SCRIB

Summary

SCRIB (scribble planar cell polarity protein, HGNC:30377) is a protein-coding gene on chromosome 8q24.3, encoding SCRIB overlapping open reading frame protein (C0HLS1). Represses translation of the downstream SCRIB protein.

This gene encodes a protein that was identified as being similar to the Drosophila scribble protein. The mammalian protein is involved in tumor suppression pathways. As a scaffold protein involved in cell polarization processes, this protein binds to many other proteins. The encoded protein binds to papillomavirus E6 protein via its PDZ domain and the C-terminus of E6. Two alternatively spliced transcript variants that encode different protein isoforms have been found for this gene.

Source: NCBI Gene 23513 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autism spectrum disorder (Limited, GenCC)
• GWAS associations: 1
• Clinical variants (ClinVar): 515 total — 2 likely-pathogenic
• Phenotypes (HPO): 1
• MANE Select transcript: NM_182706

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30377
Approved symbol	SCRIB
Name	scribble planar cell polarity protein
Location	8q24.3
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0147, SCRB1, Vartul
Ensembl gene	ENSG00000180900
Ensembl biotype	protein_coding
OMIM	607733
Entrez	23513

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 11 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000320476, ENST00000356994, ENST00000377533, ENST00000525051, ENST00000526832, ENST00000531163, ENST00000531942, ENST00000546337, ENST00000674065, ENST00000674084, ENST00000921483, ENST00000956151, ENST00000956152, ENST00000956153

RefSeq mRNA: 2 — MANE Select: NM_182706 NM_015356, NM_182706

CCDS: CCDS6411, CCDS6412

Canonical transcript exons

ENST00000356994 — 37 exons

Exon	Start	End
ENSE00002431504	143807552	143807614
ENSE00002444605	143791666	143791740
ENSE00002446140	143809551	143809718
ENSE00002446793	143812817	143812961
ENSE00002449909	143795038	143795112
ENSE00002460404	143813030	143813104
ENSE00002465657	143804934	143805014
ENSE00002466841	143795420	143795530
ENSE00002467124	143804046	143804156
ENSE00002468025	143803383	143803571
ENSE00002469023	143810479	143810604
ENSE00002469473	143792220	143792405
ENSE00002476919	143808609	143809025
ENSE00002477149	143805112	143805435
ENSE00002485210	143810686	143810816
ENSE00002494398	143806924	143807013
ENSE00002497774	143813470	143813526
ENSE00002498218	143803647	143803940
ENSE00002505190	143813637	143813726
ENSE00002507390	143804568	143804825
ENSE00002511872	143795277	143795333
ENSE00002514345	143810906	143811072
ENSE00002516706	143813311	143813374
ENSE00002522903	143806407	143806484
ENSE00002530152	143813818	143813896
ENSE00002530428	143791876	143791913
ENSE00002534349	143811146	143811345
ENSE00002535957	143812266	143812384
ENSE00003469834	143791389	143791440
ENSE00003484132	143814001	143814118
ENSE00003489035	143792976	143793083
ENSE00003536741	143792485	143792635
ENSE00003548696	143793900	143793962
ENSE00003568354	143790925	143791308
ENSE00003629064	143792708	143792867
ENSE00003687500	143791991	143792133
ENSE00003848486	143815214	143815773

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.08.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 13.8831 / max 91.6704, expressed in 1760 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
95534	13.8831	1760

