IPO8

Summary

IPO8 (importin 8, HGNC:9853) is a protein-coding gene on chromosome 12p11.21, encoding Importin-8 (O15397). Involved in nuclear protein import, either by acting as autonomous nuclear transport receptor or as an adapter-like protein in association with the importin-beta subunit KPNB1.

The importin-alpha/beta complex and the GTPase Ran mediate nuclear import of proteins with a classical nuclear localization signal. The protein encoded by this gene is a member of a class of approximately 20 potential Ran targets that share a sequence motif related to the Ran-binding site of importin-beta. This protein binds to the nuclear pore complex and, along with RanGTP and RANBP1, inhibits the GAP stimulation of the Ran GTPase. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 10526 — RefSeq curated summary.

At a glance

• Gene–disease (curated): VISS syndrome (Definitive, GenCC)
• GWAS associations: 11
• Clinical variants (ClinVar): 197 total — 16 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 137
• Druggable target: yes
• MANE Select transcript: NM_006390

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9853
Approved symbol	IPO8
Name	importin 8
Location	12p11.21
Locus type	gene with protein product
Status	Approved
Aliases	IMP8
Ensembl gene	ENSG00000133704
Ensembl biotype	protein_coding
OMIM	605600
Entrez	10526

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 20 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay, 1 non_stop_decay

ENST00000256079, ENST00000358724, ENST00000535598, ENST00000535989, ENST00000538338, ENST00000540979, ENST00000542464, ENST00000543446, ENST00000544829, ENST00000545077, ENST00000611458, ENST00000910949, ENST00000910950, ENST00000910951, ENST00000910952, ENST00000910953, ENST00000910954, ENST00000910955, ENST00000910956, ENST00000936164, ENST00000936165, ENST00000936166, ENST00000936167

RefSeq mRNA: 2 — MANE Select: NM_006390 NM_001190995, NM_006390

CCDS: CCDS53773, CCDS8719

Canonical transcript exons

ENST00000256079 — 25 exons

Exon	Start	End
ENSE00000734518	30656684	30656750
ENSE00000734520	30661141	30661266
ENSE00000734522	30662327	30662487
ENSE00000734524	30663489	30663654
ENSE00000734526	30665220	30665309
ENSE00000734528	30665729	30665845
ENSE00000734530	30666175	30666251
ENSE00000734532	30669183	30669282
ENSE00000734534	30670962	30671096
ENSE00000734537	30673990	30674074
ENSE00000734540	30674659	30674753
ENSE00000734542	30676498	30676587
ENSE00000734551	30690496	30690577
ENSE00000835991	30631895	30632011
ENSE00000835992	30634083	30634286
ENSE00000835993	30636982	30637187
ENSE00000835994	30639515	30639735
ENSE00001001375	30695564	30695869
ENSE00001098302	30652192	30652289
ENSE00001098303	30652967	30653092
ENSE00001777016	30649137	30649232
ENSE00002245507	30628988	30630957
ENSE00003649374	30681659	30681817
ENSE00003789381	30680482	30680638
ENSE00003790223	30684301	30684457

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 99.51.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.6584 / max 199.4382, expressed in 1750 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
130318	9.1415	1749
130317	0.3874	173
130319	0.1296	22

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.51	gold quality
oocyte	CL:0000023	98.67	gold quality
tendon of biceps brachii	UBERON:0008188	95.47	gold quality
medial globus pallidus	UBERON:0002477	93.61	gold quality
skin of hip	UBERON:0001554	93.15	gold quality
mucosa of sigmoid colon	UBERON:0004993	93.07	gold quality
colonic mucosa	UBERON:0000317	92.95	gold quality
calcaneal tendon	UBERON:0003701	92.85	gold quality
buccal mucosa cell	CL:0002336	92.77	gold quality
superficial temporal artery	UBERON:0001614	92.75	gold quality
seminal vesicle	UBERON:0000998	92.70	gold quality
globus pallidus	UBERON:0001875	92.69	gold quality
tendon	UBERON:0000043	92.68	gold quality
jejunal mucosa	UBERON:0000399	92.67	gold quality
rectum	UBERON:0001052	92.62	gold quality
sural nerve	UBERON:0015488	92.21	gold quality
endothelial cell	CL:0000115	92.02	silver quality
colonic epithelium	UBERON:0000397	92.00	gold quality
cauda epididymis	UBERON:0004360	91.92	gold quality
renal medulla	UBERON:0000362	91.90	gold quality
trabecular bone tissue	UBERON:0002483	91.72	gold quality
urethra	UBERON:0000057	91.66	gold quality
saphenous vein	UBERON:0007318	91.50	gold quality
parotid gland	UBERON:0001831	91.38	gold quality
epithelium of nasopharynx	UBERON:0001951	91.35	gold quality
upper leg skin	UBERON:0004262	91.27	gold quality
endometrium	UBERON:0001295	91.25	gold quality
pigmented layer of retina	UBERON:0001782	91.24	gold quality
tonsil	UBERON:0002372	91.13	gold quality
lateral globus pallidus	UBERON:0002476	91.02	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.40
E-MTAB-6379	no	291.51

