KPNA6

Summary

KPNA6 (karyopherin subunit alpha 6, HGNC:6399) is a protein-coding gene on chromosome 1p35.2, encoding Importin subunit alpha-7 (O60684). Functions in nuclear protein import as an adapter protein for nuclear receptor KPNB1. It is a selective cancer dependency (DepMap: 17.1% of cell lines).

Nucleocytoplasmic transport, a signal- and energy-dependent process, takes place through nuclear pore complexes embedded in the nuclear envelope. The import of proteins containing a nuclear localization signal (NLS) requires the NLS import receptor, a heterodimer of importin alpha and beta subunits also known as karyopherins. Importin alpha binds the NLS-containing cargo in the cytoplasm and importin beta docks the complex at the cytoplasmic side of the nuclear pore complex. In the presence of nucleoside triphosphates and the small GTP binding protein Ran, the complex moves into the nuclear pore complex and the importin subunits dissociate. Importin alpha enters the nucleoplasm with its passenger protein and importin beta remains at the pore. The protein encoded by this gene is a member of the importin alpha family.

Source: NCBI Gene 23633 — RefSeq curated summary.

At a glance

• Gene–disease (curated): oocyte/zygote/embryo maturation arrest 17 (Strong, GenCC) — +3 more curated relationships
• GWAS associations: 8
• Clinical variants (ClinVar): 604 total — 2 pathogenic
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 17.1% of screened cell lines
• MANE Select transcript: NM_012316

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6399
Approved symbol	KPNA6
Name	karyopherin subunit alpha 6
Location	1p35.2
Locus type	gene with protein product
Status	Approved
Aliases	IPOA7, KPNA7, MGC17918, FLJ11249
Ensembl gene	ENSG00000025800
Ensembl biotype	protein_coding
OMIM	610563
Entrez	23633

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000373625, ENST00000446515, ENST00000469790, ENST00000471599

RefSeq mRNA: 1 — MANE Select: NM_012316 NM_012316

CCDS: CCDS352

Canonical transcript exons

ENST00000373625 — 14 exons

Exon	Start	End
ENSE00001677479	32170707	32176563
ENSE00001836098	32108056	32108134
ENSE00003462921	32156853	32156945
ENSE00003475758	32154588	32154721
ENSE00003483526	32169882	32170060
ENSE00003496372	32163235	32163313
ENSE00003508692	32166105	32166230
ENSE00003554140	32162361	32162524
ENSE00003557133	32157346	32157445
ENSE00003610496	32158267	32158361
ENSE00003611208	32160615	32160703
ENSE00003612900	32161947	32162046
ENSE00003657679	32159400	32159531
ENSE00003790681	32167169	32167296

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 96.48.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 53.7342 / max 497.7461, expressed in 1828 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
1941	39.7585	1826
1942	13.9011	1801
1944	0.0590	3
1943	0.0122	3
1945	0.0033	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	96.48	gold quality
nipple	UBERON:0002030	95.71	gold quality
oocyte	CL:0000023	95.47	gold quality
olfactory bulb	UBERON:0002264	95.11	silver quality
type B pancreatic cell	CL:0000169	95.10	gold quality
secondary oocyte	CL:0000655	94.65	gold quality
vena cava	UBERON:0004087	94.41	gold quality
saphenous vein	UBERON:0007318	94.10	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	93.92	gold quality
superior surface of tongue	UBERON:0007371	93.80	gold quality
pharyngeal mucosa	UBERON:0000355	93.68	gold quality
superior vestibular nucleus	UBERON:0007227	93.54	gold quality
body of tongue	UBERON:0011876	93.33	gold quality
parietal lobe	UBERON:0001872	93.29	gold quality
postcentral gyrus	UBERON:0002581	93.23	gold quality
ventral tegmental area	UBERON:0002691	93.21	gold quality
substantia nigra pars compacta	UBERON:0001965	93.08	gold quality
gingival epithelium	UBERON:0001949	93.05	gold quality
endothelial cell	CL:0000115	92.93	gold quality
tongue	UBERON:0001723	92.88	gold quality
substantia nigra pars reticulata	UBERON:0001966	92.52	gold quality
inferior vagus X ganglion	UBERON:0005363	92.41	gold quality
left ventricle myocardium	UBERON:0006566	92.34	gold quality
cardia of stomach	UBERON:0001162	92.09	gold quality
entorhinal cortex	UBERON:0002728	92.08	gold quality
middle temporal gyrus	UBERON:0002771	92.08	gold quality
medulla oblongata	UBERON:0001896	91.99	gold quality
decidua	UBERON:0002450	91.99	gold quality
trigeminal ganglion	UBERON:0001675	91.91	gold quality
adrenal tissue	UBERON:0018303	91.91	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.94
E-CURD-89	no	355.57

