TNPO3

Summary

TNPO3 (transportin 3, HGNC:17103) is a protein-coding gene on chromosome 7q32.1, encoding Transportin-3 (Q9Y5L0). Importin, which transports target proteins into the nucleus. It is a common-essential gene (DepMap: required in 99.8% of cancer cell lines).

The protein encoded by this gene is a nuclear import receptor for serine/arginine-rich (SR) proteins such as the splicing factors SFRS1 and SFRS2. The encoded protein has also been shown to be involved in HIV-1 infection, apparently through interaction with the HIV-1 capsid protein. Several protein-coding and non-coding transcript variants have been found for this gene.

Source: NCBI Gene 23534 — RefSeq curated summary.

At a glance

• Gene–disease (curated): muscular dystrophy, limb-girdle, autosomal dominant (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 36
• Clinical variants (ClinVar): 777 total — 3 pathogenic, 6 likely-pathogenic
• Phenotypes (HPO): 64
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.8% of screened cell lines (common-essential)
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_012470

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17103
Approved symbol	TNPO3
Name	transportin 3
Location	7q32.1
Locus type	gene with protein product
Status	Approved
Aliases	TRN-SR, MTR10A, TRN-SR2, IPO12
Ensembl gene	ENSG00000064419
Ensembl biotype	protein_coding
OMIM	610032
Entrez	23534

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 26 protein_coding

ENST00000265388, ENST00000471166, ENST00000471234, ENST00000482320, ENST00000627585, ENST00000862641, ENST00000862642, ENST00000862643, ENST00000862644, ENST00000862645, ENST00000862646, ENST00000862647, ENST00000862648, ENST00000862649, ENST00000862650, ENST00000862651, ENST00000862652, ENST00000862653, ENST00000929007, ENST00000929008, ENST00000929010, ENST00000929011, ENST00000929012, ENST00000961760, ENST00000961761, ENST00000961762

RefSeq mRNA: 10 — MANE Select: NM_012470 NM_001191028, NM_001382216, NM_001382217, NM_001382218, NM_001382219, NM_001382220, NM_001382221, NM_001382222, NM_001382223, NM_012470

CCDS: CCDS55162, CCDS5809, CCDS94196

Canonical transcript exons

ENST00000265388 — 23 exons

Exon	Start	End
ENSE00000721385	128993807	128993914
ENSE00000882208	128978983	128979123
ENSE00000882210	128982248	128982324
ENSE00000882214	128991999	128992090
ENSE00000919446	128967280	128967392
ENSE00000919447	128970148	128970315
ENSE00000919449	128974868	128974962
ENSE00000919450	128975819	128975935
ENSE00000919459	128997389	128997535
ENSE00000919461	129001059	129001234
ENSE00000919462	129005016	129005159
ENSE00001121699	128957224	128957315
ENSE00001130703	128972426	128972582
ENSE00001130707	128979971	128980031
ENSE00001130739	129014979	129015135
ENSE00001130830	129016983	129017056
ENSE00001207451	128984168	128984259
ENSE00001207453	128986729	128986920
ENSE00001207465	129000429	129000567
ENSE00001434340	128989961	128990100
ENSE00001953450	129054651	129055111
ENSE00003508544	129017957	129018157
ENSE00003916052	128954185	128955385

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 99.40.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 28.2974 / max 328.5775, expressed in 1820 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
86091	14.1738	1809
86092	13.5762	1785
86093	0.5474	296

