STIL

Summary

STIL (STIL centriolar assembly protein, HGNC:10879) is a protein-coding gene on chromosome 1p33, encoding SCL-interrupting locus protein (Q15468). Immediate-early gene. It is a selective cancer dependency (DepMap: 59.7% of cell lines).

This gene encodes a cytoplasmic protein implicated in regulation of the mitotic spindle checkpoint, a regulatory pathway that monitors chromosome segregation during cell division to ensure the proper distribution of chromosomes to daughter cells. The protein is phosphorylated in mitosis and in response to activation of the spindle checkpoint, and disappears when cells transition to G1 phase. It interacts with a mitotic regulator, and its expression is required to efficiently activate the spindle checkpoint. It is proposed to regulate Cdc2 kinase activity during spindle checkpoint arrest. Chromosomal deletions that fuse this gene and the adjacent locus commonly occur in T cell leukemias, and are thought to arise through illegitimate V-(D)-J recombination events. Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 6491 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive primary microcephaly (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 10
• Clinical variants (ClinVar): 475 total — 14 pathogenic, 16 likely-pathogenic
• Phenotypes (HPO): 109
• Cancer dependency (DepMap): dependent in 59.7% of screened cell lines
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_001048166

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:10879
Approved symbol	STIL
Name	STIL centriolar assembly protein
Location	1p33
Locus type	gene with protein product
Status	Approved
Aliases	MCPH7
Ensembl gene	ENSG00000123473
Ensembl biotype	protein_coding
OMIM	181590
Entrez	6491

Gene structure

Transcript identifiers

Ensembl transcripts: 27 — 21 protein_coding, 4 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000337817, ENST00000360380, ENST00000371877, ENST00000396221, ENST00000413565, ENST00000418131, ENST00000433827, ENST00000436811, ENST00000447475, ENST00000682165, ENST00000682940, ENST00000682977, ENST00000683977, ENST00000684618, ENST00000893432, ENST00000893433, ENST00000893434, ENST00000936918, ENST00000936919, ENST00000936920, ENST00000936921, ENST00000936922, ENST00000936923, ENST00000936924, ENST00000936925, ENST00000936926, ENST00000948671

RefSeq mRNA: 7 — MANE Select: NM_001048166 NM_001048166, NM_001282936, NM_001282937, NM_001282938, NM_001282939, NM_001377417, NM_003035

CCDS: CCDS41329, CCDS548, CCDS72785, CCDS72786, CCDS90946

Canonical transcript exons

ENST00000371877 — 17 exons

Exon	Start	End
ENSE00000902624	47299905	47300152
ENSE00000902627	47304889	47304996
ENSE00001064464	47310276	47310362
ENSE00001456351	47314036	47314147
ENSE00001601298	47295765	47295848
ENSE00001654497	47282345	47282459
ENSE00001659435	47293458	47293544
ENSE00001718191	47262903	47263116
ENSE00001736582	47250139	47251922
ENSE00001738495	47289435	47289585
ENSE00001753690	47287551	47287660
ENSE00002158332	47301561	47301748
ENSE00002256838	47260289	47260539
ENSE00003491580	47272076	47272241
ENSE00003578797	47280241	47281209
ENSE00003786071	47269635	47269866
ENSE00003789078	47302234	47302346

Expression profiles

Bgee: expression breadth ubiquitous, 221 present calls, max score 95.96.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 7.0150 / max 77.5790, expressed in 1257 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
12232	6.8491	1248
12233	0.1658	56

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	95.96	gold quality
oocyte	CL:0000023	93.91	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	84.57	gold quality
trabecular bone tissue	UBERON:0002483	84.14	gold quality
ventricular zone	UBERON:0003053	83.74	gold quality
embryo	UBERON:0000922	82.39	gold quality
epithelium of nasopharynx	UBERON:0001951	82.33	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.76	gold quality
amniotic fluid	UBERON:0000173	81.63	gold quality
bone marrow	UBERON:0002371	81.59	gold quality
gingival epithelium	UBERON:0001949	81.38	silver quality
mucosa of paranasal sinus	UBERON:0005030	81.12	silver quality
esophagus squamous epithelium	UBERON:0006920	80.79	gold quality
mucosa of sigmoid colon	UBERON:0004993	80.75	gold quality
bronchial epithelial cell	CL:0002328	80.65	gold quality
tongue squamous epithelium	UBERON:0006919	80.39	gold quality
nasal cavity epithelium	UBERON:0005384	80.25	silver quality
bone marrow cell	CL:0002092	80.05	gold quality
colonic mucosa	UBERON:0000317	79.62	gold quality
oral cavity	UBERON:0000167	79.57	gold quality
tibia	UBERON:0000979	79.20	gold quality
epithelium of bronchus	UBERON:0002031	78.56	gold quality
ganglionic eminence	UBERON:0004023	78.51	gold quality
epithelium of esophagus	UBERON:0001976	78.37	gold quality
bronchus	UBERON:0002185	78.03	gold quality
epithelial cell of pancreas	CL:0000083	77.41	silver quality
squamous epithelium	UBERON:0006914	76.98	gold quality
gingiva	UBERON:0001828	76.62	silver quality
rectum	UBERON:0001052	76.19	gold quality
stromal cell of endometrium	CL:0002255	76.07	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.43