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
lower esophagus mucosa	UBERON:0035834	99.08	gold quality
esophagus mucosa	UBERON:0002469	97.97	gold quality
right uterine tube	UBERON:0001302	97.82	gold quality
skin of abdomen	UBERON:0001416	97.06	gold quality
mucosa of transverse colon	UBERON:0004991	97.04	gold quality
skin of leg	UBERON:0001511	97.03	gold quality
zone of skin	UBERON:0000014	96.92	gold quality
vagina	UBERON:0000996	96.17	gold quality
amygdala	UBERON:0001876	95.78	gold quality
ventricular zone	UBERON:0003053	95.76	gold quality
temporal lobe	UBERON:0001871	95.74	gold quality
tibial nerve	UBERON:0001323	95.70	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	95.32	gold quality
minor salivary gland	UBERON:0001830	95.29	gold quality
ectocervix	UBERON:0012249	95.28	gold quality
pituitary gland	UBERON:0000007	95.26	gold quality
adenohypophysis	UBERON:0002196	95.19	gold quality
Ammon’s horn	UBERON:0001954	95.08	gold quality
metanephros cortex	UBERON:0010533	95.05	gold quality
esophagus	UBERON:0001043	95.01	gold quality
saliva-secreting gland	UBERON:0001044	94.95	gold quality
fundus of stomach	UBERON:0001160	94.86	gold quality
hindlimb stylopod muscle	UBERON:0004252	94.81	gold quality
transverse colon	UBERON:0001157	94.65	gold quality
substantia nigra	UBERON:0002038	94.46	gold quality
endocervix	UBERON:0000458	94.44	gold quality
body of stomach	UBERON:0001161	94.29	gold quality
right frontal lobe	UBERON:0002810	94.15	gold quality
sural nerve	UBERON:0015488	94.15	gold quality
right lobe of thyroid gland	UBERON:0001119	94.14	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.55

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

32 targeting SCRIB, 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-9-5P	100.00	72.28	2361
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-8087	99.90	69.55	1351
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-548AU-3P	99.70	68.22	1373
HSA-MIR-7161-5P	99.68	68.92	1592
HSA-MIR-548U	99.65	67.78	1463
HSA-MIR-497-3P	99.61	69.71	1990
HSA-MIR-486-3P	99.51	66.82	1901
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-130A-5P	99.33	70.26	2623
HSA-MIR-122B-3P	99.21	68.90	1333
HSA-MIR-21-3P	99.21	68.95	1312
HSA-MIR-499A-3P	99.18	69.20	1392
HSA-MIR-499B-3P	99.18	69.27	1391
HSA-MIR-3135B	98.61	65.33	1470
HSA-MIR-3613-5P	98.40	68.91	604
HSA-MIR-7852-3P	98.37	67.98	823
HSA-MIR-5007-5P	97.95	64.71	614
HSA-MIR-924	97.78	66.21	681

Literature-anchored findings (GeneRIF, showing 40)