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.40	gold quality
tendon of biceps brachii	UBERON:0008188	98.29	silver quality
medial globus pallidus	UBERON:0002477	97.85	gold quality
oocyte	CL:0000023	97.58	gold quality
globus pallidus	UBERON:0001875	96.95	gold quality
substantia nigra pars reticulata	UBERON:0001966	96.68	gold quality
substantia nigra pars compacta	UBERON:0001965	96.60	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.05	gold quality
lateral globus pallidus	UBERON:0002476	95.98	gold quality
olfactory bulb	UBERON:0002264	95.11	gold quality
endometrium epithelium	UBERON:0004811	94.44	gold quality
cortical plate	UBERON:0005343	94.03	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	93.77	gold quality
type B pancreatic cell	CL:0000169	93.43	gold quality
oviduct epithelium	UBERON:0004804	93.25	gold quality
ventricular zone	UBERON:0003053	93.24	gold quality
nasal cavity epithelium	UBERON:0005384	92.71	gold quality
cardia of stomach	UBERON:0001162	92.70	gold quality
inferior olivary complex	UBERON:0002127	92.49	gold quality
trabecular bone tissue	UBERON:0002483	92.48	gold quality
pylorus	UBERON:0001166	92.28	gold quality
embryo	UBERON:0000922	92.22	gold quality
ganglionic eminence	UBERON:0004023	92.05	gold quality
cerebellar vermis	UBERON:0004720	91.78	gold quality
tendon	UBERON:0000043	91.43	gold quality
nipple	UBERON:0002030	91.40	gold quality
ventral tegmental area	UBERON:0002691	91.26	gold quality
renal medulla	UBERON:0000362	91.25	gold quality
inferior vagus X ganglion	UBERON:0005363	91.20	gold quality
mucosa of paranasal sinus	UBERON:0005030	90.97	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.74

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

74 targeting TNPO3, 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-6867-5P	100.00	82.21	3464
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
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-3692-3P	99.98	70.27	2139
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-4778-3P	99.93	70.40	1818
HSA-MIR-4648	99.91	67.00	710
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-6783-3P	99.89	67.92	2059
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-1343-3P	99.89	66.78	1815
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-3681-3P	99.88	70.46	2254
HSA-MIR-576-5P	99.84	70.46	2582
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-3680-3P	99.75	72.51	3095

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 99.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 32)