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

142 targeting IPO8, 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-4262	100.00	73.26	3931
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-101-3P	99.94	75.03	2230

Literature-anchored findings (GeneRIF, showing 9)

• TGF-beta-induced and basal state spontaneous nuclear import of Smad4 require importin 7 and 8. (PMID:18519565)
• IPO8 is the most accurate reference gene for clinical lung specimens. (PMID:19014639)
• Study provides evidence that Imp8 is required for cytoplasmic miRNA-guided gene silencing and affects nuclear localization of Ago proteins. (PMID:19167051)
• Knockdown of IPO8 reduced the amount of nuclear p65 following TNF stimulation. IPO8 binding to p65 is NLS independent. (PMID:23906023)
• importin alpha8 functions as a cNLS receptor with distinct cargo specificity, and that heterodimerization by importin alpha8 is a novel regulatory mode of cNLS binding, in addition to the autoinhibitory regulation by the importin beta binding domain. (PMID:26220098)
• Our studies also suggest that nuclear entry is important for the prooncogenic activity of eIF4E, at least in this context. These findings position nuclear trafficking of eIF4E as a critical step in its regulation and position the importin 8-eIF4E complex as a novel therapeutic target. (PMID:27114554)
• the findings of the present study provided novel insights into the control of IPO8 transcription, and may enhance understanding regarding RUNX2 regulatory mechanisms in osteoblast differentiation, bone development, and degenerative bone disease. (PMID:27277970)
• Bi-allelic variants in IPO8 cause a connective tissue disorder associated with cardiovascular defects, skeletal abnormalities, and immune dysregulation. (PMID:34010604)
• A human importin-beta-related disorder: Syndromic thoracic aortic aneurysm caused by bi-allelic loss-of-function variants in IPO8. (PMID:34010605)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	ipo8	ENSDARG00000058159
mus_musculus	Ipo8	ENSMUSG00000040029
rattus_norvegicus	Ipo8	ENSRNOG00000056041

Paralogs (4): IPO11 (ENSG00000086200), CSE1L (ENSG00000124207), IPO9 (ENSG00000198700), IPO7 (ENSG00000205339)

Protein

Protein identifiers

Importin-8 — O15397 (reviewed: O15397)

Alternative names: Ran-binding protein 8

All UniProt accessions (9): A0A087WXH2, O15397, F5GXT5, F5H009, F5H244, F5H292, F5H2I3, F5H815, H0YH64

UniProt curated annotations — full annotation on UniProt →

Function. Involved in nuclear protein import, either by acting as autonomous nuclear transport receptor or as an adapter-like protein in association with the importin-beta subunit KPNB1. Acting autonomously, may serve as receptor for nuclear localization signals (NLS) and promote translocation of import substrates through the nuclear pore complex (NPC) by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to importin, the importin/substrate complex dissociates and importin is re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran. 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 the signal recognition particle protein SRP19. May also be involved in cytoplasm-to-nucleus shuttling of a broad spectrum of other cargos, including Argonaute-microRNAs complexes, the JUN protein, RELA/NF-kappa-B p65 subunit, the translation initiation factor EIF4E and a set of receptor-activated mothers against decapentaplegic homolog (SMAD) transcription factors that play a critical role downstream of the large family of transforming growth factor beta and bone morphogenetic protein (BMP) cytokines.

Subunit / interactions. Forms a heterodimer with KPNB1. Interacts with SRP19. Interacts with RPL23A. Binds directly to nuclear pore complexes. Interacts with LRPPRC; the interaction occurs when LRPPRC is in its RNA-free form and promotes import of LRPPRC to the nucleus to allow for EIF4E-mediated export of mRNAS from the nucleus to the cytoplasm.

Subcellular location. Cytoplasm. Nucleus.