• KIAA0147 encodes the human homolog of Drosophila Scribble. hScrib is targeted for ubiquitin-mediated degradation by the HPV E6 oncoprotein, and mutations in Dros. scrib result in loss of polarity and growth control of epithelial cells. (PMID:11027293)
• hScrib is a functional homologue of DmScrib and therefore predict an important role for hScrib in the suppression of mammalian tumorigenesis (PMID:14681682)
• Degradation by human papilloma virus E6 may cause progressive decrease of hScrib expression during disease progression from low-grade squamous intraepithelial lesions (SIL) to high-grade SIL (PMID:14710229)
• May act as a tumor suppressor (PMID:15261375)
• LPP and Scrib proteins localize in cell-cell contacts. This interaction links Scrib to a communication pathway between cell-cell contacts and the nucleus, and implicates LPP in Scrib-associated functions (PMID:15649318)
• hScrib directly binds to the G protein-coupled thyroid stimulating hormone receptor (TSHR), inhibits basal receptor endocytosis and promotes recycling, and thus TSHR signalling, at the cell membrane. (PMID:15775968)
• data establishs a potential link between the E-cadherin and hScrib tumor suppressors (PMID:15806148)
• The direct interaction between hScrib and ZO-2, a junction-associated protein, was reported. (PMID:15975580)
• mapped the binding site of E6 on hScrib and shown that the interaction of E6 with hScrib is distinct from its interactions with other PDZ domain-containing targets (PMID:16103886)
• interacts with TRIP6; binding between two of zyxin’s family members and Scrib links Scrib to a communication pathway between cell-cell contacts and the nucleus, and implicates these zyxin family members in Scrib-associated functions (PMID:16137684)
• These results suggest that Scrib stabilizes the coupling between E-cadherin and the catenins and are consistent with the idea that mammalian Scrib could behave as a tumor suppressor by regulating epithelial cell adhesion and migration. (PMID:16344308)
• E6AP is extensively involved in the ubiquitin-mediated degradation of SCRIB (an HPV E6-dependent substrate) as a cellular E3 ubiquitin-protein ligase. (PMID:16482544)
• Knockdown of hScrib expression by RNAi disrupts localization of adenomatous polyposis coli(APC) at the adherens junction. These data suggest hScrib may participate in the hDlg-APC complex through PDZ domains and regulate cell cycle and neural function (PMID:16611247)
• Down-regulation of scrib is associated with colon cancer progression (PMID:16619250)
• The association of hScrib with APC would be important for mediating the cell cycle regulations. (PMID:16965391)
• essential role for mammalian Scribble in the regulation of the polarity specifically involved in directed epithelial migration. (PMID:17043654)
• Human scribble accumulates in colorectal neoplasia in association with an altered distribution of beta-catenin. (PMID:17509663)
• hDlg and hScrib are both targeted by Tax underlies their importance in T cell function (PMID:17855372)
• this study demonstrates a novel interaction between TBEV NS5 and the PDZ protein scribble (hScrib) affecting interferon (IFN) type I and II mediated JAK-STAT signalling. (PMID:18042258)
• Cleavage of Scrib by executioner caspases is a critical step for detachment of cell contact during the process of apoptosis. (PMID:18513328)
• Scribble is an important mediator of MAPK signalling and cooperates with H-ras to promote cell invasion. (PMID:18641685)
• Tax1 induces aberrant clustering of Scribble, thereby altering the functions in HTLV-1-infected cells. (PMID:18661220)
• data underscore the role of Scrib in cell migration and show the strong impact of Scrib in the function of PAK and Rac, two key molecules implicated in this process (PMID:18716323)
• Study demonstrates that scribble inhibits breast cancer formation and that deregulation of polarity pathways promotes dysplastic and neoplastic growth in mammals by disrupting morphogenesis and inhibiting cell death. (PMID:19041750)
• The upregulation of vimentin expression during epithelial to mesenchymal transitions may stabilize Scrib to promote directed cell migration. (PMID:19386766)
• Results identify MCC as a potential scaffold protein regulating cell movement and able to bind Scrib, beta-catenin and NHERF1/2. (PMID:19555689)
• Scribble is an important regulator of tight junctions functions and plasticity in the intestinal epithelium. (PMID:19959811)
• HMGB1 release, as well as its redox state, thus links autophagy and apoptosis, representing a suitable target when coupled with conventional tumor treatments (PMID:20622900)
• one function of the avian NS1 ESEV PBM sequence is to reduce apoptosis during infection through disruption of Scribble’s proapoptotic function (PMID:20702615)
• genetic variability in the SCRIB polarity gene does not contribute to breast cancer development (PMID:20936341)
• hScrib is involved in the development of endometrial cancer. (PMID:20939435)
• single nucleotide polymorphisms in scrib is not associated with breast cancer. (PMID:21086040)
• HPV16 E6 association with PDZ domain-containing proteins, MAGI1, Dlg1 or Scrib, stabilized the levels of E6. (PMID:21489588)
• These data uncover a previously unrecognized exploitation of Scrib for aberrant tumor cell motility and invasion, thus potentially contributing to disease progression in humans. (PMID:21549346)
• Knockdown of Scribble (Scrib) results in redistribution of PHLPP1 from the membrane to the cytoplasm and an increase in Akt phosphorylation. (PMID:21701506)
• These findings indicate that binding of NS1 to Scribble and Dlg1 functions to disrupt the cellular tight junction and that this effect likely contributes to the severe disease associated with highly pathogenic H5N1 influenza A viruses. (PMID:21849460)
• SCRIB deregulation strongly correlated with poor survival in prostate cancer (PMID:21965329)
• Missense variants in SCRIB may represent a cause of craniorachischisis in humans, as in mice, with defective planar cell polarity protein trafficking to the plasma membrane a likely pathogenic mechanism. (PMID:22095531)
• NOS1AP colocalizes with both SCRIB and VANGL1 along cellular protrusions in metastatic breast cancer cells, but does not colocalize with either SCRIB or VANGL1 at cell junctions in normal breast cells (PMID:22179838)
• During anoikis, hScrib and hDlg1 have distinct and opposing functions in human keratinocytes. (PMID:22792261)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	scrib	ENSDARG00000000861
mus_musculus	Scrib	ENSMUSG00000022568
rattus_norvegicus	Scrib	ENSRNOG00000032574