• Results imply that the mechanism by which SR proteins are imported to the nucleus is conserved between Drosophila and humans and involves the nuclear import receptor transportin-SR (PMID:12134081)
• capsid, not integrase, is the dominant viral factor that dictates transportin 3 dependency during HIV-1 infection (PMID:19846519)
• Here the authors discover a link between the viral entry of HIV and its interaction with TRN-SR2. (PMID:21276267)
• Transportin 3 and importin alpha act as receptors and are required for effective nuclear import of HIV-1 integrase in virus-infected cells. (PMID:21326825)
• Tnp3 binds to tRNAs and capsids proteins, and is required for efficient HIV-1 integration. (PMID:21901095)
• The authors demonstrated that TNPO3 was required by several lentiviruses for nuclear import. (PMID:21976643)
• a novel nuclear localization signal and mechanism for serpinF1 nuclear import (PMID:22028839)
• TNPO3 promotes HIV-1 infectivity at a step in the virus life cycle that is detectable after the preintegration complex arrives in the nucleus and capsid is the viral determinant for TNPO3 dependence. (PMID:22145813)
• TNPO3 binds to a surface of monomeric HIV-1 integrase that remains exposed after tetramerization. (PMID:22176773)
• TNPO3 interacts with HIV-1 gag in the cytoplasm to assist HIV-1 infection after nuclear import. (PMID:22398280)
• Identification of residues in the C-terminal domain of HIV-1 integrase that mediate binding to the transportin-SR2 protein. (PMID:22872638)
• TNPO3 can directly engage the HIV-1 IN tetramer prebound to the cognate DNA. (PMID:22872640)
• These results suggest that TNPO3 and cyclophilin A facilitate HIV-1 infection by coordinating proper uncoating of the core in target cells. (PMID:23097435)
• TNPO3 promotes HIV-1 infectivity indirectly, by shifting the CA-binding protein CPSF6 to the nucleus, thus preventing the excessive HIV-1 CA stability that would otherwise result from cytoplasmic accumulation of CPSF6. (PMID:23414560)
• In skeletal muscle of limb-girdle muscular dystrophy 1F individuals, expression of transportin 3 indicates altered transportin 3 function. (PMID:23543484)
• TNPO3 mutation is the cause of limb-girdle muscular dystrophy 1F, expands knowledge of the molecular basis of muscular dystrophies and bolsters the importance of defects of nuclear envelope proteins as causes of inherited myopathies. (PMID:23543484)
• These results suggested that inhibition of HIV-1 by TNPO3-depleted cells requires CPSF6. (PMID:23622145)
• The TNPO3 gene is mapped within the Limb-girdle muscular dystrophy 1F critical interval and its 923-amino acid human gene product is also expressed in skeletal muscle. (PMID:23667635)
• a model wherein one monomer of TRN-SR2 is bound to one monomer of RanGTP. (PMID:23878195)
• Tnpo3 mutants that are not able to interact with cleavage and polyadenylation specificity factor 6 do not facilitate HIV-1 infectivity, suggesting a potential route of pharmacological intervention in the treatment of AIDS. (PMID:24449914)
• Data suggest that the HIV-1 integrase (IN)/transportin-SR2 (TRN-SR2) interaction interface is a potential target for antiviral therapy. (PMID:25063804)
• IRF5-TNPO3 genetic variation is associated systemic lupus erythematosus. (PMID:25205108)
• Combining these results with small-angle X-ray scattering data for the complex of TRN-SR2 with truncated integrase, we propose a molecular model of the complex. We speculate that nuclear import of the PIC may proceed concurrently with the normal nuclear transport. (PMID:28356354)
• The crystal structure of the RSLD-TNPO3 complex revealed potential CPSF6 interaction residues, which were confirmed to mediate TNPO3 binding and CPSF6 nuclear import. Both binding and nuclear import were independent of RSLD phosphorylation, though a hyperphosphorylated mimetic mutant failed to bind TNPO3 and mislocalized to the cell cytoplasm (PMID:30916345)
• A novel pathogenic variant (Arg923AspfsTer17) in TNPO3 segregates with limb-girdle muscular dystrophy 1F in a Hungarian family. (PMID:31071488)
• our results support a model in which miR-128 is expressed in primary HIV-1 target cells, is a type I IFN response gene, and functions as a novel antiviral defense mechanism during HIV-1 infection, partly by repressing the nuclear import factors TNPO3 and by inhibiting HIV-1 replication and viral spreading (PMID:31341054)
• An Allele-Specific Functional SNP Associated with Two Systemic Autoimmune Diseases Modulates IRF5 Expression by Long-Range Chromatin Loop Formation. (PMID:31421124)
• TNPO3 mutant protein expressed in limb girdle muscular dystrophy 1F cells is the second genetic defect leading to strong HIV-1 restriction. (PMID:31465518)
• TNPO3-Mediated Nuclear Entry of the Rous Sarcoma Virus Gag Protein Is Independent of the Cargo-Binding Domain. (PMID:32581109)
• CRISPR/Cas9-Induced Mutagenesis Corroborates the Role of Transportin-SR2 in HIV-1 Nuclear Import. (PMID:34612665)
• Transportin-3 Facilitates Uncoating of Influenza A Virus. (PMID:35456945)
• IRF5-TNOP3 polymorphisms are associated with elite control of HIV infection: A retrospective study. (PMID:37254791)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	tnpo3	ENSDARG00000045680
mus_musculus	Tnpo3	ENSMUSG00000012535
rattus_norvegicus	Tnpo3	ENSRNOG00000021758
drosophila_melanogaster	Tnpo-SR	FBGN0031456
caenorhabditis_elegans		WBGENE00006647

Paralogs (1): IPO13 (ENSG00000117408)

Protein

Protein identifiers

Transportin-3 — Q9Y5L0 (reviewed: Q9Y5L0)

Alternative names: Importin-12, Transportin-SR

All UniProt accessions (3): Q9Y5L0, C9J7E5, E9PFH4

UniProt curated annotations — full annotation on UniProt →

Function. Importin, which transports target proteins into the nucleus. Specifically mediates the nuclear import of splicing factor serine/arginine (SR) proteins, such as RBM4, SFRS1 and SFRS2, by recognizing phosphorylated SR domains. Also mediates the nuclear import of serine/arginine (SR) protein CPSF6, independently of CPSF6 phosphorylation. The nuclear import process is regulated by the small GTPase Ran that partitions between cytoplasm and nucleus in the predominantly GDP- and GTP-bound form, respectively. Importin associates with target cargo proteins in the cytoplasm, and the competitive binding of GTP-bound Ran induces the release of cargos in the nucleus. (Microbial infection) Involved in immunodeficiency virus (HIV-1) infection by importing the pre-integration complex (PIC) into the nucleus. Required for a nuclear maturation step of HIV-1 prior to integration.

