KPNA3

Summary

KPNA3 (karyopherin subunit alpha 3, HGNC:6396) is a protein-coding gene on chromosome 13q14.2, encoding Importin subunit alpha-4 (O00505). 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.

Source: NCBI Gene 3839 — RefSeq curated summary.

At a glance

• Gene–disease (curated): spastic paraplegia 88, autosomal dominant (Strong, GenCC)
• GWAS associations: 7
• Clinical variants (ClinVar): 75 total — 5 pathogenic, 2 likely-pathogenic
• Phenotypes (HPO): 39
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_002267

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6396
Approved symbol	KPNA3
Name	karyopherin subunit alpha 3
Location	13q14.2
Locus type	gene with protein product
Status	Approved
Aliases	SRP1gamma, SRP4, hSRP1, IPOA4
Ensembl gene	ENSG00000102753
Ensembl biotype	protein_coding
OMIM	601892
Entrez	3839

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 6 protein_coding

ENST00000261667, ENST00000436760, ENST00000912490, ENST00000912491, ENST00000912492, ENST00000950770

RefSeq mRNA: 1 — MANE Select: NM_002267 NM_002267

CCDS: CCDS9421

Canonical transcript exons

ENST00000261667 — 17 exons

Exon	Start	End
ENSE00000682716	49702386	49702480
ENSE00000682718	49705621	49705783
ENSE00000682720	49706098	49706169
ENSE00001296343	49699320	49701898
ENSE00001307048	49792438	49792682
ENSE00001596438	49722477	49722563
ENSE00001600215	49709572	49709700
ENSE00001613452	49710891	49711022
ENSE00001621952	49706268	49706372
ENSE00001629663	49719775	49719819
ENSE00001641720	49732371	49732466
ENSE00001651618	49732747	49732776
ENSE00001676183	49732605	49732657
ENSE00001713340	49746949	49746993
ENSE00001758034	49721955	49722124
ENSE00001778144	49732957	49733046
ENSE00001780462	49725416	49725501

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 99.02.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.0346 / max 237.6272, expressed in 1812 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
137327	22.6099	1806
137329	3.5093	1559
137328	2.2148	1349
137330	1.4351	989
137331	0.2655	112

Top tissues by expression

303 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 rectus abdominis	UBERON:0004511	98.97	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.95	gold quality
deltoid	UBERON:0001476	98.59	gold quality
tibialis anterior	UBERON:0001385	98.34	gold quality
vastus lateralis	UBERON:0001379	98.30	gold quality
gluteal muscle	UBERON:0002000	98.21	gold quality
quadriceps femoris	UBERON:0001377	98.13	gold quality
skeletal muscle tissue	UBERON:0001134	98.08	gold quality
secondary oocyte	CL:0000655	97.90	gold quality
triceps brachii	UBERON:0001509	97.84	gold quality
diaphragm	UBERON:0001103	97.20	gold quality
muscle tissue	UBERON:0002385	97.14	gold quality
body of tongue	UBERON:0011876	97.01	gold quality
muscle organ	UBERON:0001630	96.99	gold quality
hindlimb stylopod muscle	UBERON:0004252	96.99	gold quality
skeletal muscle organ	UBERON:0014892	96.99	gold quality
gastrocnemius	UBERON:0001388	96.73	gold quality
muscle of leg	UBERON:0001383	96.52	gold quality
heart right ventricle	UBERON:0002080	96.28	gold quality
sperm	CL:0000019	95.69	gold quality
myocardium	UBERON:0002349	95.52	gold quality
left ventricle myocardium	UBERON:0006566	95.52	gold quality
ventricular zone	UBERON:0003053	95.13	gold quality
tongue	UBERON:0001723	95.12	gold quality
male germ cell	CL:0000015	95.06	gold quality
bronchial epithelial cell	CL:0002328	94.85	gold quality
CA1 field of hippocampus	UBERON:0003881	94.81	gold quality
cortical plate	UBERON:0005343	94.57	gold quality
cardiac muscle of right atrium	UBERON:0003379	94.55	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.37

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

296 targeting KPNA3, 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-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-3613-3P	100.00	76.36	7965
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4682	100.00	68.89	1258
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-450A-1-3P	100.00	69.33	1837
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-499A-5P	99.98	70.79	1323
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-8068	99.98	73.85	2376

Literature-anchored findings (GeneRIF, showing 10)

