactions of Vpr with host cellular proteins
R-HSA-5357801	Programmed Cell Death
R-HSA-5663205	Infectious disease
R-HSA-68867	Assembly of the pre-replicative complex
R-HSA-69002	DNA Replication Pre-Initiation
R-HSA-69306	DNA Replication
R-HSA-75153	Apoptotic execution phase
R-HSA-913531	Interferon Signaling
R-HSA-9635486	Infection with Mycobacterium tuberculosis
R-HSA-9637687	Suppression of phagosomal maturation

MSigDB gene sets: 319 (showing top): REACTOME_DNA_REPLICATION, ELVIDGE_HYPOXIA_DN, REACTOME_APOPTOSIS_INDUCED_DNA_FRAGMENTATION, GOBP_REGULATION_OF_DNA_RECOMBINATION, REACTOME_INTERACTIONS_OF_VPR_WITH_HOST_CELLULAR_PROTEINS, GOBP_SKELETAL_MUSCLE_TISSUE_REGENERATION, REACTOME_INTEGRATION_OF_PROVIRUS, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_GROWTH, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_REGENERATION

GO Biological Process (10): regulation of DNA recombination (GO:0000018), protein import into nucleus (GO:0006606), NLS-bearing protein import into nucleus (GO:0006607), skeletal muscle satellite cell proliferation (GO:0014841), satellite cell activation involved in skeletal muscle regeneration (GO:0014901), regulation of apoptotic process (GO:0042981), regulation of canonical Wnt signaling pathway (GO:0060828), postsynapse to nucleus signaling pathway (GO:0099527), protein transport (GO:0015031), skeletal muscle tissue regeneration (GO:0043403)

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

GO Cellular Component (9): nucleus (GO:0005634), nuclear pore (GO:0005643), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), postsynaptic density (GO:0014069), dendrite (GO:0030425), NLS-dependent protein nuclear import complex (GO:0042564), glutamatergic synapse (GO:0098978)

Reactome top-level categories

Rollup of top-14 pathways:

Category	Pathways
Influenza Infection	2
Interferon Signaling	2
HIV Infection	2
Viral Infection Pathways	2
Antimicrobial mechanism of IFN-stimulated genes	1
Apoptotic execution phase	1
Early Phase of HIV Life Cycle	1
Interactions of Vpr with host cellular proteins	1
Assembly of the pre-replicative complex	1
Suppression of phagosomal maturation	1
Dengue Virus Genome Translation and Replication	1
Programmed Cell Death	1
Immune System	1
HIV Life Cycle	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
import into nucleus	2
DNA recombination	1
regulation of DNA metabolic process	1
intracellular protein transport	1
protein localization to nucleus	1
establishment of protein localization to organelle	1
protein import into nucleus	1
skeletal muscle cell proliferation	1
skeletal muscle satellite cell activation	1
skeletal muscle tissue regeneration	1
apoptotic process	1
regulation of programmed cell death	1
regulation of Wnt signaling pathway	1
canonical Wnt signaling pathway	1
postsynaptic signal transduction	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
tissue regeneration	1
signal sequence receptor activity	1
nucleocytoplasmic carrier activity	1
binding	1
intracellular membrane-bounded organelle	1
nuclear envelope	1
nuclear protein-containing complex	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
asymmetric synapse	1
postsynaptic specialization	1
neuron projection	1
dendritic tree	1
nucleocytoplasmic transport complex	1
synapse	1

Protein interactions and networks

STRING

3506 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KPNA1	STAT1	P42224	993
KPNA1	KPNB1	Q14974	983
KPNA1	CSE1L	P55060	834
KPNA1	RCC1	P18754	803
KPNA1	PHGDH	O43175	796
KPNA1	HNRNPK	P61978	761
KPNA1	STAT2	P52630	739
KPNA1	RAG1	P15918	737
KPNA1	HNRNPC	P07910	724
KPNA1	TOPBP1	Q92547	653
KPNA1	RECQL	P46063	648
KPNA1	NUP98	P52948	644
KPNA1	RELB	Q01201	633
KPNA1	IPO5	O00410	626
KPNA1	XPO1	O14980	622

IntAct

267 interactions, top by confidence:

A	B	Type	Score
KPNA1	NUP50	psi-mi:“MI:0915”(physical association)	0.930
NUP50	KPNA1	psi-mi:“MI:0915”(physical association)	0.930
NOP10	DKC1	psi-mi:“MI:0914”(association)	0.890
CDK8	MED19	psi-mi:“MI:2364”(proximity)	0.850
HNRNPC	KPNA3	psi-mi:“MI:0914”(association)	0.850
KPNA1	ANP32B	psi-mi:“MI:0915”(physical association)	0.840
ANP32B	KPNA1	psi-mi:“MI:0915”(physical association)	0.840
KPNA1	ANP32B	psi-mi:“MI:0403”(colocalization)	0.840
NUP50	KPNA4	psi-mi:“MI:0914”(association)	0.830
KPNA6	RNMT	psi-mi:“MI:0914”(association)	0.800
HDAC1	TNRC18	psi-mi:“MI:0914”(association)	0.790
KPNB1	KPNA1	psi-mi:“MI:0407”(direct interaction)	0.760
TAF9	KPNA1	psi-mi:“MI:0915”(physical association)	0.740
LMNB1	KPNA1	psi-mi:“MI:0915”(physical association)	0.740
KPNA1	POLR3C	psi-mi:“MI:0915”(physical association)	0.740
FBXO28	TRAF5	psi-mi:“MI:0914”(association)	0.740
USP1	PHLPP1	psi-mi:“MI:0914”(association)	0.740
TADA3	TADA2A	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
KPNA1	PB2	psi-mi:“MI:0407”(direct interaction)	0.680

BioGRID (512): TAF9 (Two-hybrid), ANP32B (Two-hybrid), NUP50 (Two-hybrid), CLK4 (Two-hybrid), KPNA1 (Affinity Capture-MS), FANCD2 (Co-fractionation), KPNA1 (Co-fractionation), KPNA1 (Co-fractionation), KPNA1 (Co-fractionation), KPNA1 (Co-fractionation), KPNA1 (Co-fractionation), KPNA1 (Co-fractionation), MORF4L1 (Co-fractionation), MORF4L2 (Co-fractionation), RAN (Co-fractionation)

ESM2 similar proteins: A2VE08, A7Y521, E1C6Q1, O15131, O35116, O35142, O35345, O55029, O60684, O70133, O88544, O94973, P17427, P18484, P26233, P35605, P35606, P52294, P52297, P70188, P83953, Q08211, Q0V7M0, Q0VCK5, Q13098, Q28141, Q3SZA0, Q4R5E6, Q503E9, Q56R16, Q5F418, Q5R648, Q5R664, Q5R874, Q5R909, Q5RBV0, Q5ZHN3, Q5ZML1, Q60960, Q68FK8

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

1 interactions.

A	Effect	B	Mechanism
KPNA1	“up-regulates activity”	KPNB1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 196 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
Regulation of TP53 Activity through Acetylation	8	27.7×	2e-07
Transcriptional regulation of brown and beige adipocyte differentiation by EBF2	8	23.1×	3e-07
Nuclear import of Rev protein	8	20.4×	6e-07
NS1 Mediated Effects on Host Pathways	9	19.5×	2e-07
Transport of the SLBP independent Mature mRNA	7	17.3×	1e-05
Transport of the SLBP Dependant Mature mRNA	7	16.8×	1e-05
Transport of Ribonucleoproteins into the Host Nucleus	6	16.2×	5e-05
NEP/NS2 Interacts with the Cellular Export Machinery	6	15.7×	6e-05

GO biological processes:

GO term	Partners	Fold	FDR
regulation of stem cell differentiation	7	31.0×	3e-07
NLS-bearing protein import into nucleus	6	27.8×	9e-06
regulation of DNA repair	8	12.8×	2e-05
protein import into nucleus	14	11.7×	5e-09
regulation of RNA splicing	9	11.4×	1e-05
nucleocytoplasmic transport	5	11.3×	4e-03
positive regulation of transcription elongation by RNA polymerase II	6	10.4×	2e-03
heterochromatin formation	7	10.3×	4e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	31
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

3030 predictions. Top by Δscore:

Variant	Effect	Δscore
3:122427016:CA:C	donor_gain	1.0000
3:122427168:CAGAC:C	acceptor_gain	1.0000
3:122427172:CCTAA:C	acceptor_loss	1.0000
3:122427173:C:CC	acceptor_gain	1.0000
3:122427173:CTA:C	acceptor_loss	1.0000
3:122427178:A:AC	acceptor_gain	1.0000
3:122427532:TCTTA:T	donor_loss	1.0000
3:122427533:CTTA:C	donor_loss	1.0000
3:122427534:TTACC:T	donor_loss	1.0000
3:122427535:TA:T	donor_loss	1.0000
3:122427536:A:AT	donor_loss	1.0000
3:122427586:T:A	donor_gain	1.0000
3:122427597:T:TA	donor_gain	1.0000
3:122427717:C:CA	acceptor_loss	1.0000
3:122433653:GTACT:G	donor_loss	1.0000
3:122433654:TACTT:T	donor_loss	1.0000
3:122433656:CT:C	donor_loss	1.0000
3:122433657:T:TG	donor_gain	1.0000
3:122433657:TTA:T	donor_loss	1.0000
3:122433658:T:TC	donor_gain	1.0000
3:122433658:TACTT:T	donor_loss	1.0000
3:122433659:A:AC	donor_gain	1.0000
3:122433660:C:CC	donor_gain	1.0000
3:122433660:CT:C	donor_gain	1.0000
3:122433660:CTT:C	donor_gain	1.0000
3:122433660:CTTG:C	donor_gain	1.0000
3:122433660:CTTGA:C	donor_gain	1.0000
3:122433785:CAGT:C	acceptor_gain	1.0000
3:122433789:C:CC	acceptor_gain	1.0000
3:122433789:CT:C	acceptor_loss	1.0000