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1, TAL1

miRNA regulators (miRDB)

58 targeting STIL, 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-3613-3P	100.00	76.36	7965
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-4482-3P	99.98	72.50	3147
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-4755-5P	99.71	70.34	2716
HSA-MIR-5006-3P	99.71	70.26	2728
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-561-3P	99.64	70.90	3647
HSA-MIR-548AV-5P	99.60	70.84	2107
HSA-MIR-548K	99.60	70.84	2107
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-6727-3P	99.49	65.92	1333
HSA-MIR-8054	99.48	70.81	2084

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map DepMap (CRISPR cell-line fitness): dependent in 59.7% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• dHPLC techniques were used to screen for mutations and these studies identified several common polymorphisms but no disease-associated mutations, suggesting that SIL is not a common factor in holoprosencephaly pathogenesis in humans. (PMID:12438740)
• isolation and characterization of a cloned promoter as well as its role in leukemogenesis (PMID:12531481)
• Children with t-cell malignancies and with SIL-TAL fusion had low levels of residual disease at the end of induction and a favorable prognosis (PMID:14504110)
• Sil has a role in increased mitotic activity in tumor cells (PMID:15107824)
• Cell cycle-dependent phosphorylation of Sil is required for its interaction with Pin1, a regulator of mitosis. (PMID:16024801)
• SIL is important for the transition from the G(2) to the M phases of the cell cycle. Inducible knockdown of SIL in cancer cells in vitro delayed entrance into mitosis, decreased activation of the CDK1 (CDC2)-cyclin B complex, and induced apoptosis. (PMID:17456584)
• Mice carrying both SILloxloxSCL and Cre transgenes have increased CD4-negative/CD8-negative thymocytes compared with transgene-negative mice. (PMID:17460775)
• These data, taken together, identify SIL as a novel, vertebrate-specific regulator of mitotic spindle assembly. (PMID:17576815)
• LMO2, TAL1, Ttg-1, and SIL support levels of V(D)J recombination above background levels in cell culture and are also cleaved by the RAG proteins, while Hox11 and SCL are nicked but not cleaved efficiently in vitro (PMID:18187418)
• A role ofor SIL in derepressing GLI1 from the negative control of SUFU. (PMID:18829525)
• Primary microcephaly is an autosomal-recessive congenital disorder characterized by smaller brain size and mental retardation, in which homozygote mutations in STIL proteins are found. (PMID:19215732)
• STIL depletion inhibited normal centriole duplication, Plk4-induced centriole amplification, and CPAP-induced centriole elongation, and resulted in a failure to localize hSAS6 and CPAP to the base of the nascent procentriole. (PMID:22020124)
• STIL and CPAP are essential for centriole formation and for proper spindle position. (PMID:22100914)
• STIL cooperates with SAS-6 and PLK4 in the control of centriole number and represents a key centriole duplication factor in human cells. (PMID:22349698)
• These findings demonstrate that STIL is an essential component of the centriole replication machinery in mammalian cells. (PMID:22349705)
• Identification of a novel STIL mutation in a family with primary microcephaly. (PMID:22989186)
• studies provide the first structural insight into how the malfunction of centriole proteins results in human disease and also reveal that the CPAP-STIL interaction constitutes a conserved key step in centriole biogenesis (PMID:24052813)
• A novel function for Stil protein is neural progenitor cell proliferation but not neural differentiation. (PMID:24240054)
• propose that centriole amplification triggered by STIL stabilization is the underlying cause of microcephaly in human patients with corresponding STIL mutations (PMID:24485834)
• Egyptian T-cell acute lymphoblastic leukemia cases seemed to have a different genetic pattern compared to other populations, with a lower incidence of TLX3/HOX11L2 and SIL/TAL but a higher incidence of NKX2-5 expression than recorded in Western countries (PMID:24571118)
• results provide direct evidence for the involvement of Stil in dopaminergic cell proliferation (PMID:24853807)
• STIL mutation causes autosomal recessive microcephalic lobar holoprosencephaly. (PMID:25218063)