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): NFE2L2

miRNA regulators (miRDB)

256 targeting KPNA6, 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-1277-5P	100.00	73.95	5056
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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3120-5P	100.00	65.56	965
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-3185	99.99	68.12	1959
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-4650-5P	99.98	64.69	999
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 17.1% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 11)

• Importin alpha5 and alpha7 bind to Stat3 upon cytokine stimulation. (PMID:16298512)
• Overexpression of KPNA6 facilitates KEAP1 nuclear import and attenuates NRF2 signaling, whereas knockdown of KPNA6 slows down KEAP1 nuclear import and enhances the NRF2-mediated adaptive response induced by oxidative stress. (PMID:21383067)
• Importin alpha1 and alpha7 are positive regulators of human-like polymerase activity and pathogenicity beyond their role in nuclear transport. (PMID:22275867)
• 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)
• a decreased H7N9 influenza A virus polymerase activity when importin-alpha7 was silenced by siRNA, is reported. (PMID:28189564)
• Development of a pipeline for automated, high-throughput analysis of PSPC1 paraspeckle protein isoforms reveals specific roles for KPNA2, KPNA4 and KPNA6 proteins. (PMID:28240251)
• the data showed that viral infection induced an elevation of the KPNA6 protein level due to an extension of the KPNA6 half-life via viral interference of the ubiquitin-proteasomal degradation of KPNA6. Notably, KPNA6 silencing or knockout dramatically reduced the replication of PRRSV and ZIKV. (PMID:29444946)
• HNF1A-MODY Mutations in Nuclear Localization Signal Impair HNF1A-Import Receptor KPNA6 Interactions. (PMID:33459938)
• Structural characterization of human importin alpha 7 in its cargo-free form at 2.5 A resolution. (PMID:35013395)
• KPNA6 is a Cofactor of ANP32A/B in Supporting Influenza Virus Polymerase Activity. (PMID:35044222)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	kpna6	ENSDARG00000044980
mus_musculus	Kpna6	ENSMUSG00000003731
rattus_norvegicus	Kpna6	ENSRNOG00000000127
drosophila_melanogaster	Kap-alpha1	FBGN0024889

Paralogs (6): KPNA3 (ENSG00000102753), KPNA1 (ENSG00000114030), KPNA2 (ENSG00000182481), KPNA7 (ENSG00000185467), KPNA4 (ENSG00000186432), KPNA5 (ENSG00000196911)

Protein

Protein identifiers

Importin subunit alpha-7 — O60684 (reviewed: O60684)

Alternative names: Karyopherin subunit alpha-6

All UniProt accessions (3): O60684, Q5TFJ7, S4R3E5

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.

Subunit / interactions. Interacts with ZIC3. Forms a complex with importin subunit beta-1. (Microbial infection) Interacts with ebolavirus protein VP24. (Microbial infection) Interacts with human parainfluenza virus type 2 proteins P and V.

Tissue specificity. Widely expressed.

Similarity. Belongs to the importin alpha family.

RefSeq proteins (1): NP_036448* (*=MANE)

Domains & families (InterPro)

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

Pfam: PF00514, PF01749, PF16186

UniProt features (57 total): helix 34, repeat 10, region of interest 3, modified residue 3, strand 2, turn 2, chain 1, domain 1, short sequence motif 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
4UAD	X-RAY DIFFRACTION	2.42
7RHT	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O60684-F1	86.45	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 (3): 1, 6, 113

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-68616	Assembly of the ORC complex at the origin of replication
R-HSA-68867	Assembly of the pre-replicative complex
R-HSA-69002	DNA Replication Pre-Initiation
R-HSA-69306	DNA Replication

MSigDB gene sets: 298 (showing top): REACTOME_DNA_REPLICATION, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, KAAB_FAILED_HEART_ATRIUM_DN, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, BROWNE_HCMV_INFECTION_16HR_UP, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, MARKS_ACETYLATED_NON_HISTONE_PROTEINS, GOBP_NUCLEAR_TRANSPORT, WEI_MYCN_TARGETS_WITH_E_BOX, CCANNAGRKGGC_UNKNOWN, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT, MARTINEZ_RB1_TARGETS_DN