Paralogs (31): LRRC7 (ENSG00000033122), PHLPP2 (ENSG00000040199), LRRC40 (ENSG00000066557), LRCH4 (ENSG00000077454), PHLPP1 (ENSG00000081913), SHOC2 (ENSG00000108061), ERBIN (ENSG00000112851), LRRC39 (ENSG00000122477), LRCH2 (ENSG00000130224), LRCH1 (ENSG00000136141), LRRC8A (ENSG00000136802), LRRC1 (ENSG00000137269), MFHAS1 (ENSG00000147324), LRRC27 (ENSG00000148814), LRRK1 (ENSG00000154237), LRRC58 (ENSG00000163428), LRRC2 (ENSG00000163827), LRRC18 (ENSG00000165383), LRRC28 (ENSG00000168904), LRRC8E (ENSG00000171017), LRRC8C (ENSG00000171488), LRRC8D (ENSG00000171492), PIDD1 (ENSG00000177595), LRCH3 (ENSG00000186001), LRRIQ4 (ENSG00000188306), LRRC8B (ENSG00000197147), LRRC10 (ENSG00000198812), LRRC10B (ENSG00000204950), LRRC30 (ENSG00000206422), LRRC69 (ENSG00000214954), LRRD1 (ENSG00000240720)

Protein

Protein identifiers

SCRIB overlapping open reading frame protein — C0HLS1 (reviewed: C0HLS1, Q14160)

All UniProt accessions (5): A0A669KAX5, A0A669KB89, Q14160, H0YCG0, H0YDF9

UniProt curated annotations — full annotation on UniProt →

Function. Represses translation of the downstream SCRIB protein. Translation of oSCRIB hinders SCRIB translation but does not completely abolish it, probably due to leaky scanning which allows the ribosome to bypass the weaker oSCRIB start codon and initiate translation at the stronger SCRIB start codon.

Miscellaneous. This protein is produced by a polycistronic gene which also produces the tumor suppressor gene SCRIB from an overlapping reading frame.

RefSeq proteins (2): NP_056171, NP_874365* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001478	PDZ	Domain
IPR001611	Leu-rich_rpt	Repeat
IPR003591	Leu-rich_rpt_typical-subtyp	Repeat
IPR032675	LRR_dom_sf	Homologous_superfamily
IPR036034	PDZ_sf	Homologous_superfamily
IPR050614	Synaptic_Scaffolding_LAP-MAGUK	Family
IPR055414	LRR_R13L4/SHOC2-like	Domain

Pfam: PF00595, PF13855, PF23598

UniProt features (151 total): modified residue 38, strand 34, repeat 16, region of interest 14, compositionally biased region 14, helix 10, mutagenesis site 9, domain 4, coiled-coil region 3, sequence variant 3, chain 2, splice variant 2, sequence conflict 1, turn 1

Structure

Experimental structures (PDB)

42 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
6MYE	X-RAY DIFFRACTION	1.1
6EEY	X-RAY DIFFRACTION	1.15
2W4F	X-RAY DIFFRACTION	1.3
6MS1	X-RAY DIFFRACTION	1.35
6MYF	X-RAY DIFFRACTION	1.6
9UK3	X-RAY DIFFRACTION	1.69
9KQS	X-RAY DIFFRACTION	1.72
5VWI	X-RAY DIFFRACTION	1.75
7QRS	X-RAY DIFFRACTION	1.77
9KFM	X-RAY DIFFRACTION	1.8
7QS9	X-RAY DIFFRACTION	1.8
7QSB	X-RAY DIFFRACTION	1.84
7QS8	X-RAY DIFFRACTION	1.85
7QRT	X-RAY DIFFRACTION	1.9
7QTP	X-RAY DIFFRACTION	1.9
8CD3	X-RAY DIFFRACTION	1.9
5VWC	X-RAY DIFFRACTION	1.91
6XA6	X-RAY DIFFRACTION	1.95
8B87	X-RAY DIFFRACTION	2
9UK1	X-RAY DIFFRACTION	2.02
7QSA	X-RAY DIFFRACTION	2.02
6MTU	X-RAY DIFFRACTION	2.14
9KFO	X-RAY DIFFRACTION	2.2
6XA8	X-RAY DIFFRACTION	2.2
5VWK	X-RAY DIFFRACTION	2.35
8BIA	X-RAY DIFFRACTION	2.4
7JO7	X-RAY DIFFRACTION	2.44
4WYU	X-RAY DIFFRACTION	2.5
6XA7	X-RAY DIFFRACTION	2.5
8B9T	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-C0HLS1-F1	52.33	0.00
AF-Q14160-F1	63.06	0.32

