INSC

Summary

INSC (INSC spindle orientation adaptor protein, HGNC:33116) is a protein-coding gene on chromosome 11p15.2, encoding Protein inscuteable homolog (Q1MX18). May function as an adapter linking the Par3 complex to the GPSM1/GPSM2 complex.

In Drosophila, neuroblasts divide asymmetrically into another neuroblast at the apical side and a smaller ganglion mother cell on the basal side. Cell polarization is precisely regulated by 2 apically localized multiprotein signaling complexes that are tethered by Inscuteable, which regulates their apical localization (Izaki et al., 2006 [PubMed 16458856]).

Source: NCBI Gene 387755 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 121 total
• MANE Select transcript: NM_001042536

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:33116
Approved symbol	INSC
Name	INSC spindle orientation adaptor protein
Location	11p15.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000188487
Ensembl biotype	protein_coding
OMIM	610668
Entrez	387755

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 12 protein_coding, 2 protein_coding_CDS_not_defined

ENST00000379554, ENST00000379556, ENST00000424273, ENST00000447214, ENST00000525218, ENST00000526102, ENST00000528567, ENST00000530161, ENST00000876188, ENST00000876189, ENST00000876190, ENST00000876191, ENST00000961585, ENST00000961586

RefSeq mRNA: 6 — MANE Select: NM_001042536 NM_001031853, NM_001042536, NM_001278313, NM_001278314, NM_001278315, NM_001278316

CCDS: CCDS41621, CCDS41622, CCDS60735, CCDS60736

Canonical transcript exons

ENST00000379556 — 13 exons

Exon	Start	End
ENSE00001379365	15177111	15177163
ENSE00001383198	15178324	15178447
ENSE00001538075	15114923	15115003
ENSE00001599511	15175741	15176086
ENSE00002184057	15245912	15247208
ENSE00002687078	15200824	15200949
ENSE00003458444	15238919	15239074
ENSE00003495607	15235602	15235668
ENSE00003497422	15190701	15190814
ENSE00003509945	15240447	15240523
ENSE00003529591	15221477	15221648
ENSE00003581028	15225650	15225828
ENSE00003649808	15149130	15149230

Expression profiles

Bgee: expression breadth ubiquitous, 158 present calls, max score 89.71.

FANTOM5 (CAGE): breadth broad, TPM avg 1.9315 / max 151.2291, expressed in 240 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
113231	1.6337	224
113232	0.2265	84
206198	0.0713	2

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
tibia	UBERON:0000979	89.71	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	86.77	gold quality
secondary oocyte	CL:0000655	86.51	gold quality
dorsal root ganglion	UBERON:0000044	85.10	gold quality
oocyte	CL:0000023	85.08	gold quality
tibial nerve	UBERON:0001323	83.40	gold quality
trigeminal ganglion	UBERON:0001675	83.23	gold quality
sural nerve	UBERON:0015488	80.26	gold quality
mucosa of transverse colon	UBERON:0004991	76.64	gold quality
muscle layer of sigmoid colon	UBERON:0035805	76.11	gold quality
buccal mucosa cell	CL:0002336	76.07	gold quality
cartilage tissue	UBERON:0002418	73.67	silver quality
transverse colon	UBERON:0001157	72.21	gold quality
trabecular bone tissue	UBERON:0002483	71.85	silver quality
colon	UBERON:0001155	71.52	gold quality
small intestine Peyer’s patch	UBERON:0003454	71.26	gold quality
lower esophagus muscularis layer	UBERON:0035833	71.05	gold quality
lower esophagus	UBERON:0013473	70.98	gold quality
large intestine	UBERON:0000059	70.52	gold quality
intestine	UBERON:0000160	70.22	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	70.10	gold quality
small intestine	UBERON:0002108	69.95	gold quality
rectum	UBERON:0001052	68.92	gold quality
body of stomach	UBERON:0001161	66.07	gold quality
right atrium auricular region	UBERON:0006631	65.16	gold quality
popliteal artery	UBERON:0002250	64.82	gold quality
tibial artery	UBERON:0007610	64.77	gold quality
stomach	UBERON:0000945	64.32	gold quality
cardiac atrium	UBERON:0002081	64.18	gold quality
vermiform appendix	UBERON:0001154	63.88	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.57

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

49 targeting INSC, 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-656-3P	100.00	72.15	2788
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4455	100.00	65.48	1587
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4789-5P	99.98	70.76	2721
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-1297	99.91	73.41	3162
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-494-3P	99.70	71.45	2795
HSA-MIR-33A-3P	99.70	70.27	3362
HSA-MIR-4729	99.69	72.18	4233
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-8061	99.63	69.44	1411
HSA-MIR-6716-5P	99.56	68.62	1244
HSA-MIR-510-3P	99.54	70.06	2965
HSA-MIR-4519	99.48	66.10	859
HSA-MIR-6083	99.47	68.73	2393