• Negative feedback by centriolar STIL regulates bimodal centriolar distribution of Plk4 and seemingly restricts occurrence of procentriole formation to one site on each parental centriole. (PMID:25342035)
• The STIL p.Gly717Glu mutation was not able to fully restore the centriole duplication failure following depletion of endogenous STIL protein indicating the deleterious role of the mutation. (PMID:25658757)
• The authors suggest that the STIL-coiled-coil region/PLK4 interaction mediates PLK4 activation as well as stabilization of centriolar PLK4 and plays a key role in centriole duplication. (PMID:26188084)
• Results from a study on gene expression variability markers in early-stage human embryos shows that STIL is a putative expression variability marker for the 3-day, 8-cell embryo stage. (PMID:26288249)
• data provide evidence for novel functions of the human oncogene Stil in neural toxic susceptibility. (PMID:26549353)
• Reconstituting mouse embryonic fibroblasts lacking endogenous Stil, the authors show that STIL oligomerization mediated by these residues is not only important for the centrosomal functions of STIL during the canonical duplication process but also for de-novo formation of centrosomes. (PMID:27075531)
• These data show that complementary mechanisms, such as mother-daughter centriole proximity and CDK1-CyclinB interaction with centriolar components, ensure that centriole biogenesis occurs once and only once per cell cycle, raising parallels to the cell-cycle regulation of DNA replication and centromere formation. (PMID:27112295)
• Deletions of Stil is associated with acute T-lymphoblastic leukemia. (PMID:27759908)
• Studies indicate that depletion of any one of the protein kinase polo-like kinase 4 (PLK4) and the two proteins STIL and SAS-6 blocks centriole duplication, and, conversely, overexpression causes centriole amplification. (PMID:27911707)
• we observed that depletion of STIL enhanced canonical homologous recombination repair and increased BRCA1 and RAD51 foci in response to DNA double strand breaks. Thus, inhibition of STIL significantly enhances the efficacy of DNA damaging chemotherapeutic drugs in treatment of ovarian cancer. (PMID:28423708)
• RTTN directly interacts with STIL and acts downstream of STIL-mediated centriole assembly, contributing to building full-length centrioles. (PMID:28811500)
• Data describe a novel mechanism that contributes to centriole homeostasis in human cells by controlling the abundance and localization of the centriole duplication factor STIL which was identified as a direct target of bTrCP. bTrCP binds aDSG motif located within the N-terminus of STIL, and that mutation of this degron leads to STIL stabilization and consequent centriole overduplication. (PMID:29445034)
• Direct binding of CEP85 to STIL ensures robust PLK4 activation and efficient centriole assembly. (PMID:29712910)
• The conserved short coiled-coil region of STIL binds to and protects Plk4 from protein degradation at the site of procentriole formation. On the other hand, the conserved C-terminal region of STIL named truncated in microcephaly (TIM) domain promotes autophosphorylation and degradation of adjacent Plk4 by the direct interaction. (PMID:29898389)
• suggesting that STIL-TAL1 fusion genes are most probably postnatal events in paediatric T-cell acute lymphoblastic leukaemia (PMID:29968961)
• blocking of PLK4 or STIL functions leads to centrosome loss followed by both p53-dependent and -independent defects, including prolonged cell divisions, upregulation of p53, chromosome instability, and, importantly, reduction of pluripotency markers and induction of differentiation. (PMID:30197118)
• Knockdown of STIL suppresses the progression of gastric cancer by down-regulating the IGF-1/PI3K/AKT pathway. (PMID:31187582)
• these results demonstrate that SFI1 is a centrosomal protein that localizes USP9X to the centrosome to stabilize STIL and promote centriole duplication. We propose that the USP9X protection of STIL to facilitate centriole duplication underlies roles of both proteins in human neurodevelopment. (PMID:31197030)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	stil	ENSDARG00000024904
mus_musculus	Stil	ENSMUSG00000028718
rattus_norvegicus	Stil	ENSRNOG00000057760