Disease relevance. VISS syndrome (VISS) [MIM:619472] An autosomal recessive disease characterized by early-onset thoracic aortic aneurysm, aneurysm and tortuosity of other arteries, motor developmental delay, connective tissue findings such as joint hypermobility, skin laxity and hernias, and craniofacial dysmorphic features. Immune dysregulation has been reported in some patients. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the importin beta family.

Isoforms (2)

UniProt ID	Names	Canonical?
O15397-1	1	yes
O15397-2	2

RefSeq proteins (2): NP_001177924, NP_006381* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001494	Importin-beta_N	Domain
IPR011989	ARM-like	Homologous_superfamily
IPR013713	XPO2_central	Domain
IPR016024	ARM-type_fold	Homologous_superfamily
IPR058669	TPR_IPO7/11-like	Domain

Pfam: PF03810, PF08506, PF25758

UniProt features (25 total): sequence variant 13, compositionally biased region 4, sequence conflict 2, modified residue 2, chain 1, domain 1, region of interest 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O15397-F1	87.59	0.72

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (2): 902, 903

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-5578749	Transcriptional regulation by small RNAs
R-HSA-211000	Gene Silencing by RNA
R-HSA-74160	Gene expression (Transcription)

MSigDB gene sets: 462 (showing top): BROWNE_HCMV_INFECTION_30MIN_DN, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOMF_GTPASE_BINDING, GOBP_NUCLEAR_TRANSPORT, chr12p11, BROWNE_HCMV_INFECTION_48HR_DN, MORF_RAB3A, MORF_BMPR2, GOBP_PROTEIN_LOCALIZATION_TO_ORGANELLE, DING_LUNG_CANCER_EXPRESSION_BY_COPY_NUMBER, ZHANG_BREAST_CANCER_PROGENITORS_UP, GOBP_PROTEIN_LOCALIZATION_TO_NUCLEUS

GO Biological Process (4): protein import into nucleus (GO:0006606), signal transduction (GO:0007165), intracellular protein transport (GO:0006886), protein transport (GO:0015031)

GO Molecular Function (2): small GTPase binding (GO:0031267), protein binding (GO:0005515)

GO Cellular Component (5): nuclear envelope (GO:0005635), nucleoplasm (GO:0005654), cytosol (GO:0005829), nucleus (GO:0005634), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Gene Silencing by RNA	1
Gene expression (Transcription)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
intracellular protein localization	2
intracellular protein transport	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
protein transport	1
intracellular transport	1
transport	1
establishment of protein localization	1
GTPase binding	1
binding	1
nucleus	1
endomembrane system	1
organelle envelope	1
nuclear lumen	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

2624 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
IPO8	AGO2	Q9UKV8	837
IPO8	RANBP1	P43487	805
IPO8	IPO9	Q96P70	787
IPO8	XPO1	O14980	759
IPO8	XPOT	O43592	753
IPO8	TNPO1	Q92973	745
IPO8	UBAC1	Q9BSL1	728
IPO8	IPO13	O94829	707
IPO8	AGO1	Q9UL18	705
IPO8	IPO11	Q9UI26	694
IPO8	XPO5	Q9HAV4	691
IPO8	IPO4	Q8TEX9	668
IPO8	TNPO3	Q9Y5L0	636
IPO8	IPO5	O00410	624
IPO8	RAP2B	P17964	609

IntAct

261 interactions, top by confidence:

A	B	Type	Score
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
IPO8	AGO2	psi-mi:“MI:0915”(physical association)	0.690
AGO2	IPO8	psi-mi:“MI:0915”(physical association)	0.690
TNFSF13B	IPO8	psi-mi:“MI:0914”(association)	0.640
AGO3	IPO8	psi-mi:“MI:0915”(physical association)	0.640
IPO8	AGO3	psi-mi:“MI:0915”(physical association)	0.640
IPO8	AGO3	psi-mi:“MI:0403”(colocalization)	0.640
IPO8	TRIM28	psi-mi:“MI:0914”(association)	0.640
IPO8	AGO4	psi-mi:“MI:0915”(physical association)	0.580
IPO8	ZFP2	psi-mi:“MI:0915”(physical association)	0.560
WT1	IPO8	psi-mi:“MI:0915”(physical association)	0.560
IPO8	ZNF774	psi-mi:“MI:0915”(physical association)	0.560
IPO8	ZNF264	psi-mi:“MI:0915”(physical association)	0.560
SMAD1	IPO8	psi-mi:“MI:0915”(physical association)	0.540
SMAD1	IPO8	psi-mi:“MI:0407”(direct interaction)	0.540
SMAD3	IPO8	psi-mi:“MI:0407”(direct interaction)	0.540
SMAD3	IPO8	psi-mi:“MI:0915”(physical association)	0.540
PTGER3	PIK3R2	psi-mi:“MI:0914”(association)	0.530
ZNF331	USP9Y	psi-mi:“MI:0914”(association)	0.530
HP1BP3	IPO8	psi-mi:“MI:0914”(association)	0.530
ZNF354C	IPO8	psi-mi:“MI:0914”(association)	0.530
ZNF382	IPO8	psi-mi:“MI:0914”(association)	0.530