AlphaMissense

3545 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:122427172:C:T	G477D	1.000
3:122427538:C:G	G477R	1.000
3:122427606:C:T	G454E	1.000
3:122427607:C:G	G454R	1.000
3:122427607:C:T	G454R	1.000
3:122427615:A:G	L451P	1.000
3:122427630:C:T	G446D	1.000
3:122427631:C:G	G446R	1.000
3:122427636:A:G	L444P	1.000
3:122427672:A:G	L432P	1.000
3:122427675:A:G	L431P	1.000
3:122427680:A:C	C429W	1.000
3:122427681:C:T	C429Y	1.000
3:122433679:C:T	G411E	1.000
3:122433691:G:T	A407E	1.000
3:122433692:C:G	A407P	1.000
3:122433693:A:C	N406K	1.000
3:122433693:A:T	N406K	1.000
3:122433695:T:C	N406D	1.000
3:122433703:G:T	A403D	1.000
3:122433704:C:G	A403P	1.000
3:122433705:C:A	W402C	1.000
3:122433705:C:G	W402C	1.000
3:122433707:A:G	W402R	1.000
3:122433707:A:T	W402R	1.000
3:122433709:G:T	A401D	1.000
3:122433712:G:T	A400E	1.000
3:122433713:C:G	A400P	1.000
3:122433714:T:A	E399D	1.000
3:122433714:T:G	E399D	1.000

dbSNP variants (sampled 300 via entrez): RS1000001019 (3:122495428 A>T), RS1000001640 (3:122453260 A>T), RS1000032121 (3:122495056 C>T), RS1000065394 (3:122422702 G>A,C), RS1000091868 (3:122513927 C>A), RS1000130889 (3:122489608 C>A,T), RS1000156795 (3:122462714 C>T), RS1000189609 (3:122443200 G>A), RS1000245835 (3:122489332 C>G,T), RS1000262231 (3:122434737 T>G), RS1000311783 (3:122445763 A>G), RS1000331833 (3:122422945 T>C,G), RS1000332744 (3:122452472 G>A), RS1000341495 (3:122489236 T>C), RS1000392021 (3:122495669 A>G)

Disease associations

OMIM: gene MIM:600686 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST000769_5	Calcium levels	2.000000e-22
GCST004233_33	LDL cholesterol levels	3.000000e-08
GCST006612_8	LDL cholesterol	1.000000e-08
GCST009325_93	Parkinson’s disease or first degree relation to individual with Parkinson’s disease	1.000000e-11
GCST90002390_155	Mean corpuscular hemoglobin	4.000000e-11

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004838	calcium measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004527	mean corpuscular hemoglobin

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724654 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1232461	MOLIBRESIB	2	1,538

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
7.52	IC50	30	nM	MOLIBRESIB
7.22	Kd	60	nM	MOLIBRESIB

PubChem BioAssay actives

2 with measured affinity, of 7 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
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178429: Inhibition of KPNA1 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.0300	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression	4
Calcitriol	decreases expression, increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
FR900359	increases phosphorylation	1
2,4,6-tribromophenol	decreases expression	1
bisphenol A	decreases expression	1
beta-lapachone	increases expression	1
sodium arsenite	increases expression	1
butyraldehyde	decreases expression	1
tetrabromobisphenol A	decreases expression	1
periodate-oxidized adenosine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	affects expression	1
jinfukang	decreases expression	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	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Acetaminophen	decreases expression	1
Arsenic	affects methylation	1
Benzene	increases expression	1
Carbamazepine	affects expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ethyl Methanesulfonate	increases expression	1
Formaldehyde	increases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	increases expression	1

ChEMBL screening assays

7 unique, capped per target: 7 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697159	Binding	Inhibition of KPNA1 (unknown origin) assessed as fold change at 10 uM incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. — Nature

Clinical trials (associated diseases)

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