• The present study suggests that the KPNA3 may contribute genetically to schizophrenia in a small effect size. (PMID:15882913)
• The present work suggests that the combination of the KPNA3 gene and the KPNB3 gene may increase a genetic risk for schizophrenia. (PMID:16644122)
• SNP rs2273816 is significantly associated with schizophrenia, opiate dependence and alcohol dependence at the genotype and allele level (PMID:22960338)
• Karyopherin alpha 3 and karyopherin alpha 4 proteins mediate the nuclear import of methyl-CpG binding protein 2. (PMID:26245896)
• These results suggest that the Japanese encephalitis virus NS5 inhibits the induction of type I interferon by targeting KPNA3 and KPNA4. (PMID:28179530)
• Studied the role of KPNA3 (karyopherin subunit alpha 3) in nuclear transport of ataxin-3 in spinocerebellar ataxia type 3. (PMID:29476013)
• Increased expression of KPNA3 was observed in colorectal cancer (CRC) along with that of DLEU1 and associated with lower survival rate and poorer prognosis. Its expression is promoted by DLEU1 which recruits SMARCA1 in CRC. (PMID:30098595)
• Dominant KPNA3 Mutations Cause Infantile-Onset Hereditary Spastic Paraplegia. (PMID:34564892)
• KPNA3 promotes epithelial-mesenchymal transition by regulating TGF-beta and AKT signaling pathways in MDA-MB-231, a triple-negative breast cancer cell line. (PMID:36593106)
• SIRT1 promotes the progression and chemoresistance of colorectal cancer through the p53/miR-101/KPNA3 axis. (PMID:37575080)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	kpna3	ENSDARG00000052641
mus_musculus	Kpna3	ENSMUSG00000021929
rattus_norvegicus	Kpna3	ENSRNOG00000014945
drosophila_melanogaster	Kap-alpha3	FBGN0027338
drosophila_melanogaster	alphaKap4	FBGN0035657
caenorhabditis_elegans		WBGENE00002074

Paralogs (6): KPNA6 (ENSG00000025800), KPNA1 (ENSG00000114030), KPNA2 (ENSG00000182481), KPNA7 (ENSG00000185467), KPNA4 (ENSG00000186432), KPNA5 (ENSG00000196911)

Protein

Protein identifiers

Importin subunit alpha-4 — O00505 (reviewed: O00505)

Alternative names: Importin alpha Q2, Karyopherin subunit alpha-3, SRP1-gamma

All UniProt accessions (2): O00505, H0Y4S9

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. In vitro, mediates the nuclear import of human cytomegalovirus UL84 by recognizing a non-classical NLS. Recognizes NLSs of influenza A virus nucleoprotein probably through ARM repeats 7-9.

Subunit / interactions. Forms a complex with importin subunit beta-1. Interacts with DDX21. Interacts with NCBP1, NCBP2/CBP20 and NCBP3. Interacts with RCC1. Interacts with ZC3H11A. (Microbial infection) Interacts with HIV-1 integrase; this interaction might play a role in nuclear import of HIV pre-integration complex. (Microbial infection) Interacts with influenza virus nucleoprotein; this interaction might play a role in nuclear import of viral genome.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Ubiquitous. Highest levels in heart and skeletal muscle.

Disease relevance. Spastic paraplegia 88, autosomal dominant (SPG88) [MIM:620106] A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG88 is characterized by onset of symptoms in the first year of life. Most SPG88 patients have a pure form of the disorder, although rarely patients may manifest additional features, including peripheral neuropathy, speech delay, attention deficit-hyperactivity disorder, and non-specific brain imaging abnormalities. The disease is caused by variants affecting the gene represented in this entry.

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_002258* (*=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 (39 total): repeat 10, sequence conflict 10, sequence variant 7, modified residue 4, region of interest 3, initiator methionine 1, chain 1, short sequence motif 1, compositionally biased region 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00505-F1	86.15	0.74

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): 2, 56, 60, 484

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: 414 (showing top): GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, TGCACTT_MIR519C_MIR519B_MIR519A, AAGCCAT_MIR135A_MIR135B, GCM_ZNF198, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GTTAAAG_MIR302B, MEF2_02, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, ACTGCAG_MIR173P, BONCI_TARGETS_OF_MIR15A_AND_MIR16_1, GOBP_NUCLEAR_TRANSPORT, GTGCCTT_MIR506, AGTCTTA_MIR499

GO Biological Process (6): protein import into nucleus (GO:0006606), NLS-bearing protein import into nucleus (GO:0006607), symbiont entry into host cell (GO:0046718), protein-containing complex assembly (GO:0065003), viral penetration into host nucleus (GO:0075732), protein transport (GO:0015031)