Protein

Protein identifiers

SCL-interrupting locus protein — Q15468 (reviewed: Q15468)

Alternative names: TAL-1-interrupting locus protein

All UniProt accessions (6): A0A0A0MR87, A0A804HJM8, E9PSF2, Q15468, H0Y702, Q5T0C7

UniProt curated annotations — full annotation on UniProt →

Function. Immediate-early gene. Plays an important role in embryonic development as well as in cellular growth and proliferation; its long-term silencing affects cell survival and cell cycle distribution as well as decreases CDK1 activity correlated with reduced phosphorylation of CDK1. Plays a role as a positive regulator of the sonic hedgehog pathway, acting downstream of PTCH1. Plays an important role in the regulation of centriole duplication. Required for the onset of procentriole formation and proper mitotic progression. During procentriole formation, is essential for the correct loading of SASS6 and CPAP to the base of the procentriole to initiate procentriole assembly. In complex with STIL acts as a modulator of PLK4-driven cytoskeletal rearrangements and directional cell motility.

Subunit / interactions. Homodimer. Interacts with PIN1 via its WW domain. This interaction is dependent on STIL mitotic phosphorylation. Interacts with CPAP. Interacts with RBM14 and this interaction interferes with the interaction of STIL with CPAP. Forms a complex with CPAP and SASS6. Interacts (via N-terminus) with CEP85; this interaction is essential for efficient centriolar targeting of STIL and subsequent PLK4 activation.

Subcellular location. Cytoplasm. Cytosol. Cytoskeleton. Microtubule organizing center. Centrosome. Centriole. Cell cortex.

Tissue specificity. Expressed in all hematopoietic tissues and cell lines. Highly expressed in a variety of tumors characterized by increased mitotic activity with highest expression in lung cancer.

Post-translational modifications. Ubiquitinated. Phosphorylated following the activation of the mitotic checkpoint.

Disease relevance. A chromosomal aberration involving STIL may be a cause of some T-cell acute lymphoblastic leukemias (T-ALL). A deletion at 1p32 between STIL and TAL1 genes leads to STIL/TAL1 fusion mRNA with STIL exon 1 splicing to TAL1 exon 3. As both STIL exon 1 and TAL1 exon 3 are 5’-untranslated exons, STIL/TAL1 fusion mRNA predicts a full-length TAL1 protein under the control of the STIL promoter, leading to inappropriate TAL1 expression. In childhood T-cell malignancies (T-ALL), a type of defect such as STIL/TAL1 fusion is associated with a good prognosis. In cultured lymphocytes from healthy adults, STIL/TAL1 fusion mRNA may be detected after 7 days of culture. Microcephaly 7, primary, autosomal recessive (MCPH7) [MIM:612703] A disease defined as a head circumference more than 3 standard deviations below the age-related mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small. Despite this marked reduction in size, the gyral pattern is relatively well preserved, with no major abnormality in cortical architecture. Affected individuals have mild to severe intellectual disability. Primary microcephaly is further defined by the absence of other syndromic features or significant neurological deficits due to degenerative brain disorder. The disease is caused by variants affecting the gene represented in this entry.

Induction. Down-regulated when cell proliferation ceased. Accumulates during G2 phase and falls at completion of the cell cycle.

Isoforms (2)

UniProt ID	Names	Canonical?
Q15468-1	1	yes
Q15468-2	2

RefSeq proteins (7): NP_001041631, NP_001269865, NP_001269866, NP_001269867, NP_001269868, NP_001364346, NP_003026 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026123	STIL	Family
IPR057655	STIL_CC	Domain
IPR057731	STIL_N	Domain
IPR058559	PRM_STIL	Conserved_site

Pfam: PF15253, PF25775, PF26399

UniProt features (22 total): region of interest 5, modified residue 5, sequence variant 5, mutagenesis site 2, chain 1, splice variant 1, sequence conflict 1, helix 1, compositionally biased region 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
5LHW	X-RAY DIFFRACTION	0.91
8OYK	X-RAY DIFFRACTION	1.9
8OYL	X-RAY DIFFRACTION	1.92
5LHZ	X-RAY DIFFRACTION	2.51
4YYP	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15468-F1	54.29	0.20

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 (5): 779, 1135, 1, 395, 753

Mutagenesis-validated functional residues (2):