GO Biological Process (10): transcription by RNA polymerase II (GO:0006366), protein import into nucleus (GO:0006606), NLS-bearing protein import into nucleus (GO:0006607), viral genome replication (GO:0019079), positive regulation of transcription by RNA polymerase II (GO:0045944), maternal process involved in female pregnancy (GO:0060135), entry of viral genome into host nucleus through nuclear pore complex via importin (GO:0075506), positive regulation of cytokine production involved in inflammatory response (GO:1900017), positive regulation of viral life cycle (GO:1903902), 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), nucleoplasm (GO:0005654), cytosol (GO:0005829), membrane (GO:0016020), NLS-dependent protein nuclear import complex (GO:0042564), host cell (GO:0043657), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Assembly of the pre-replicative complex	1
DNA Replication Pre-Initiation	1
DNA Replication	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
import into nucleus	2
viral life cycle	2
DNA-templated transcription	1
intracellular protein transport	1
protein localization to nucleus	1
establishment of protein localization to organelle	1
protein import into nucleus	1
viral process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
female pregnancy	1
multicellular organismal reproductive process	1
viral penetration into host nucleus	1
positive regulation of cytokine production	1
cytokine production involved in inflammatory response	1
regulation of cytokine production involved in inflammatory response	1
positive regulation of viral process	1
regulation of viral life cycle	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 lumen	1
cytoplasm	1
nucleocytoplasmic transport complex	1
host cellular component	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2956 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KPNA6	KPNB1	Q14974	882
KPNA6	IL1F10	Q8WWZ1	768
KPNA6	RCC1	P18754	732
KPNA6	STAT1	P42224	690
KPNA6	HNRNPK	P61978	649
KPNA6	BTN3A1	O00481	599
KPNA6	ZIC3	O60481	561
KPNA6	FOXP1	Q9H334	559
KPNA6	MUC3A	Q02505	552
KPNA6	IPO5	O00410	543
KPNA6	KEAP1	Q14145	526
KPNA6	SMURF1	Q9HCE7	508
KPNA6	A0A3B3IT14	A0A3B3IT14	506
KPNA6	TNPO1	Q92973	495
KPNA6	XPO1	O14980	485

IntAct

229 interactions, top by confidence:

A	B	Type	Score
NUP50	KPNA6	psi-mi:“MI:0915”(physical association)	0.870
KPNA6	NUP50	psi-mi:“MI:0915”(physical association)	0.870
RNMT	KPNA6	psi-mi:“MI:0915”(physical association)	0.800
KPNA6	RNMT	psi-mi:“MI:0914”(association)	0.800
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
KPNB1	KPNA6	psi-mi:“MI:0407”(direct interaction)	0.690
KPNA6	ANP32B	psi-mi:“MI:0915”(physical association)	0.670
KPNA6	TAF9	psi-mi:“MI:0915”(physical association)	0.670
KPNA6	LMNB1	psi-mi:“MI:0915”(physical association)	0.670
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640
VP24	KPNA6	psi-mi:“MI:0914”(association)	0.620
VP24	KPNA6	psi-mi:“MI:0915”(physical association)	0.620
PB2	KPNA6	psi-mi:“MI:0407”(direct interaction)	0.620
ORF4b	KPNA3	psi-mi:“MI:0914”(association)	0.620
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
	KPNA6	psi-mi:“MI:0915”(physical association)	0.560
KPNA6	NOP2	psi-mi:“MI:0915”(physical association)	0.560
KPNA6		psi-mi:“MI:0915”(physical association)	0.560

BioGRID (266): KPNA6 (Two-hybrid), KPNA6 (Two-hybrid), FRG1B (Two-hybrid), KPNA6 (Affinity Capture-MS), KPNA6 (Affinity Capture-MS), KPNA6 (Affinity Capture-RNA), EXOSC4 (Co-fractionation), HDAC1 (Co-fractionation), IPO5 (Co-fractionation), KPNA6 (Co-fractionation), KPNA6 (Co-fractionation), KPNA6 (Co-fractionation), KPNA6 (Co-fractionation), MORF4L1 (Co-fractionation), MORF4L2 (Co-fractionation)