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 (38): 37, 378, 475, 504, 688, 689, 708, 764, 826, 835, 853, 875, 939, 1140, 1220, 1223, 1226, 1232, 1276, 1279 …

Mutagenesis-validated functional residues (9):

Position	Phenotype
1111–1112	alters interaction with lpp.
4	loss of palmitoylation. loss of palmitoylation, localization to cell-cell junctions and function in epithelial cell pola
10	loss of palmitoylation. loss of palmitoylation, localization to cell-cell junctions and function in epithelial cell pola
22	no effect on palmitoylation.
305	decreased palmitoylation. loss of localization at the plasma membrane. loss of targeting to cell-cell junctions. alters
738–739	alters interaction with lpp.
738	loss of anti-proliferative activity.
872–873	alters interaction with lpp.
1014–1015	loss of interaction with lpp and trip6.

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-4608870	Asymmetric localization of PCP proteins
R-HSA-9013148	CDC42 GTPase cycle
R-HSA-9013406	RHOQ GTPase cycle
R-HSA-9013409	RHOJ GTPase cycle
R-HSA-9696264	RND3 GTPase cycle
R-HSA-9696270	RND2 GTPase cycle
R-HSA-162582	Signal Transduction
R-HSA-194315	Signaling by Rho GTPases
R-HSA-195721	Signaling by WNT
R-HSA-3858494	Beta-catenin independent WNT signaling
R-HSA-4086400	PCP/CE pathway
R-HSA-9012999	RHO GTPase cycle
R-HSA-9716542	Signaling by Rho GTPases, Miro GTPases and RHOBTB3

MSigDB gene sets: 351 (showing top): GSE18804_BRAIN_VS_COLON_TUMORAL_MACROPHAGE_DN, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_HINDBRAIN_DEVELOPMENT, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_MAMMARY_GLAND_MORPHOGENESIS, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_MONOPOLAR_CELL_POLARITY, GOBP_METENCEPHALON_DEVELOPMENT, GOBP_GLAND_MORPHOGENESIS, GOBP_ESTABLISHMENT_OR_MAINTENANCE_OF_CELL_POLARITY, GOBP_VESICLE_LOCALIZATION

GO Biological Process (39): negative regulation of translational initiation (GO:0045947), establishment of T cell polarity (GO:0001768), neural tube closure (GO:0001843), positive regulation of receptor recycling (GO:0001921), cell population proliferation (GO:0008283), epithelial structure maintenance (GO:0010669), obsolete synaptic vesicle targeting (GO:0016080), cell migration (GO:0016477), cochlear nucleus development (GO:0021747), polarized epithelial cell differentiation (GO:0030859), positive regulation of type II interferon production (GO:0032729), establishment of apical/basal cell polarity (GO:0035089), post-anal tail morphogenesis (GO:0036342), wound healing (GO:0042060), positive regulation of apoptotic process (GO:0043065), receptor clustering (GO:0043113), astrocyte cell migration (GO:0043615), establishment or maintenance of epithelial cell apical/basal polarity (GO:0045197), negative regulation of mitotic cell cycle (GO:0045930), negative regulation of activated T cell proliferation (GO:0046007), synaptic vesicle endocytosis (GO:0048488), positive chemotaxis (GO:0050918), auditory receptor cell stereocilium organization (GO:0060088), apoptotic process involved in morphogenesis (GO:0060561), mammary gland duct morphogenesis (GO:0060603), protein localization to adherens junction (GO:0071896), activation of GTPase activity (GO:0090630), cell-cell adhesion (GO:0098609), neurotransmitter receptor transport, endosome to postsynaptic membrane (GO:0098887), regulation of postsynaptic neurotransmitter receptor internalization (GO:0099149), auditory receptor cell morphogenesis (GO:0002093), intracellular protein localization (GO:0008104), positive regulation of epithelial to mesenchymal transition (GO:0010718), morphogenesis of embryonic epithelium (GO:0016331), establishment of cell polarity (GO:0030010), cell differentiation (GO:0030154), establishment or maintenance of apical/basal cell polarity (GO:0035088), inner ear receptor cell stereocilium organization (GO:0060122), vesicle-mediated transport in synapse (GO:0099003)