Subunit / interactions. Interacts with (GTP-bound) Ran. Interacts with (phosphorylated) SFRS1 and SFRS2; leading to their nuclear import. Interacts with NUP62. Interacts with RBM4. Interacts with CPSF6, promoting its nuclear import. (Microbial infection) Interacts with the HIV-1 pre-integration complex (PIC), which is composed of viral genome, matrix protein, Vpr and integrase. Interacts with HIV-1 integrase protein; the interaction is direct.

Subcellular location. Nucleus envelope. Cytoplasm.

Tissue specificity. Expressed in skeletal muscle.

Disease relevance. Muscular dystrophy, limb-girdle, autosomal dominant 2 (LGMDD2) [MIM:608423] An autosomal dominant myopathy characterized by proximal muscle weakness primarily affecting the lower limbs, but also affecting the upper limbs in most patients. Affected individuals also have distal muscle weakness of the hands and lower leg muscles. The disease has generally a benign clinical course but some individuals with childhood or juvenile onset manifest severe widespread myopathy, leading to wheelchair dependency and respiratory insufficiency. Muscle biopsy shows dystrophic changes with abnormal nuclei, rimmed vacuoles, and filamentous inclusions. The disease is caused by variants affecting the gene represented in this entry.

Polymorphism. Variations in TNPO3 are associated with resistance or susceptibility to immunodeficiency virus type 1 (resistance or susceptibility to HIV-1) [MIM:609423]. A variation that causes LGMDD2 muscular dystrophy induces protection against HIV-1 infection.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9Y5L0-2	2, Transportin-SR2, TRN-SR2	yes
Q9Y5L0-1	1
Q9Y5L0-3	3
Q9Y5L0-5	4

RefSeq proteins (10): NP_001177957, NP_001369145, NP_001369146, NP_001369147, NP_001369148, NP_001369149, NP_001369150, NP_001369151, NP_001369152, NP_036602* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR011989	ARM-like	Homologous_superfamily
IPR013598	Exportin-1/Importin-b-like	Domain
IPR016024	ARM-type_fold	Homologous_superfamily
IPR051345	Importin_beta-like_NTR	Family
IPR057941	TPR_TNPO3_IPO13_2nd	Repeat
IPR057942	TPR_TNPO3_IPO13_3rd	Repeat
IPR058537	TPR_TNPO3_IPO13_4th	Repeat

Pfam: PF08389, PF24138, PF24139, PF24140

UniProt features (104 total): helix 61, mutagenesis site 11, turn 10, strand 6, sequence conflict 5, sequence variant 4, modified residue 3, splice variant 3, chain 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
4C0O	X-RAY DIFFRACTION	2.56
6GX9	X-RAY DIFFRACTION	2.7
4OL0	X-RAY DIFFRACTION	2.9
8CMK	X-RAY DIFFRACTION	2.94
4C0P	X-RAY DIFFRACTION	2.95
4C0Q	X-RAY DIFFRACTION	3.42

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y5L0-F1	94.47	0.91

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 (3): 1, 74, 896

Mutagenesis-validated functional residues (11):

Position	Phenotype
145–153	decreased interaction with gtp-bound ran.
620	in 9ala; abolished interaction with srsf1 and cpsf6 without affecting interaction with gtp-bound ran; when associated wi
660	in 9ala; abolished interaction with srsf1 and cpsf6 without affecting interaction with gtp-bound ran; when associated wi
664	abolished interaction with srsf1. in 9ala; abolished interaction with srsf1 and cpsf6 without affecting interaction with
667	in 9ala; abolished interaction with srsf1 and cpsf6 without affecting interaction with gtp-bound ran; when associated wi
671	abolished interaction with srsf1. in 9ala; abolished interaction with srsf1 and cpsf6 without affecting interaction with
702	abolished interaction with srsf1. in 9ala; abolished interaction with srsf1 and cpsf6 without affecting interaction with
750	abolished interaction with srsf1. in 9ala; abolished interaction with srsf1 and cpsf6 without affecting interaction with
751	in 9ala; abolished interaction with srsf1 and cpsf6 without affecting interaction with gtp-bound ran; when associated wi
754	abolished interaction with srsf1.
758	abolished interaction with srsf1. in 9ala; abolished interaction with srsf1 and cpsf6 without affecting interaction with