ESM2 similar proteins: A0JMG1, A2VE52, D3K5L7, E0CZ16, E1C6Q1, E2R222, F1LZ52, F1LZF0, F1MBP6, O13016, O35345, O43791, O60684, O95164, O95198, O95544, P35815, P36993, P54797, P58058, P63143, P63144, Q0IHH9, Q0V7M0, Q0VCW1, Q15645, Q28528, Q28F89, Q2M2N2, Q2TA46, Q3UA06, Q4PJK1, Q5BL35, Q5NVK7, Q5RBV0, Q5REP9, Q5U1X1, Q5XHZ9, Q6GR09, Q6IQ16

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
KPNA6	up-regulates	NOTCH1	relocalization
KPNA6	up-regulates	NOTCH	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 133 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
NS1 Mediated Effects on Host Pathways	8	28.2×	8e-08
Transport of the SLBP independent Mature mRNA	6	24.2×	2e-05
Transport of the SLBP Dependant Mature mRNA	6	23.5×	2e-05
Transport of Ribonucleoproteins into the Host Nucleus	5	22.0×	2e-04
Nuclear import of Rev protein	5	20.7×	2e-04
Transport of Mature mRNA Derived from an Intronless Transcript	6	20.1×	3e-05
ISG15 antiviral mechanism	10	18.6×	7e-08
snRNP Assembly	7	18.3×	2e-05

GO biological processes:

GO term	Partners	Fold	FDR
NLS-bearing protein import into nucleus	5	39.3×	7e-05
protein import into nucleus	10	14.1×	2e-06
mRNA transport	5	12.9×	5e-03
circadian regulation of gene expression	5	11.5×	6e-03
regulation of apoptotic process	10	8.2×	1e-04
chromatin remodeling	8	5.7×	6e-03
defense response to virus	8	5.4×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	331
Likely benign	227
Benign	17

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
2498074	NM_001145715.3(KPNA7):c.523C>A (p.Gln175Lys)	Pathogenic
2498075	NM_001145715.3(KPNA7):c.1350_1356del (p.Leu450_Cys451insTer)	Pathogenic

SpliceAI

2029 predictions. Top by Δscore:

Variant	Effect	Δscore
1:32108133:GG:G	donor_gain	1.0000
1:32108134:GG:G	donor_gain	1.0000
1:32108135:G:GG	donor_gain	1.0000
1:32108136:T:A	donor_loss	1.0000
1:32108139:G:GG	donor_gain	1.0000
1:32154584:CTA:C	acceptor_loss	1.0000
1:32154586:A:AG	acceptor_gain	1.0000
1:32154586:A:G	acceptor_loss	1.0000
1:32154587:G:GC	acceptor_gain	1.0000
1:32154587:GA:G	acceptor_gain	1.0000
1:32154587:GAGA:G	acceptor_gain	1.0000
1:32154587:GAGAC:G	acceptor_gain	1.0000
1:32154717:AACAA:A	donor_gain	1.0000
1:32154718:ACAA:A	donor_gain	1.0000
1:32154719:CAA:C	donor_gain	1.0000
1:32154720:AA:A	donor_gain	1.0000
1:32154721:AG:A	donor_loss	1.0000
1:32154722:G:C	donor_loss	1.0000
1:32154722:GTGA:G	donor_gain	1.0000
1:32154727:T:G	donor_gain	1.0000
1:32154733:G:GT	donor_gain	1.0000
1:32154733:G:T	donor_gain	1.0000
1:32156846:C:G	acceptor_gain	1.0000
1:32156848:TTCA:T	acceptor_loss	1.0000
1:32156849:TCA:T	acceptor_loss	1.0000
1:32156850:CA:C	acceptor_loss	1.0000
1:32156851:A:AG	acceptor_gain	1.0000
1:32156851:A:AT	acceptor_loss	1.0000
1:32156852:G:GA	acceptor_gain	1.0000
1:32156852:GC:G	acceptor_gain	1.0000