GO Molecular Function (4): protein kinase binding (GO:0019901), signaling adaptor activity (GO:0035591), cadherin binding (GO:0045296), protein binding (GO:0005515)

GO Cellular Component (25): immunological synapse (GO:0001772), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), plasma membrane (GO:0005886), cell-cell junction (GO:0005911), adherens junction (GO:0005912), postsynaptic density (GO:0014069), basolateral plasma membrane (GO:0016323), lamellipodium (GO:0030027), cell junction (GO:0030054), Scrib-APC-beta-catenin complex (GO:0034750), myelin sheath abaxonal region (GO:0035748), cell-cell contact zone (GO:0044291), extracellular exosome (GO:0070062), presynapse (GO:0098793), glutamatergic synapse (GO:0098978), extrinsic component of postsynaptic density membrane (GO:0099147), membrane (GO:0016020), cell leading edge (GO:0031252), presynaptic membrane (GO:0042734), cell projection (GO:0042995), synapse (GO:0045202), postsynaptic membrane (GO:0045211), anchoring junction (GO:0070161), postsynapse (GO:0098794)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
RHO GTPase cycle	5
Signal Transduction	2
PCP/CE pathway	1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1
Signaling by WNT	1
Beta-catenin independent WNT signaling	1
Signaling by Rho GTPases	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	8
establishment or maintenance of apical/basal cell polarity	2
plasma membrane	2
cell-cell junction	2
synapse	2
translational initiation	1
regulation of translational initiation	1
negative regulation of translation	1
establishment of lymphocyte polarity	1
T cell activation	1
primary neural tube formation	1
tube closure	1
receptor recycling	1
regulation of receptor recycling	1
positive regulation of macromolecule metabolic process	1
positive regulation of signaling	1
cellular process	1
tissue homeostasis	1
cell motility	1
pons development	1
neural nucleus development	1
morphogenesis of a polarized epithelium	1
epithelial cell differentiation	1
positive regulation of cytokine production	1
type II interferon production	1
regulation of type II interferon production	1
establishment of monopolar cell polarity	1
anatomical structure morphogenesis	1
response to wounding	1
tissue regeneration	1
apoptotic process	1
regulation of apoptotic process	1
positive regulation of programmed cell death	1
protein localization to membrane	1
glial cell migration	1
mitotic cell cycle	1
regulation of mitotic cell cycle	1
negative regulation of cell cycle	1
negative regulation of T cell proliferation	1
regulation of activated T cell proliferation	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

8 interactions, top by confidence:

A	B	Type	Score
WDR5	SCRIB	psi-mi:“MI:0915”(physical association)	0.590
WDR5	SCRIB	psi-mi:“MI:0407”(direct interaction)	0.590
SCRIB	CHD2	psi-mi:“MI:0914”(association)	0.350
AGGF1	BLTP3B	psi-mi:“MI:2364”(proximity)	0.270

ESM2 similar proteins: A0A1W2PPE3, A0A3B3IS91, A0A6I8MX38, A0A6I8PU40, A8MTW9, B1AH88, B3EWF7, C0HLS1, C0HMD6, H3BQW9, I3L0S3, I3L1E1, O70738, O75638, P03289, P0C880, P0DI83, P11300, P13985, P16807, P29164, P33485, P59091, P80612, Q01480, Q01900, Q3SYB3, Q5JLA7, Q5SY85, Q5T4H9, Q63003, Q6EEV4, Q6VB84, Q86SI9, Q8N1I8, Q8N1X5, Q8N319, Q8N6K4, Q8N6U2, Q8N726

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	2
Uncertain significance	347
Likely benign	61
Benign	22

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1077121	NM_182706.5(SCRIB):c.1177C>T (p.Gln393Ter)	Likely pathogenic
979858	GRCh37/hg19 8q24.3(chr8:144262042-146295771)x3	Likely pathogenic

SpliceAI

6099 predictions. Top by Δscore:

Variant	Effect	Δscore
8:143791441:C:CC	acceptor_gain	1.0000
8:143791742:T:C	acceptor_gain	1.0000
8:143791742:T:TC	acceptor_gain	1.0000
8:143791754:C:CT	acceptor_gain	1.0000
8:143791755:G:C	acceptor_gain	1.0000
8:143791993:T:TA	donor_gain	1.0000
8:143792074:T:A	donor_gain	1.0000
8:143792130:CATC:C	acceptor_gain	1.0000
8:143792131:ATC:A	acceptor_gain	1.0000
8:143792131:ATCC:A	acceptor_loss	1.0000
8:143792132:TC:T	acceptor_gain	1.0000
8:143792132:TCC:T	acceptor_loss	1.0000
8:143792133:CC:C	acceptor_gain	1.0000
8:143792133:CCT:C	acceptor_loss	1.0000
8:143792134:C:CC	acceptor_gain	1.0000
8:143792134:CTGCA:C	acceptor_loss	1.0000
8:143792135:T:A	acceptor_loss	1.0000
8:143792214:GCTCA:G	donor_loss	1.0000
8:143792216:TCA:T	donor_loss	1.0000
8:143792217:CACCT:C	donor_loss	1.0000
8:143792218:A:T	donor_loss	1.0000
8:143792219:CCTGG:C	donor_gain	1.0000
8:143792401:TCTGC:T	acceptor_loss	1.0000
8:143792402:CTGC:C	acceptor_gain	1.0000
8:143792402:CTGCC:C	acceptor_loss	1.0000
8:143792405:CCTGG:C	acceptor_loss	1.0000
8:143792406:C:CC	acceptor_gain	1.0000
8:143792406:CT:C	acceptor_loss	1.0000
8:143792407:T:A	acceptor_loss	1.0000
8:143792480:CTCA:C	donor_loss	1.0000

AlphaMissense

10546 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:143813067:A:G	L202P	1.000
8:143813326:G:C	N184K	1.000
8:143813326:G:T	N184K	1.000
8:143813342:A:G	L179P	1.000
8:143813490:G:C	N161K	1.000
8:143813490:G:T	N161K	1.000
8:143813500:A:G	L158P	1.000
8:143813500:A:T	L158H	1.000
8:143813506:A:G	L156P	1.000
8:143813679:A:G	L135P	1.000
8:143813685:A:G	L133P	1.000
8:143813829:G:C	N115K	1.000
8:143813829:G:T	N115K	1.000
8:143813839:A:G	F112S	1.000
8:143813854:A:G	L107P	1.000
8:143814002:G:C	N92K	1.000
8:143814002:G:T	N92K	1.000
8:143814003:T:A	N92I	1.000
8:143814018:A:G	L87P	1.000
8:143814027:A:G	L84P	1.000
8:143814071:G:C	N69K	1.000
8:143814071:G:T	N69K	1.000
8:143814081:A:G	L66P	1.000
8:143814087:A:G	L64P	1.000
8:143814096:A:C	L61W	1.000
8:143814096:A:G	L61S	1.000
8:143815251:A:G	L41P	1.000
8:143803888:A:G	I1058T	0.999
8:143804053:A:T	I1038N	0.999
8:143804941:A:T	V915D	0.999

dbSNP variants (sampled 300 via entrez): RS1000231349 (8:143809278 C>T), RS1000477636 (8:143816408 G>A,C), RS1000572913 (8:143802294 C>A,T), RS1000632758 (8:143809461 C>G,T), RS1000810620 (8:143790501 C>T), RS1000895085 (8:143816321 C>G,T), RS1000980414 (8:143794365 T>C), RS1001180917 (8:143814268 A>G), RS1001238660 (8:143815031 G>A), RS1001297016 (8:143814161 C>G,T), RS1001351007 (8:143803787 C>T), RS1001421095 (8:143807424 C>A,T), RS1001582273 (8:143796118 G>A,C), RS1001657393 (8:143795891 C>A), RS1001927784 (8:143792286 C>T)

Disease associations

OMIM: gene MIM:607733 | disease phenotypes:

GenCC curated gene-disease

Disease	Classification	Inheritance
autism spectrum disorder	Limited	Autosomal dominant

Mondo (3): neural tube defect (MONDO:0018075), microcephaly (MONDO:0001149), autism spectrum disorder (MONDO:0005258)

Orphanet (2): Neural tube defect (Orphanet:3388), Spina bifida and other spinal dysraphisms (Orphanet:823)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000252	Microcephaly

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST002541_68	Menarche (age at onset)	1.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004703	age at menarche