BioGRID (260): IPO8 (Affinity Capture-RNA), IPO8 (Affinity Capture-MS), IPO8 (Affinity Capture-MS), IPO8 (Affinity Capture-MS), IPO8 (Affinity Capture-MS), IPO8 (Affinity Capture-MS), IPO8 (Affinity Capture-MS), IPO8 (Co-fractionation), IPO8 (Co-fractionation), IPO8 (Co-fractionation), IPO8 (Co-fractionation), IPO9 (Co-fractionation), PPM1G (Co-fractionation), IPO8 (Affinity Capture-MS), IPO8 (Proximity Label-MS)

ESM2 similar proteins: A5D785, A5WW24, O00410, O04375, O04376, O15397, O35638, O46563, O60518, O95373, Q08AM6, Q16401, Q499Y0, Q569Z2, Q5IFJ8, Q5R9G4, Q5R9J2, Q5ZLT0, Q5ZMR9, Q68F38, Q6GMY9, Q704U0, Q7PC79, Q7TMY7, Q802D3, Q8AY73, Q8BIV3, Q8BKC5, Q8GUL2, Q8K2V6, Q8N3U4, Q8VI75, Q8WVM7, Q91YE6, Q924C1, Q96P70, Q99NF8, Q9C0E2, Q9D3E6, Q9DGN0

Diamond homologs: A5WW24, O15397, O95373, Q7TMY7, Q9EPL8, F4IRR2, O59809

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 207 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
TGFBR3 expression	5	15.0×	8e-04
Pre-NOTCH Expression and Processing	5	12.1×	2e-03
Regulation of MECP2 expression and activity	5	12.1×	2e-03
Signaling by TGFBR3	5	12.1×	2e-03
NR1H3 & NR1H2 regulate gene expression linked to cholesterol transport and efflux	5	10.2×	3e-03
Signaling by ALK in cancer	5	8.9×	5e-03
MAPK6/MAPK4 signaling	8	7.2×	8e-04
Signaling by NOTCH	6	6.9×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	16
Likely pathogenic	8
Uncertain significance	110
Likely benign	19
Benign	3

Top pathogenic / likely-pathogenic (24)

Variant ID	HGVS	Classification
1047908	NM_006390.4(IPO8):c.1420C>T (p.Arg474Ter)	Pathogenic
1047909	NM_006390.4(IPO8):c.770_777del (p.Val257fs)	Pathogenic
1047910	NM_006390.4(IPO8):c.1000dup (p.Val334fs)	Pathogenic
1047911	NM_006390.4(IPO8):c.1428+5G>A	Pathogenic
1047912	NM_006390.4(IPO8):c.2597_2601del (p.Leu866fs)	Pathogenic
1047913	NM_006390.4(IPO8):c.776G>A (p.Trp259Ter)	Pathogenic
1047914	NM_006390.4(IPO8):c.2347_2369del (p.Leu783fs)	Pathogenic
1064722	NM_006390.4(IPO8):c.82C>T (p.Gln28Ter)	Pathogenic
1064723	NM_006390.4(IPO8):c.2695+3_2695+7del	Pathogenic
1064724	NM_006390.4(IPO8):c.1538del (p.Pro513fs)	Pathogenic
1064727	NM_006390.4(IPO8):c.2279del (p.Leu760fs)	Pathogenic
1064728	NM_006390.4(IPO8):c.728del (p.Pro243fs)	Pathogenic
1192309	NM_006390.4(IPO8):c.2695+4_2695+8del	Pathogenic
2572415	NM_006390.4(IPO8):c.639+1G>A	Pathogenic
3390931	NM_006390.4(IPO8):c.2600_2601delinsAA (p.Phe867Ter)	Pathogenic
4533347	NM_006390.4(IPO8):c.686G>A (p.Trp229Ter)	Pathogenic
1064720	NM_006390.4(IPO8):c.262G>A (p.Asp88Asn)	Likely pathogenic
1064725	NM_006390.4(IPO8):c.2245T>C (p.Cys749Arg)	Likely pathogenic
1064726	NM_006390.4(IPO8):c.2500C>T (p.Arg834Trp)	Likely pathogenic
1064729	NM_006390.4(IPO8):c.2129C>G (p.Ser710Ter)	Likely pathogenic
1526425	NM_006390.4(IPO8):c.700C>T (p.Arg234Ter)	Likely pathogenic
1526426	NM_006390.4(IPO8):c.1933C>T (p.Gln645Ter)	Likely pathogenic
2070383	NM_006390.4(IPO8):c.85-1G>C	Likely pathogenic
3387778	NM_006390.4(IPO8):c.1216_1220del (p.Lys406fs)	Likely pathogenic