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

GO Cellular Component (7): nucleus (GO:0005634), nuclear pore (GO:0005643), nucleoplasm (GO:0005654), cytosol (GO:0005829), NLS-dependent protein nuclear import complex (GO:0042564), host cell (GO:0043657), cytoplasm (GO:0005737)

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
intracellular protein transport	1
protein localization to nucleus	1
establishment of protein localization to organelle	1
protein import into nucleus	1
viral life cycle	1
symbiont entry into host	1
cellular component assembly	1
protein-containing complex organization	1
intracellular transport of virus	1
transport	1
intracellular protein localization	1
establishment of protein localization	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
cytoplasm	1
nucleocytoplasmic transport complex	1
host cellular component	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2972 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KPNA3	RCC1	P18754	884
KPNA3	KPNB1	Q14974	836
KPNA3	PHGDH	O43175	790
KPNA3	TNP2	Q05952	771
KPNA3	IPO5	O00410	737
KPNA3	HNRNPK	P61978	688
KPNA3	TNP1	P09430	645
KPNA3	CSE1L	P55060	570
KPNA3	XPO1	O14980	569
KPNA3	RANBP1	P43487	557
KPNA3	RECQL	P46063	550
KPNA3	SMARCA1	P28370	535
KPNA3	TNPO1	Q92973	517
KPNA3	CRY2	Q49AN0	486
KPNA3	TNPO2	O14787	475

IntAct

330 interactions, top by confidence:

A	B	Type	Score
HNRNPC	KPNA3	psi-mi:“MI:0915”(physical association)	0.850
KPNA3	HNRNPC	psi-mi:“MI:0915”(physical association)	0.850
NUP50	KPNA3	psi-mi:“MI:0915”(physical association)	0.780
KPNA3	NUP50	psi-mi:“MI:0915”(physical association)	0.780
DDX21	KPNA3	psi-mi:“MI:0915”(physical association)	0.740
KIF22	KPNA3	psi-mi:“MI:0914”(association)	0.730
MAT2B	KPNA3	psi-mi:“MI:0915”(physical association)	0.720
KPNA3	MAT2B	psi-mi:“MI:0915”(physical association)	0.720
KPNB1	KPNA3	psi-mi:“MI:0407”(direct interaction)	0.690
KPNA3	TSSC4	psi-mi:“MI:0915”(physical association)	0.670
KPNA3	ERCC3	psi-mi:“MI:0915”(physical association)	0.670
KPNA3	FAM90A1	psi-mi:“MI:0915”(physical association)	0.670
KPNA3	HTT	psi-mi:“MI:0915”(physical association)	0.670
KPNA3	PB2	psi-mi:“MI:0915”(physical association)	0.660
HSF1	KPNA3	psi-mi:“MI:0914”(association)	0.640
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
MECP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
ORF4b	KPNA3	psi-mi:“MI:0914”(association)	0.620

BioGRID (350): KPNA3 (Two-hybrid), KPNA3 (Two-hybrid), MTA1 (Two-hybrid), DDX21 (Two-hybrid), ZBTB24 (Two-hybrid), TSSC4 (Two-hybrid), NUP50 (Two-hybrid), MAT2B (Two-hybrid), ZCCHC10 (Two-hybrid), RPRD1A (Two-hybrid), APOL6 (Two-hybrid), SLC5A11 (Two-hybrid), TEX37 (Two-hybrid), KPNA3 (Affinity Capture-MS), KPNA3 (Affinity Capture-MS)

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
KPNA3	up-regulates	NOTCH1	relocalization
KPNA3	up-regulates	NOTCH	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 107 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	7	42.0×	1e-07
Transport of the SLBP independent Mature mRNA	6	35.0×	3e-06
Transport of the SLBP Dependant Mature mRNA	6	34.0×	3e-06
Transport of Ribonucleoproteins into the Host Nucleus	5	31.9×	3e-05
Transport of Mature mRNA Derived from an Intronless Transcript	6	29.1×	6e-06
Rev-mediated nuclear export of HIV RNA	5	28.3×	5e-05
NS1 Mediated Effects on Host Pathways	5	25.5×	7e-05
snRNP Assembly	6	22.7×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
cellular response to estradiol stimulus	5	25.7×	2e-04
mRNA transport	6	19.8×	2e-04
protein import into nucleus	7	12.6×	2e-04
chromatin remodeling	9	8.2×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	5
Likely pathogenic	2
Uncertain significance	46
Likely benign	3
Benign	2