AlphaMissense

3517 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:32154676:A:C	R31S	1.000
1:32154676:A:T	R31S	1.000
1:32156866:G:C	R51T	1.000
1:32156866:G:T	R51I	1.000
1:32156867:A:C	R51S	1.000
1:32156867:A:T	R51S	1.000
1:32157428:G:C	R105P	1.000
1:32157437:T:A	L108H	1.000
1:32157437:T:C	L108P	1.000
1:32158333:T:C	L133P	1.000
1:32159400:T:C	F143L	1.000
1:32159402:T:A	F143L	1.000
1:32159402:T:G	F143L	1.000
1:32159406:G:C	A145P	1.000
1:32159412:T:A	W147R	1.000
1:32159412:T:C	W147R	1.000
1:32159414:G:C	W147C	1.000
1:32159414:G:T	W147C	1.000
1:32159419:T:A	L149Q	1.000
1:32159419:T:C	L149P	1.000
1:32159424:A:G	N151D	1.000
1:32159426:T:A	N151K	1.000
1:32159426:T:G	N151K	1.000
1:32159428:T:A	I152N	1.000
1:32159431:C:A	A153D	1.000
1:32159433:T:C	S154P	1.000
1:32159436:G:A	G155R	1.000
1:32159436:G:C	G155R	1.000
1:32159437:G:A	G155E	1.000
1:32159437:G:T	G155V	1.000

dbSNP variants (sampled 300 via entrez): RS1000082384 (1:32138076 G>A,C,T), RS1000166616 (1:32151904 C>A,G), RS1000215220 (1:32168451 G>C), RS1000265528 (1:32161552 G>A), RS1000305565 (1:32144810 C>T), RS1000326047 (1:32163486 C>T), RS1000337214 (1:32161834 G>A), RS1000376351 (1:32112708 G>A), RS1000414069 (1:32126175 C>T), RS1000446647 (1:32127485 A>G), RS1000531893 (1:32167432 G>A), RS1000538139 (1:32142022 A>C,G), RS1000598879 (1:32133408 C>T), RS1000666563 (1:32165041 G>A), RS1000707532 (1:32111196 A>G)

Disease associations

OMIM: gene MIM:610563 | disease phenotypes: MIM:620319

GenCC curated gene-disease

Disease	Classification	Inheritance
oocyte/zygote/embryo maturation arrest 17	Strong	Autosomal recessive
neurodevelopmental disorder	Moderate	Autosomal recessive
partial corpus callosum agenesis-cerebellar vermis hypoplasia with posterior fossa cysts syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
epilepsy	Limited	AR

Mondo (3): oocyte/zygote/embryo maturation arrest 17 (MONDO:0957220), partial corpus callosum agenesis-cerebellar vermis hypoplasia with posterior fossa cysts syndrome (MONDO:0018430), neurodevelopmental disorder (MONDO:0700092)

Orphanet (0):

HPO phenotypes

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

GWAS associations

8 associations (top):

Study	Trait	p-value
GCST000623_2	Ulcerative colitis	9.000000e-11
GCST004131_62	Inflammatory bowel disease	8.000000e-09
GCST004133_29	Ulcerative colitis	7.000000e-07
GCST004730_2	Facial emotion recognition (sad faces)	3.000000e-06
GCST005951_36	Body mass index	9.000000e-10
GCST007623_3	Lack of premeditation	2.000000e-06
GCST008161_119	Waist circumference adjusted for body mass index	9.000000e-06
GCST90002381_454	Eosinophil count	3.000000e-11

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0008329	facial emotion recognition measurement
EFO:0004340	body mass index
EFO:0006946	behavioural disinhibition measurement
EFO:0007789	BMI-adjusted waist circumference
EFO:0004842	eosinophil count

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5724655 (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

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

pChembl	Type	Value	Unit	Molecule
6.89	IC50	130	nM	MOLIBRESIB

PubChem BioAssay actives

1 with measured affinity, of 6 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	2178806: Inhibition of KPNA6 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	0.1300	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, increases expression, affects cotreatment	3
Aflatoxin B1	decreases methylation, increases methylation	2
bisphenol F	increases expression, affects cotreatment	1
2,4,6-tribromophenol	decreases expression	1
triphenyl phosphate	affects expression	1
decabromobiphenyl ether	decreases expression	1
tetrabromobisphenol A	decreases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
coumarin	decreases phosphorylation	1
chloropicrin	decreases expression	1
clothianidin	increases expression	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
bisphenol S	affects cotreatment, 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
Benzo(a)pyrene	increases expression	1
Cadmium	decreases reaction, increases abundance, increases palmitoylation	1
Caffeine	decreases phosphorylation	1
Cisplatin	increases expression	1
Dexamethasone	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, increases expression	1
Ivermectin	decreases expression	1
Lead	decreases expression	1
Selenium	increases expression	1
Valproic Acid	increases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression	1
Cyclosporine	decreases methylation	1

ChEMBL screening assays

6 unique, capped per target: 6 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5697536	Binding	Inhibition of KPNA6 (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)

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

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