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D008831	Microcephaly	C05.660.207.620; C10.500.507.400.500; C16.131.621.207.620; C16.131.666.507.400.500
D009436	Neural Tube Defects	C10.500.680; C16.131.666.680

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases methylation, decreases expression	2
sodium arsenite	decreases expression, increases expression	2
bisphenol S	increases expression, affects cotreatment, decreases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, affects expression	2
Ozone	increases oxidation, increases abundance, affects expression, affects cotreatment	2
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
dicrotophos	increases expression	1
2,4,6-tribromophenol	decreases expression	1
alpha-pinene	increases abundance, affects cotreatment, increases oxidation	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
decabromobiphenyl ether	decreases expression	1
arsenite	affects binding, decreases reaction	1
cobaltous chloride	decreases expression	1
tetrabromobisphenol A	decreases expression	1
coumarin	affects phosphorylation	1
muconaldehyde	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
evodiamine	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
Grape Seed Proanthocyanidins	decreases expression, affects cotreatment	1
hexabrominated diphenyl ether 153	decreases expression	1
LDN 193189	affects cotreatment, increases expression	1
MT19c compound	decreases 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	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2EU	Abcam HeLa SCRIB KO	Cancer cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT01302964	PHASE3	COMPLETED	Mirtazapine Treatment of Anxiety in Children and Adolescents With Pervasive Developmental Disorders
NCT01706523	PHASE3	TERMINATED	Open Label Extension Study of STX209 (Arbaclofen) in Autism Spectrum Disorders
NCT01825798	PHASE3	COMPLETED	Treatment of Overweight Induced by Antipsychotic Medication in Young People With Autism Spectrum Disorders (ASD)
NCT01972074	PHASE3	COMPLETED	Behavioral and Neural Response to Memantine in Adolescents With Autism Spectrum Disorder
NCT02985749	PHASE3	COMPLETED	A Study of Oxytocin for the Treatment of Social Impairment in Individuals With High Functioning Autism Spectrum Disorder
NCT03197922	PHASE3	COMPLETED	Treatment of Encopresis in Children With Autism Spectrum Disorders
NCT03504917	PHASE3	TERMINATED	A Study of Balovaptan in Adults With Autism Spectrum Disorder With a 2-Year Open-Label Extension
NCT03553875	PHASE3	TERMINATED	Memantine for the Treatment of Social Deficits in Youth With Disorders of Impaired Social Interactions
NCT03640156	PHASE3	COMPLETED	Modulating Socially Adaptive Mirror System Functioning in Autism by Oxytocin
NCT03715153	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children Aged From 2 to Less Than 7 Years Old With Autism Spectrum Disorder.
NCT03715166	PHASE3	TERMINATED	Efficacy and Safety of Bumetanide Oral Liquid Formulation in Children and Adolescents Aged From 7 to Less Than 18 Years Old With Autism Spectrum Disorder
NCT04233502	PHASE3	WITHDRAWN	Efficacy and Safety of Slenyto for Insomnia in Children With ASD
NCT04578756	PHASE3	COMPLETED	Open-Label, Flexible-dose Study to Evaluate the Long-Term Safety and Tolerability of Cariprazine in the Treatment of Pediatric Participants With Schizophrenia, Bipolar I Disorder, or Autism Spectrum Disorder
NCT04623398	PHASE3	COMPLETED	Effect of Lithium in Patients With Autism Spectrum Disorder and Phelan-McDermid Syndrome (SHANK3 Haploinsufficiency)
NCT04725383	PHASE3	TERMINATED	Amitriptyline for Repetitive Behaviors in Autism Spectrum Disorders
NCT05212493	PHASE3	COMPLETED	The Effects of Medical Cannabis in Children With Autistic Spectrum Disorder
NCT05361707	PHASE3	UNKNOWN	Evaluating the Effects of Tasimelteon in Individuals With Autism Spectrum Disorder (ASD) and Sleep Disturbances
NCT05439616	PHASE3	COMPLETED	Study of Cariprazine Oral Capsules or Solution to Assess Adverse Events and Change in Irritability Due to Autism Spectrum Disorder (ASD) in Participants Aged 5-17 Years With ASD
NCT06229210	PHASE3	RECRUITING	Safety and Tolerability Trial of Lumateperone in Pediatric Patients With Schizophrenia, Bipolar Disorder or Autism Spectrum Disorder