Literature-anchored findings (GeneRIF, showing 7)

• cloning of two distinct cDNAs from Insc gene, which is differentially expressed from alternative first exons;Insc proteins bind to the Pins homologues LGN and AGS3, and also to Par3 and Par3beta (PMID:16458856)
• These data present AGS3, G-proteins, and mInsc as candidate proteins involved in regulating cellular stress associated with protein-processing pathologies. (PMID:20065032)
• mInsc-LGN interaction is vital for stabilization of LGN and for intracellular localization of mInsc. (PMID:22074847)
• Studies indicate that the Inscuteable (Insc)and NuMA are mutually exclusive interactors of LGN. (PMID:22977735)
• In mammary stem cells, the asymmetric domain of Insc bound to LGN:Galphai(GDP) suffices to drive asymmetric fate, and reverts aberrant symmetric divisions induced by p53 loss. (PMID:29523789)
• Genome-wide association study identified INSC gene associated with Trail Making Test Part A and Alzheimer’s disease related cognitive phenotypes. (PMID:34224794)
• A missense mutation in human INSC causes peripheral neuropathy. (PMID:38589651)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
mus_musculus	Insc	ENSMUSG00000048782
rattus_norvegicus	Insc	ENSRNOG00000024712
drosophila_melanogaster	insc	FBGN0011674
caenorhabditis_elegans		WBGENE00018392

Protein

Protein identifiers

Protein inscuteable homolog — Q1MX18 (reviewed: Q1MX18)

All UniProt accessions (2): A0A0A0MSI1, Q1MX18

UniProt curated annotations — full annotation on UniProt →

Function. May function as an adapter linking the Par3 complex to the GPSM1/GPSM2 complex. Involved in spindle orientation during mitosis. May regulate cell proliferation and differentiation in the developing nervous system. May play a role in the asymmetric division of fibroblasts and participate in the process of stratification of the squamous epithelium.

Subunit / interactions. Interacts with ALS2CR19/PAR3B and F2RL2/PAR3. Interacts with GPSM1/AGS3 and GPSM2/LGN (via TPR repeat region). Identified in a complex with GPSM2 and F2RL2.

Subcellular location. Cytoplasm. Cell cortex.

Tissue specificity. Isoform 1 is expressed in various tissues with stronger expression in liver, kidney and small intestine. Isoform 2 is abundantly expressed in small intestine and to a lower extent in lung and pancreas.

Isoforms (6)

UniProt ID	Names	Canonical?
Q1MX18-1	1, Long	yes
Q1MX18-2	2, Short
Q1MX18-3	3
Q1MX18-4	4
Q1MX18-5	5
Q1MX18-6	6

RefSeq proteins (6): NP_001027024, NP_001036001, NP_001265242, NP_001265243, NP_001265244, NP_001265245 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000225	Armadillo	Repeat
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR031938	INSC_LBD	Domain
IPR038205	INSC_LBD_sf	Homologous_superfamily
IPR039921	Inscuteable	Family
IPR045789	Insc_C	Domain

Pfam: PF16748, PF19427

UniProt features (24 total): sequence conflict 6, splice variant 6, mutagenesis site 3, sequence variant 2, helix 2, strand 2, chain 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
3SF4	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q1MX18-F1	83.44	0.70

Functional residue map

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

Mutagenesis-validated functional residues (3):

Position	Phenotype
78	abolishes interaction with gpsm2.
89	strongly reduces interaction with gpsm2. abolishes interaction with gpsm2 and gpsm1; when associated with d-97.
97	abolishes interaction with gpsm2 and gpsm1; when associated with r-89.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 51 (showing top): GOBP_APICAL_PROTEIN_LOCALIZATION, GOBP_ASYMMETRIC_CELL_DIVISION, GOBP_REGULATION_OF_CELL_DIVISION, GOBP_REGULATION_OF_PROTEIN_STABILITY, GOCC_CYTOPLASMIC_REGION, GOCC_APICAL_PART_OF_CELL, GOCC_CELL_CORTEX_REGION, GOBP_CELL_DIVISION, GOMF_CYTOSKELETAL_ANCHOR_ACTIVITY, BOCHKIS_FOXA2_TARGETS, OHGUCHI_LIVER_HNF4A_TARGETS_DN, GOCC_APICAL_CORTEX, GSE13522_CTRL_VS_T_CRUZI_BRAZIL_STRAIN_INF_SKIN_DN, PAX3_TARGET_GENES, MIR3658