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 346 (showing top): AHRARNT_01, MORF_DNMT1, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, THEILGAARD_NEUTROPHIL_AT_SKIN_WOUND_DN, MORF_HDAC2, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOMF_GTPASE_BINDING, GGGTGGRR_PAX4_03, GOBP_NUCLEAR_TRANSPORT, WEI_MYCN_TARGETS_WITH_E_BOX, BLALOCK_ALZHEIMERS_DISEASE_UP, ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_DN, GATA1_01, chr7q32

GO Biological Process (2): protein import into nucleus (GO:0006606), protein transport (GO:0015031)

GO Molecular Function (4): small GTPase binding (GO:0031267), identical protein binding (GO:0042802), nuclear import signal receptor activity (GO:0061608), protein binding (GO:0005515)

GO Cellular Component (6): nuclear envelope (GO:0005635), annulate lamellae (GO:0005642), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), nucleus (GO:0005634)

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
transport	1
intracellular protein localization	1
establishment of protein localization	1
GTPase binding	1
protein binding	1
nucleocytoplasmic carrier activity	1
binding	1
nucleus	1
endomembrane system	1
organelle envelope	1
membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2384 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TNPO3	TNPO1	Q92973	955
TNPO3	SRSF1	Q07955	940
TNPO3	NUP153	P49790	850
TNPO3	CPSF6	Q16630	815
TNPO3	RANBP2	P49792	789
TNPO3	PSIP1	O75475	775
TNPO3	VPS53	Q5VIR6	773
TNPO3	RGPD1	P0C839	768
TNPO3	TRIM5	Q9C035	768
TNPO3	IPO7	O95373	766
TNPO3	IPO11	Q9UI26	756
TNPO3	SRSF2	Q01130	752
TNPO3	XPO1	O14980	719
TNPO3	IRF5	Q13568	684
TNPO3	TNPO2	O14787	679

IntAct

263 interactions, top by confidence:

A	B	Type	Score
HRAS	RAF1	psi-mi:“MI:0914”(association)	0.980
TNPO3	CIRBP	psi-mi:“MI:0407”(direct interaction)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
gag-pol	TNPO3	psi-mi:“MI:0407”(direct interaction)	0.640
TNPO3	gag-pol	psi-mi:“MI:0915”(physical association)	0.640
TNPO3	gag-pol	psi-mi:“MI:0407”(direct interaction)	0.640
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
SCN2B	EXOC5	psi-mi:“MI:0914”(association)	0.640
P2RX4	FAM20B	psi-mi:“MI:0914”(association)	0.640
RSRP1	C1QBP	psi-mi:“MI:0914”(association)	0.640
TNPO3	TNPO3	psi-mi:“MI:0407”(direct interaction)	0.620
TNPO3	ICA1L	psi-mi:“MI:0915”(physical association)	0.560
TNPO3	SSX2	psi-mi:“MI:0915”(physical association)	0.560
TNPO3	CLPP	psi-mi:“MI:0915”(physical association)	0.560
TNPO3	PPP1R1C	psi-mi:“MI:0915”(physical association)	0.560
TNPO3	ECI2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (323): TNPO3 (Affinity Capture-RNA), TNPO3 (Affinity Capture-MS), TNPO3 (Affinity Capture-MS), TNPO3 (Affinity Capture-MS), TNPO3 (Affinity Capture-MS), TNPO3 (Affinity Capture-MS), TNPO3 (Affinity Capture-MS), TNPO3 (Affinity Capture-MS), TNPO3 (Affinity Capture-MS), TNPO3 (Affinity Capture-MS), TNPO3 (Affinity Capture-MS), TNPO3 (Affinity Capture-MS), TNPO3 (Affinity Capture-MS), TNPO3 (Affinity Capture-MS), TNPO3 (Affinity Capture-MS)

ESM2 similar proteins: A0JMZ3, A7YWD2, A9UHW6, F4IRR2, F4J738, O35841, O43592, O75031, O94829, O95373, Q05AL1, Q15386, Q2KI54, Q3UBZ5, Q3UFS0, Q3ZC21, Q53I77, Q5R644, Q5R6S3, Q5R974, Q5RA02, Q5SPJ8, Q5TYQ1, Q5ZIC8, Q5ZJZ6, Q6AXU7, Q6NTZ5, Q6P2B1, Q6QI06, Q6R327, Q7Z3V4, Q80U95, Q8BHL5, Q8IUR7, Q8K0C1, Q8QHJ8, Q8R5L3, Q91W86, Q924Z6, Q96JC1