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
1713272	NM_002267.4(KPNA3):c.1001T>G (p.Leu334Arg)	Pathogenic
1713274	NM_002267.4(KPNA3):c.1049T>C (p.Leu350Pro)	Pathogenic
1713275	NM_002267.4(KPNA3):c.983T>C (p.Leu328Pro)	Pathogenic
1713276	NM_002267.4(KPNA3):c.1220T>G (p.Leu407Arg)	Pathogenic
979371	GRCh37/hg19 13q14.2(chr13:50179353-50506923)x3	Pathogenic
1713273	NM_002267.4(KPNA3):c.944C>T (p.Thr315Ile)	Likely pathogenic
1879259	NM_002267.4(KPNA3):c.656A>G (p.Asn219Ser)	Likely pathogenic

SpliceAI

2260 predictions. Top by Δscore:

Variant	Effect	Δscore
13:49701894:TCAAT:T	acceptor_gain	1.0000
13:49701895:CAAT:C	acceptor_gain	1.0000
13:49701895:CAATC:C	acceptor_gain	1.0000
13:49701896:AAT:A	acceptor_gain	1.0000
13:49701897:AT:A	acceptor_gain	1.0000
13:49701899:C:CC	acceptor_gain	1.0000
13:49701899:C:CG	acceptor_loss	1.0000
13:49701901:G:C	acceptor_gain	1.0000
13:49701901:G:GC	acceptor_gain	1.0000
13:49701909:C:CT	acceptor_gain	1.0000
13:49701910:A:T	acceptor_gain	1.0000
13:49702382:TTACA:T	donor_loss	1.0000
13:49702383:TAC:T	donor_loss	1.0000
13:49702384:A:AC	donor_gain	1.0000
13:49702384:ACAT:A	donor_gain	1.0000
13:49702385:C:CC	donor_gain	1.0000
13:49702385:CA:C	donor_gain	1.0000
13:49702385:CAT:C	donor_gain	1.0000
13:49702385:CATC:C	donor_gain	1.0000
13:49702385:CATCA:C	donor_gain	1.0000
13:49702476:CAAAC:C	acceptor_gain	1.0000
13:49702477:AAAC:A	acceptor_gain	1.0000
13:49702478:AAC:A	acceptor_gain	1.0000
13:49702479:AC:A	acceptor_gain	1.0000
13:49702479:ACCTG:A	acceptor_loss	1.0000
13:49702480:CCTGG:C	acceptor_gain	1.0000
13:49702481:C:CC	acceptor_gain	1.0000
13:49702484:G:C	acceptor_gain	1.0000
13:49702484:G:GC	acceptor_gain	1.0000
13:49702490:A:AC	acceptor_gain	1.0000

AlphaMissense

3435 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
13:49705677:A:G	L439P	1.000
13:49705689:A:G	L435P	1.000
13:49705692:C:T	G434D	1.000
13:49705693:C:G	G434R	1.000
13:49705698:A:G	L432P	1.000
13:49705734:A:G	L420P	1.000
13:49706111:C:T	G399D	1.000
13:49706125:G:C	N394K	1.000
13:49706125:G:T	N394K	1.000
13:49706126:T:A	N394I	1.000
13:49706127:T:C	N394D	1.000
13:49706128:G:C	S393R	1.000
13:49706128:G:T	S393R	1.000
13:49706130:T:G	S393R	1.000
13:49706135:G:T	A391E	1.000
13:49706136:C:G	A391P	1.000
13:49706137:C:A	W390C	1.000
13:49706137:C:G	W390C	1.000
13:49706138:C:G	W390S	1.000
13:49706139:A:G	W390R	1.000
13:49706139:A:T	W390R	1.000
13:49706141:G:T	A389D	1.000
13:49706144:G:T	A388D	1.000
13:49706145:C:G	A388P	1.000
13:49706146:T:A	E387D	1.000
13:49706146:T:G	E387D	1.000
13:49706147:T:A	E387V	1.000
13:49706148:C:T	E387K	1.000
13:49706275:A:G	L377P	1.000
13:49706338:C:A	G356V	1.000

dbSNP variants (sampled 300 via entrez): RS1000002269 (13:49774883 G>T), RS1000025938 (13:49755964 T>C), RS1000089497 (13:49726298 T>A,C), RS1000099725 (13:49743417 C>T), RS1000105397 (13:49737258 T>C), RS1000112766 (13:49715987 A>C), RS1000158136 (13:49781565 T>C), RS1000186303 (13:49707492 G>C), RS1000189623 (13:49793369 A>G), RS1000219733 (13:49742490 A>G), RS1000229935 (13:49768562 A>G,T), RS1000248570 (13:49761413 AT>A,ATT), RS1000285546 (13:49700360 T>C), RS1000320692 (13:49725317 T>C), RS1000333200 (13:49713603 AATAGCCTT>A)