GO Biological Process (6): nervous system development (GO:0007399), asymmetric cell division (GO:0008356), regulation of asymmetric cell division (GO:0009786), cell differentiation (GO:0030154), regulation of protein stability (GO:0031647), apical protein localization (GO:0045176)

GO Molecular Function (4): cytoskeletal adaptor activity (GO:0008093), protein domain specific binding (GO:0019904), protein-macromolecule adaptor activity (GO:0030674), protein binding (GO:0005515)

GO Cellular Component (5): plasma membrane (GO:0005886), protein-containing complex (GO:0032991), apical cortex (GO:0045179), cytoplasm (GO:0005737), cell cortex (GO:0005938)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	2
cell periphery	2
system development	1
cell division	1
asymmetric cell division	1
regulation of cell division	1
cellular developmental process	1
regulation of biological quality	1
intracellular protein localization	1
cytoskeletal protein binding	1
protein-macromolecule adaptor activity	1
molecular adaptor activity	1
binding	1
membrane	1
cellular_component	1
cell cortex region	1
intracellular anatomical structure	1
cellular anatomical structure	1
cytoplasm	1

Protein interactions and networks

STRING

790 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
INSC	GPSM2	P81274	853
INSC	PARD3B	Q8TEW8	831
INSC	PARD3	Q8TEW0	620
INSC	LGALS4	P56470	598
INSC	GPSM1	Q86YR5	583
INSC	NUMA1	Q14980	518
INSC	TH	P07101	471
INSC	NUMBL	Q9Y6R0	450
INSC	NUMB	P49757	447
INSC	NES	P48681	435
INSC	POU3F4	P49335	434
INSC	PAX6	P26367	426
INSC	SOX2	P48431	417
INSC	PRR12	Q9ULL5	412
INSC	SCAF1	Q9H7N4	382

IntAct

43 interactions, top by confidence:

A	B	Type	Score
GPSM2	INSC	psi-mi:“MI:0915”(physical association)	0.670
INSC	TTC23	psi-mi:“MI:0915”(physical association)	0.560
INSC	USP54	psi-mi:“MI:0915”(physical association)	0.560
INSC	LHX3	psi-mi:“MI:0915”(physical association)	0.560
SORBS3	INSC	psi-mi:“MI:0915”(physical association)	0.560
INSC	RUSC1	psi-mi:“MI:0915”(physical association)	0.560
INSC	MGC50722	psi-mi:“MI:0915”(physical association)	0.560
INSC	TEKT3	psi-mi:“MI:0915”(physical association)	0.560
GEM	INSC	psi-mi:“MI:0915”(physical association)	0.560
PRR35	INSC	psi-mi:“MI:0915”(physical association)	0.560
GPANK1	INSC	psi-mi:“MI:0915”(physical association)	0.560
INSC	ZNF587	psi-mi:“MI:0915”(physical association)	0.560
INSC	SMARCD1	psi-mi:“MI:0915”(physical association)	0.560
INSC	A2ML1	psi-mi:“MI:0914”(association)	0.350
INSC	GPSM2	psi-mi:“MI:0915”(physical association)	0.000
INSC	USP54	psi-mi:“MI:0915”(physical association)	0.000
INSC	SORBS3	psi-mi:“MI:0915”(physical association)	0.000
INSC	LHX3	psi-mi:“MI:0915”(physical association)	0.000
INSC	RUSC1	psi-mi:“MI:0915”(physical association)	0.000
MGC50722	INSC	psi-mi:“MI:0915”(physical association)	0.000
TEKT3	INSC	psi-mi:“MI:0915”(physical association)	0.000
GEM	INSC	psi-mi:“MI:0915”(physical association)	0.000
PRR35	INSC	psi-mi:“MI:0915”(physical association)	0.000
GPANK1	INSC	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (29): INSC (Two-hybrid), INSC (Two-hybrid), INSC (Two-hybrid), INSC (Two-hybrid), INSC (Two-hybrid), INSC (Two-hybrid), INSC (Two-hybrid), INSC (Two-hybrid), INSC (Two-hybrid), INSC (Two-hybrid), ZNF587 (Two-hybrid), GPANK1 (Two-hybrid), MGC50722 (Two-hybrid), GPSM2 (Affinity Capture-MS), DNAJC1 (Affinity Capture-MS)

ESM2 similar proteins: A0A8M9QN10, A0JM49, A0JP94, A1EC95, A2AKG8, A2BID5, A9JRI0, B2RYI0, C5J7W8, E7FAW3, E7FGT5, E7FH61, O60287, P42695, P42858, P42859, P49815, P49816, P51111, P51112, Q1MX18, Q3HNM7, Q3U829, Q3UGY8, Q3UHQ6, Q3URQ0, Q571H0, Q5JWR5, Q5R5R2, Q5R6T6, Q5RDK1, Q5TH69, Q5VW36, Q5ZM41, Q61037, Q640K1, Q642P2, Q6A009, Q6AI08, Q6GN08