Diamond homologs: Q6P2B1, Q9Y5L0

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 215 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
Pyroptosis	5	16.8×	2e-03
Phase 0 - rapid depolarisation	5	13.7×	4e-03
RAF activation	5	13.3×	4e-03
Late endosomal microautophagy	5	12.9×	4e-03
Signaling by RAF1 mutants	5	11.1×	7e-03
Signaling by moderate kinase activity BRAF mutants	5	10.1×	7e-03
Paradoxical activation of RAF signaling by kinase inactive BRAF	5	10.1×	7e-03
Signaling downstream of RAS mutants	5	10.1×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
nuclear membrane reassembly	5	27.7×	2e-04
late endosome to lysosome transport	5	27.7×	2e-04
viral budding via host ESCRT complex	5	22.4×	4e-04
multivesicular body sorting pathway	5	22.4×	4e-04
midbody abscission	5	20.5×	5e-04
regulation of mitotic spindle assembly	5	20.5×	5e-04
plasma membrane repair	5	16.2×	1e-03
nucleus organization	5	15.7×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	6
Uncertain significance	378
Likely benign	278
Benign	48

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
1323699	NM_012470.4(TNPO3):c.163C>T (p.Gln55Ter)	Pathogenic
135660	NM_012470.4(TNPO3):c.2771del (p.Ter924CysextTer?)	Pathogenic
135661	NM_012470.4(TNPO3):c.2453G>C (p.Arg818Pro)	Pathogenic
1319792	NM_012470.4(TNPO3):c.1543del (p.Leu515fs)	Likely pathogenic
1335692	NM_012470.4(TNPO3):c.2760del (p.Arg920fs)	Likely pathogenic
2434191	NM_012470.4(TNPO3):c.1423dup (p.Thr475fs)	Likely pathogenic
2585348	NM_012470.4(TNPO3):c.2430+1G>A	Likely pathogenic
591000	NM_012470.4(TNPO3):c.2767del (p.Arg923fs)	Likely pathogenic
987299	NM_012470.4(TNPO3):c.1920+1G>A	Likely pathogenic

SpliceAI

3668 predictions. Top by Δscore:

Variant	Effect	Δscore
7:128967276:TCACC:T	donor_loss	1.0000
7:128967278:A:AC	donor_gain	1.0000
7:128967278:A:AT	donor_loss	1.0000
7:128967279:C:A	donor_loss	1.0000
7:128967279:C:CC	donor_gain	1.0000
7:128967279:CCTA:C	donor_gain	1.0000
7:128967388:AAAGT:A	acceptor_gain	1.0000
7:128967389:AAGT:A	acceptor_gain	1.0000
7:128967390:AGT:A	acceptor_gain	1.0000
7:128967391:GT:G	acceptor_gain	1.0000
7:128967392:TC:T	acceptor_loss	1.0000
7:128967393:C:CA	acceptor_loss	1.0000
7:128967393:C:CC	acceptor_gain	1.0000
7:128970143:CTTA:C	donor_loss	1.0000
7:128970144:TTA:T	donor_loss	1.0000
7:128970145:TA:T	donor_loss	1.0000
7:128970146:A:AC	donor_gain	1.0000
7:128970147:C:CC	donor_gain	1.0000
7:128970147:CCG:C	donor_gain	1.0000
7:128970147:CCGGT:C	donor_gain	1.0000
7:128970311:TCATG:T	acceptor_gain	1.0000
7:128970312:CATG:C	acceptor_gain	1.0000
7:128970312:CATGC:C	acceptor_gain	1.0000
7:128970313:ATG:A	acceptor_gain	1.0000
7:128970313:ATGC:A	acceptor_loss	1.0000
7:128970314:TG:T	acceptor_gain	1.0000
7:128970314:TGCT:T	acceptor_loss	1.0000
7:128970315:GC:G	acceptor_loss	1.0000
7:128970316:C:CC	acceptor_gain	1.0000
7:128970316:C:CG	acceptor_loss	1.0000