SpliceAI

4351 predictions. Top by Δscore:

Variant	Effect	Δscore
12:30630966:T:TC	acceptor_gain	1.0000
12:30630969:C:CT	acceptor_gain	1.0000
12:30630970:A:T	acceptor_gain	1.0000
12:30631884:CT:C	donor_gain	1.0000
12:30631896:TGCC:T	donor_gain	1.0000
12:30631933:T:TA	donor_gain	1.0000
12:30632010:AG:A	acceptor_gain	1.0000
12:30632011:GC:G	acceptor_loss	1.0000
12:30632012:C:CC	acceptor_gain	1.0000
12:30632015:T:C	acceptor_gain	1.0000
12:30632015:T:TC	acceptor_gain	1.0000
12:30632018:CATTT:C	acceptor_gain	1.0000
12:30632019:A:AC	acceptor_gain	1.0000
12:30632019:A:C	acceptor_gain	1.0000
12:30632019:A:T	acceptor_gain	1.0000
12:30632020:T:C	acceptor_gain	1.0000
12:30632020:T:TC	acceptor_gain	1.0000
12:30632021:T:C	acceptor_gain	1.0000
12:30632021:T:TC	acceptor_gain	1.0000
12:30632022:T:C	acceptor_gain	1.0000
12:30632022:T:TC	acceptor_gain	1.0000
12:30634081:A:AC	donor_gain	1.0000
12:30634082:C:CC	donor_gain	1.0000
12:30634085:A:AC	donor_gain	1.0000
12:30634085:AT:A	donor_gain	1.0000
12:30634144:A:AC	donor_gain	1.0000
12:30634145:C:CC	donor_gain	1.0000
12:30634148:AAC:A	donor_gain	1.0000
12:30634148:AACC:A	donor_gain	1.0000
12:30634149:A:C	donor_gain	1.0000

AlphaMissense

6889 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:30674069:C:T	G277E	1.000
12:30684358:C:G	R89P	1.000
12:30684422:A:G	W68R	1.000
12:30684422:A:T	W68R	1.000
12:30695571:A:G	L26P	1.000
12:30637158:C:T	G840E	0.999
12:30637176:C:G	R834P	0.999
12:30639543:A:G	W821R	0.999
12:30639543:A:T	W821R	0.999
12:30649183:A:G	L741P	0.999
12:30663531:C:G	A518P	0.999
12:30663542:A:T	V514D	0.999
12:30665766:A:G	L434P	0.999
12:30666181:T:A	R405S	0.999
12:30666181:T:G	R405S	0.999
12:30666215:G:T	A394D	0.999
12:30669220:C:A	W369C	0.999
12:30669220:C:G	W369C	0.999
12:30669222:A:G	W369R	0.999
12:30669222:A:T	W369R	0.999
12:30670988:A:G	W340R	0.999
12:30670988:A:T	W340R	0.999
12:30674659:C:G	R275P	0.999
12:30674671:C:G	R271P	0.999
12:30674708:A:G	W259R	0.999
12:30674708:A:T	W259R	0.999
12:30676542:A:G	W229R	0.999
12:30676542:A:T	W229R	0.999
12:30680503:T:A	K206N	0.999
12:30680503:T:G	K206N	0.999

dbSNP variants (sampled 300 via entrez): RS1000050354 (12:30661731 A>C), RS1000110195 (12:30696364 G>A), RS1000248678 (12:30642762 G>A), RS1000386443 (12:30642456 G>A), RS1000397962 (12:30642398 A>G), RS1000477793 (12:30676779 G>T), RS1000511713 (12:30649298 C>A,G,T), RS1000604610 (12:30657356 G>T), RS1000605386 (12:30691529 G>C), RS1000684095 (12:30636567 C>A), RS1000713788 (12:30684491 C>A,T), RS1000736506 (12:30644042 T>G), RS1000813989 (12:30629296 T>C), RS1000848368 (12:30684845 G>C), RS1000876390 (12:30631027 C>T)