Diamond homologs: Q1MX18, Q3HNM7

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	103
Likely benign	6
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2795 predictions. Top by Δscore:

Variant	Effect	Δscore
11:15112578:G:T	donor_gain	1.0000
11:15138711:TCA:T	donor_gain	1.0000
11:15149228:GCG:G	donor_gain	1.0000
11:15175732:T:A	acceptor_gain	1.0000
11:15175736:TGCA:T	acceptor_loss	1.0000
11:15175737:GCA:G	acceptor_loss	1.0000
11:15175738:CAGG:C	acceptor_loss	1.0000
11:15175739:A:AG	acceptor_gain	1.0000
11:15175739:AGGC:A	acceptor_loss	1.0000
11:15175740:G:GG	acceptor_gain	1.0000
11:15176062:G:GT	donor_gain	1.0000
11:15176075:G:GT	donor_gain	1.0000
11:15176076:A:T	donor_gain	1.0000
11:15178439:G:T	donor_gain	1.0000
11:15178443:TTCAG:T	donor_loss	1.0000
11:15178444:TCAG:T	donor_loss	1.0000
11:15178445:CAGGT:C	donor_loss	1.0000
11:15178446:AGG:A	donor_loss	1.0000
11:15178447:GGTC:G	donor_loss	1.0000
11:15178448:G:C	donor_loss	1.0000
11:15178449:T:G	donor_loss	1.0000
11:15190695:TCTTA:T	acceptor_loss	1.0000
11:15190696:CTTAG:C	acceptor_loss	1.0000
11:15190697:TTAGG:T	acceptor_loss	1.0000
11:15190698:TAGGC:T	acceptor_loss	1.0000
11:15190699:A:AG	acceptor_gain	1.0000
11:15190699:A:C	acceptor_loss	1.0000
11:15190700:G:A	acceptor_loss	1.0000
11:15190700:G:GG	acceptor_gain	1.0000
11:15190813:AGGTG:A	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000045599 (11:15130822 A>G), RS1000072156 (11:15143136 A>G), RS1000091999 (11:15135997 C>G), RS1000118304 (11:15142975 A>G), RS1000118770 (11:15222736 A>G), RS1000119498 (11:15226869 A>G,T), RS1000136727 (11:15184149 A>G), RS1000140235 (11:15144917 A>C,G), RS1000157472 (11:15229006 T>C), RS1000188863 (11:15149186 G>A), RS1000193970 (11:15217649 T>G), RS1000194088 (11:15136472 G>A,T), RS1000207381 (11:15182801 T>G), RS1000209815 (11:15178600 GTGA>G), RS1000222003 (11:15269103 T>C)

Disease associations

OMIM: gene MIM:610668 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST001762_863	Obesity-related traits	6.000000e-06
GCST002013_6	Menarche (age at onset)	9.000000e-06
GCST002611_2	Expressive vocabulary in infants	2.000000e-07
GCST006288_115	Heel bone mineral density	7.000000e-07
GCST006288_29	Heel bone mineral density	1.000000e-15
GCST006288_726	Heel bone mineral density	3.000000e-09
GCST006979_620	Heel bone mineral density	8.000000e-59
GCST006979_621	Heel bone mineral density	1.000000e-16
GCST006979_622	Heel bone mineral density	1.000000e-19

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0003939	energy intake
EFO:0004703	age at menarche
EFO:0006316	infant expressive language ability
EFO:0009270	heel bone mineral density

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases methylation	5
trichostatin A	affects cotreatment, increases expression	3
Vorinostat	affects cotreatment, increases expression	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	decreases methylation, increases expression, increases methylation	2
6-hydroxy-5-((p- sulfophenyl)azo)-2-naphthalenesulfonic acid disodium salt	affects cotreatment, increases expression	1
bisphenol A	affects cotreatment, decreases methylation	1
sodium arsenite	increases expression	1
cupric chloride	increases expression	1
perfluorooctane sulfonic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Fulvestrant	affects cotreatment, decreases methylation, increases methylation	1
Arsenic	affects methylation	1
Chenodeoxycholic Acid	affects cotreatment, increases expression	1
Deoxycholic Acid	affects cotreatment, increases expression	1
Glycochenodeoxycholic Acid	affects cotreatment, increases expression	1
Glycocholic Acid	affects cotreatment, increases expression	1
Glycodeoxycholic Acid	affects cotreatment, increases expression	1
Thiram	increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	affects expression	1
Cyclosporine	increases expression	1
Tungsten Compounds	decreases expression	1
Okadaic Acid	increases expression	1

Clinical trials (associated diseases)

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