AlphaMissense

6028 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
7:128974868:C:A	R758M	1.000
7:128975877:A:G	L707P	1.000
7:128975887:C:G	G704R	1.000
7:128975889:A:G	L703P	1.000
7:128979033:G:T	R671S	1.000
7:128979035:A:T	V670D	1.000
7:128979038:G:T	A669D	1.000
7:128979040:A:C	F668L	1.000
7:128979040:A:T	F668L	1.000
7:128979042:A:G	F668L	1.000
7:128979045:G:T	R667S	1.000
7:128979053:C:A	R664M	1.000
7:128979120:A:G	W642R	1.000
7:128979120:A:T	W642R	1.000
7:128982254:A:T	I618K	1.000
7:128982266:C:G	R614P	1.000
7:128984259:C:T	G564E	1.000
7:128986729:C:A	G564W	1.000
7:128986729:C:G	G564R	1.000
7:128986729:C:T	G564R	1.000
7:128993856:A:G	L406P	1.000
7:128993874:C:G	R400P	1.000
7:128993875:G:T	R400S	1.000
7:128997407:G:C	C380W	1.000
7:128997511:A:G	W346R	1.000
7:128997511:A:T	W346R	1.000
7:129000550:C:G	R297P	1.000
7:129005090:A:G	W208R	1.000
7:129005090:A:T	W208R	1.000
7:129015034:C:G	R166P	1.000

dbSNP variants (sampled 300 via entrez): RS1000015396 (7:128981858 A>G), RS1000020610 (7:128995405 T>C), RS1000051648 (7:128994914 T>A), RS1000069163 (7:128981393 C>T), RS1000127706 (7:129034611 C>T), RS1000128416 (7:128988716 C>T), RS1000208970 (7:128999142 G>A,T), RS1000248814 (7:129020612 G>C,T), RS1000308705 (7:128972406 G>T), RS1000319767 (7:128995374 C>T), RS1000322851 (7:129020362 C>A), RS1000331019 (7:128994982 T>C), RS1000352716 (7:129040995 C>T), RS1000364874 (7:128980204 A>G), RS1000380069 (7:129048331 C>A,G)

Disease associations

OMIM: gene MIM:610032 | disease phenotypes: MIM:608423, MIM:609524, MIM:614065, MIM:617047, MIM:603511

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant limb-girdle muscular dystrophy type 1F	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
muscular dystrophy, limb-girdle, autosomal dominant	Definitive	AD

Mondo (5): autosomal dominant limb-girdle muscular dystrophy type 1F (MONDO:0012034), myofibrillar myopathy 5 (MONDO:0012289), distal myopathy with posterior leg and anterior hand involvement (MONDO:0013550), hypertrophic cardiomyopathy 26 (MONDO:0014883), muscular dystrophy, limb-girdle, autosomal dominant (MONDO:0015151)

Orphanet (5): TNP03-related limb-girdle muscular dystrophy D2 (Orphanet:55595), Muscle filaminopathy (Orphanet:171445), FLNC-related handgrip and calf weakness-distal myopathy (Orphanet:63273), Familial isolated restrictive cardiomyopathy (Orphanet:75249), Autosomal dominant limb-girdle muscular dystrophy (Orphanet:102014)

HPO phenotypes

64 total (30 of 64 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000508	Ptosis
HP:0000820	Abnormality of the thyroid gland
HP:0000939	Osteoporosis
HP:0000952	Jaundice
HP:0000953	Hyperpigmentation of the skin
HP:0000989	Pruritus
HP:0001114	Xanthelasma
HP:0001262	Excessive daytime somnolence
HP:0001270	Motor delay
HP:0001278	Orthostatic hypotension
HP:0001394	Cirrhosis
HP:0001395	Hepatic fibrosis
HP:0001399	Hepatic failure
HP:0001402	Hepatocellular carcinoma
HP:0001409	Portal hypertension
HP:0001541	Ascites
HP:0001744	Splenomegaly
HP:0002015	Dysphagia
HP:0002040	Esophageal varix
HP:0002240	Hepatomegaly
HP:0002360	Sleep disturbance
HP:0002460	Distal muscle weakness
HP:0002480	Hepatic encephalopathy
HP:0002570	Steatorrhea
HP:0002608	Celiac disease
HP:0002613	Biliary cirrhosis
HP:0002747	Respiratory insufficiency due to muscle weakness
HP:0002841	Recurrent fungal infections
HP:0002908	Conjugated hyperbilirubinemia

GWAS associations

36 associations (top):