Disease associations

OMIM: gene MIM:605600 | disease phenotypes: MIM:619472, MIM:607323

GenCC curated gene-disease

Disease	Classification	Inheritance
VISS syndrome	Definitive	Autosomal recessive

Mondo (2): VISS syndrome (MONDO:0859177), Duane-radial ray syndrome (MONDO:0011812)

Orphanet (2): Okihiro syndrome (Orphanet:93293), Acro-renal-ocular syndrome (Orphanet:959)

HPO phenotypes

137 total (30 of 137 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000023	Inguinal hernia
HP:0000098	Tall stature
HP:0000126	Hydronephrosis
HP:0000158	Macroglossia
HP:0000175	Cleft palate
HP:0000185	Cleft soft palate
HP:0000193	Bifid uvula
HP:0000202	Orofacial cleft
HP:0000218	High palate
HP:0000248	Brachycephaly
HP:0000252	Microcephaly
HP:0000268	Dolichocephaly
HP:0000272	Malar flattening
HP:0000278	Retrognathia
HP:0000308	Microretrognathia
HP:0000316	Hypertelorism
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000369	Low-set ears
HP:0000378	Cupped ear
HP:0000400	Macrotia
HP:0000426	Prominent nasal bridge
HP:0000490	Deeply set eye
HP:0000508	Ptosis
HP:0000520	Proptosis
HP:0000541	Retinal detachment
HP:0000545	Myopia
HP:0000592	Blue sclerae
HP:0000637	Long palpebral fissure

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST005023_1	Initial pursuit acceleration	8.000000e-11
GCST005023_33	Initial pursuit acceleration	2.000000e-10
GCST005026_19	Initial pursuit acceleration in psychotic disorders	9.000000e-13
GCST005026_5	Initial pursuit acceleration in psychotic disorders	8.000000e-12
GCST012071_6	Response to selenium supplementation (change in plasma selenium concentration)	4.000000e-06
GCST013216_2	Order dimension in obsessive compulsive disorder	2.000000e-06
GCST013216_4	Order dimension in obsessive compulsive disorder	2.000000e-06
GCST013216_6	Order dimension in obsessive compulsive disorder	2.000000e-06
GCST013216_7	Order dimension in obsessive compulsive disorder	3.000000e-06
GCST013216_8	Order dimension in obsessive compulsive disorder	2.000000e-06
GCST90002393_412	Monocyte count	6.000000e-15

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0008434	initial pursuit acceleration
EFO:0600021	response to dietary selenium supplementation
EFO:0007802	obsessive-compulsive symptom measurement
EFO:0005091	monocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6067044 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
methacrylaldehyde	increases abundance, affects cotreatment, increases oxidation	2
Acetaminophen	decreases expression	2
Acrolein	increases abundance, affects cotreatment, increases oxidation	2
Ozone	increases oxidation, increases abundance, affects cotreatment	2
Aflatoxin B1	decreases methylation, increases expression	2
aristolochic acid I	decreases expression	1
geldanamycin	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	decreases expression	1
methylselenic acid	increases expression	1
decabromobiphenyl ether	increases expression	1
arsenite	affects binding, decreases reaction	1
methylparaben	decreases expression	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
butyraldehyde	decreases expression	1
tetrabromobisphenol A	decreases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	increases expression	1
(+)-JQ1 compound	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Air Pollutants	increases abundance, increases oxidation, affects cotreatment	1
Air Pollutants, Occupational	decreases expression	1
Atrazine	increases expression	1
Cadmium	increases expression	1
Calcitriol	decreases expression	1
Diethylhexyl Phthalate	increases abundance, increases methylation	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
CHEMBL5651640	Binding	Binding affinity to human IPO8 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

Cellosaurus cell lines

1 cell lines: 1 induced pluripotent stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_C1KJ	BBANTWi011-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03059420	Not specified	RECRUITING	Genetic Studies of Strabismus, Congenital Cranial Dysinnervation Disorders (CCDDs), and Their Associated Anomalies