Disease associations

OMIM: gene MIM:601892 | disease phenotypes: MIM:620106

GenCC curated gene-disease

Disease	Classification	Inheritance
spastic paraplegia 88, autosomal dominant	Strong	Autosomal dominant

Mondo (1): spastic paraplegia 88, autosomal dominant (MONDO:0859309)

Orphanet (0):

HPO phenotypes

39 total (30 of 39 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000012	Urinary urgency
HP:0000750	Delayed speech and language development
HP:0001250	Seizure
HP:0001270	Motor delay
HP:0001288	Gait disturbance
HP:0001321	Cerebellar hypoplasia
HP:0001347	Hyperreflexia
HP:0001761	Pes cavus
HP:0002061	Lower limb spasticity
HP:0002064	Spastic gait
HP:0002119	Ventriculomegaly
HP:0002166	Impaired vibration sensation in the lower limbs
HP:0002169	Clonus
HP:0002314	Degeneration of the lateral corticospinal tracts
HP:0002317	Unsteady gait
HP:0002335	Agenesis of cerebellar vermis
HP:0002365	Hypoplasia of the brainstem
HP:0002395	Lower limb hyperreflexia
HP:0002921	Abnormal cerebrospinal fluid morphology
HP:0002936	Distal sensory impairment
HP:0003394	Muscle spasm
HP:0003457	EMG abnormality
HP:0003487	Babinski sign
HP:0003552	Muscle stiffness
HP:0003593	Infantile onset
HP:0003676	Progressive
HP:0007002	Motor axonal neuropathy
HP:0007018	Attention deficit hyperactivity disorder
HP:0007020	Progressive spastic paraplegia

GWAS associations

7 associations (top):

Study	Trait	p-value
GCST001381_2	Menopause (age at onset)	9.000000e-08
GCST001762_17	Obesity-related traits	8.000000e-06
GCST002740_38	Inflammatory skin disease	9.000000e-06
GCST007427_3	Triiodothyronine/thyroxine ratio	1.000000e-07
GCST010002_186	Refractive error	1.000000e-36
GCST90002405_255	Reticulocyte count	5.000000e-16
GCST90002406_409	Reticulocyte fraction of red cells	1.000000e-17

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004704	age at menopause
EFO:0005106	body composition measurement
EFO:0009779	tri-iodothyronine/thyroxine ratio measurement
EFO:0007986	reticulocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523119 (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
7.09	Kd	81	nM	MOLIBRESIB
6.85	IC50	140	nM	MOLIBRESIB

PubChem BioAssay actives

2 with measured affinity, of 8 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	2179240: Binding affinity against KPNA3 (unknown origin) assessed as apparent dissociation constant incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	kd	0.0810	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression, increases methylation, affects cotreatment	4
Estradiol	decreases expression, increases expression	3
aristolochic acid I	decreases expression	1
FR900359	increases phosphorylation	1
intybin	increases degradation, increases reaction, affects cotreatment, decreases expression	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
uranyl acetate	affects expression	1
decabromobiphenyl ether	increases expression	1
mono-(2-ethylhexyl)phthalate	decreases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	increases expression	1
tetrabromobisphenol A	decreases expression	1
manganese chloride	increases abundance, increases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol S	increases expression	1
jinfukang	decreases expression	1
bisphenol AF	increases 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
Air Pollutants	decreases expression, increases abundance	1
Aspirin	increases expression	1
Calcitriol	decreases expression	1
Cisplatin	decreases expression	1
Coumestrol	decreases expression	1
Dactinomycin	increases degradation, increases reaction	1
Doxorubicin	decreases expression	1

ChEMBL screening assays

8 unique, capped per target: 8 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4366241	Binding	Inhibition of importin alpha 3 in human KM-H2 cells at 0.2 ug/ml after 6 hrs by Western blot analysis (Rvb = 1 No_unit)	Jietacins, azoxy natural products, as novel NF-κB inhibitors: Discovery, synthesis, biological activity, and mode of action. — Eur J Med Chem

Clinical trials (associated diseases)

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