Study	Trait	p-value
GCST000142_6	Systemic lupus erythematosus	4.000000e-19
GCST000144_4	Systemic lupus erythematosus	2.000000e-11
GCST000733_3	Primary biliary cholangitis	3.000000e-10
GCST000964_12	Ulcerative colitis	2.000000e-08
GCST001146_2	Systemic sclerosis	4.000000e-07
GCST001708_2	Systemic lupus erythematosus	6.000000e-13
GCST001728_11	Ulcerative colitis	4.000000e-14
GCST002069_14	Systemic lupus erythematosus and Systemic sclerosis	1.000000e-29
GCST002463_17	Systemic lupus erythematosus	2.000000e-13
GCST003155_7	Systemic lupus erythematosus	9.000000e-110
GCST003252_26	Systemic lupus erythematosus	6.000000e-31
GCST003620_6	Systemic lupus erythematosus or rheumatoid arthritis	1.000000e-23
GCST004878_4	Sjögren’s syndrome	3.000000e-19
GCST004878_5	Sjögren’s syndrome	2.000000e-16
GCST004878_6	Sjögren’s syndrome	3.000000e-06
GCST005332_1	Systemic sclerosis (anti-topoisomerase-positive)	4.000000e-07
GCST005333_1	Systemic sclerosis (anti-centromere-positive)	9.000000e-07
GCST005334_2	Limited cutaneous systemic scleroderma	3.000000e-10
GCST005335_3	Diffuse cutaneous systemic sclerosis	1.000000e-09
GCST005336_1	Systemic sclerosis	5.000000e-10
GCST005551_2	Systemic sclerosis (anti-topoisomerase-positive)	1.000000e-08
GCST005553_3	Diffuse cutaneous systemic sclerosis	7.000000e-07
GCST005554_6	Systemic sclerosis	2.000000e-10
GCST005555_5	Limited cutaneous systemic scleroderma	9.000000e-07
GCST005581_4	Primary biliary cirrhosis	7.000000e-22
GCST005581_5	Primary biliary cirrhosis	4.000000e-09
GCST005752_126	Systemic lupus erythematosus	1.000000e-99
GCST005752_21	Systemic lupus erythematosus	8.000000e-33
GCST005752_26	Systemic lupus erythematosus	1.000000e-17
GCST006493_2	Systemic sclerosis	1.000000e-07

EFO canonical traits (6, from GWAS)

EFO ID	Trait name
EFO:0004267	biliary liver cirrhosis
EFO:0008537	anti-topoisomerase-I-antibody-positive systemic scleroderma
EFO:0008536	anti-centromere-antibody-positive systemic scleroderma
EFO:1001017	limited scleroderma
EFO:0007985	platelet crit
EFO:0004309	platelet count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C537932	Filaminopathy, autosomal dominant (supp.)
C564242	Muscular Dystrophy, Limb-Girdle, Type 1F (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067129 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 4 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.17	Kd	669.1	nM	CHEMBL5653589
6.17	ED50	669.1	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 4 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	2149629: Binding affinity to human TNPO3 incubated for 45 mins by Kinobead based pull down assay	kd	0.6691	uM

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression	2
sodium arsenite	decreases expression, increases expression	2
2,4,6-tribromophenol	decreases expression	1
testosterone enanthate	affects expression	1
arsenite	affects binding, decreases reaction	1
2,3,5-(triglutathion-S-yl)hydroquinone	increases ADP-ribosylation	1
ICG 001	increases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
Zoledronic Acid	decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Cadmium	increases abundance, increases expression	1
Doxorubicin	decreases expression	1
Enzyme Inhibitors	decreases activity, increases O-linked glycosylation	1
Ivermectin	decreases expression	1
Lead	decreases expression	1
Ozone	affects expression, increases abundance	1
Ribonucleotides	affects binding	1
Rotenone	decreases expression	1
Tetrachlorodibenzodioxin	affects expression	1
Valproic Acid	decreases expression	1
Cyclosporine	increases expression	1
Cadmium Chloride	increases abundance, increases expression	1
Okadaic Acid	increases expression	1
Acrylamide	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
CHEMBL5652671	Binding	Binding affinity to human TNPO3 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)

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

Trial	Phase	Status	Title
NCT05989620	Not specified	RECRUITING	Long-Term Development of Muscular Dystrophy Outcome Assessments