Position	Phenotype
64	reduced centriole localization; when associated with 67-a. does not fully rescue the centriole duplication defect in sti
67	reduced centriole localization; when associated with 64-a. does not fully rescue the centriole duplication defect in sti

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 492 (showing top): GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_PROTEIN_LOCALIZATION_TO_CYTOSKELETON, GOBP_AXIS_SPECIFICATION, GOBP_REGULATION_OF_MICROTUBULE_BASED_PROCESS, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_EMBRYONIC_AXIS_SPECIFICATION, CROONQUIST_NRAS_SIGNALING_DN, GOBP_CELL_CYCLE_PHASE_TRANSITION, GOBP_POSITIVE_REGULATION_OF_MITOTIC_CELL_CYCLE, GOBP_GROWTH, BROWNE_HCMV_INFECTION_16HR_UP, GOBP_NEURAL_TUBE_DEVELOPMENT

GO Biological Process (21): embryonic axis specification (GO:0000578), in utero embryonic development (GO:0001701), neural tube closure (GO:0001843), heart looping (GO:0001947), mitotic spindle organization (GO:0007052), smoothened signaling pathway (GO:0007224), determination of left/right symmetry (GO:0007368), neural tube development (GO:0021915), forebrain development (GO:0030900), notochord development (GO:0030903), microtubule organizing center organization (GO:0031023), floor plate development (GO:0033504), multicellular organism growth (GO:0035264), negative regulation of apoptotic process (GO:0043066), regulation of centriole replication (GO:0046599), positive regulation of centriole replication (GO:0046601), centrosome duplication (GO:0051298), regulation of mitotic spindle organization (GO:0060236), protein localization to centrosome (GO:0071539), positive regulation of G1/S transition of mitotic cell cycle (GO:1900087), positive regulation of spindle assembly (GO:1905832)

GO Molecular Function (2): identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (10): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), centrosome (GO:0005813), centriole (GO:0005814), microtubule organizing center (GO:0005815), cytosol (GO:0005829), cell cortex (GO:0005938), ciliary basal body (GO:0036064), procentriole replication complex (GO:0120099), cytoskeleton (GO:0005856)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
microtubule organizing center	3
cytoplasm	3
chordate embryonic development	2
anatomical structure development	2
centriole replication	2
intracellular membraneless organelle	2
axis specification	1
embryonic pattern specification	1
primary neural tube formation	1
tube closure	1
embryonic heart tube morphogenesis	1
determination of heart left/right asymmetry	1
mitotic cell cycle	1
spindle organization	1
microtubule cytoskeleton organization involved in mitosis	1
cell surface receptor signaling pathway	1
determination of bilateral symmetry	1
left/right pattern formation	1
nervous system development	1
tube development	1
epithelium development	1
brain development	1
embryonic organ development	1
microtubule cytoskeleton organization	1
microtubule-based process	1
cellular component organization	1
neural tube development	1
multicellular organismal process	1
developmental growth	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
regulation of centrosome duplication	1
regulation of organelle assembly	1
regulation of centriole replication	1
positive regulation of cytoskeleton organization	1
positive regulation of cell cycle process	1
positive regulation of organelle assembly	1
centrosome cycle	1

Protein interactions and networks

STRING

1746 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
STIL	SASS6	Q6UVJ0	967
STIL	CEP135	Q66GS9	951
STIL	CEP152	O94986	946
STIL	ASPM	Q8IZT6	943
STIL	PLK4	O00444	942
STIL	CPAP	Q9HC77	940
STIL	MCPH1	Q8NEM0	933
STIL	CDK5RAP2	Q96SN8	932
STIL	TAL1	P17542	821
STIL	WDR62	O43379	813
STIL	CEP85	Q6P2H3	806
STIL	CEP63	Q96MT8	796
STIL	CEP192	Q8TEP8	771
STIL	RTTN	Q86VV8	708
STIL	DEUP1	Q05D60	644

IntAct

70 interactions, top by confidence:

A	B	Type	Score
PLK4	CEP152	psi-mi:“MI:0914”(association)	0.850
CPAP	STIL	psi-mi:“MI:0407”(direct interaction)	0.820
CPAP	STIL	psi-mi:“MI:0914”(association)	0.820
STIL	CPAP	psi-mi:“MI:0915”(physical association)	0.820
CPAP	STIL	psi-mi:“MI:0915”(physical association)	0.820
STIL	CPAP	psi-mi:“MI:0407”(direct interaction)	0.820
IFT70B	IFT56	psi-mi:“MI:0914”(association)	0.790
PLK4	STIL	psi-mi:“MI:0403”(colocalization)	0.660
PLK4	STIL	psi-mi:“MI:0915”(physical association)	0.660
PLK4	STIL	psi-mi:“MI:0407”(direct interaction)	0.660
SASS6	STIL	psi-mi:“MI:0914”(association)	0.650
STIL	SASS6	psi-mi:“MI:0915”(physical association)	0.650
STIL	SASS6	psi-mi:“MI:0914”(association)	0.650
STIL	STIL	psi-mi:“MI:0915”(physical association)	0.590

BioGRID (237): STIL (Affinity Capture-Western), SASS6 (Affinity Capture-Western), STIL (Affinity Capture-MS), STIL (Affinity Capture-MS), STIL (Affinity Capture-MS), STIL (Affinity Capture-MS), STIL (Affinity Capture-MS), STIL (Synthetic Growth Defect), STIL (Proximity Label-MS), STIL (Proximity Label-MS), AASDHPPT (Proximity Label-MS), ABLIM1 (Proximity Label-MS), ACTR2 (Proximity Label-MS), AP3M1 (Proximity Label-MS), ARID1B (Proximity Label-MS)

ESM2 similar proteins: A0A087WRU1, A0JNH1, A2RUB1, A6QNQ6, B0S6S9, B1WC58, D3Z987, D3ZJ47, E1BC15, O60673, P28358, P28359, P56716, P70347, Q0P5X5, Q0VAV2, Q0VBV7, Q15468, Q2M2Z5, Q3UXL4, Q3V089, Q49A88, Q569L8, Q5BQN8, Q5CZC0, Q5QGS0, Q5T1N1, Q5VWN6, Q60988, Q61493, Q62924, Q6ZP01, Q6ZU52, Q6ZVD7, Q80U59, Q80WQ8, Q86WS4, Q86YC2, Q8CB14, Q8IUR6

Diamond homologs: Q15468, Q4V7H1, Q60988, Q8JGS1

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
STIL	up-regulates	PIN1	binding
CDK1	“down-regulates activity”	STIL	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 64 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.

GO biological processes:

GO term	Partners	Fold	FDR
cilium assembly	8	10.2×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	16
Uncertain significance	257
Likely benign	96
Benign	47

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
12948	NM_001048166.1(STIL):c.3718C>T (p.Gln1240Ter)	Pathogenic
12949	NM_001048166.1(STIL):c.3658del (p.Leu1219_Val1220insTer)	Pathogenic
12950	NM_001048166.1(STIL):c.2829+1G>A	Pathogenic
1801744	NM_001048166.1(STIL):c.1639C>A (p.Gln547Lys)	Pathogenic
218244	NM_001048166.1(STIL):c.453+5G>A	Pathogenic
2701697	NM_001048166.1(STIL):c.1678del (p.Ser560fs)	Pathogenic
3657323	NM_001048166.1(STIL):c.841C>T (p.Arg281Ter)	Pathogenic
423587	NM_001048166.1(STIL):c.2830-2A>G	Pathogenic
450838	NM_001048166.1(STIL):c.703dup (p.Tyr235fs)	Pathogenic
4720772	NM_001048166.1(STIL):c.78dup (p.Pro27fs)	Pathogenic
4813075	NM_001048166.1(STIL):c.2960C>G (p.Ser987Ter)	Pathogenic
546578	NM_001048166.1(STIL):c.1092dup (p.Glu365fs)	Pathogenic
872291	NM_001048166.1(STIL):c.460C>T (p.Gln154Ter)	Pathogenic
91843	NM_001048166.1(STIL):c.2393T>G (p.Leu798Trp)	Pathogenic
1320034	NM_001048166.1(STIL):c.2383+19del	Likely pathogenic
1486606	NM_001048166.1(STIL):c.2433_2434del (p.Gln812fs)	Likely pathogenic
160069	NM_001048166.1(STIL):c.895T>A (p.Phe299Ile)	Likely pathogenic
1679330	NM_001048166.1(STIL):c.1078C>T (p.Gln360Ter)	Likely pathogenic
1683274	NM_001048166.1(STIL):c.384dup (p.His129fs)	Likely pathogenic
1705699	NM_001048166.1(STIL):c.2488_2489del (p.Asp830fs)	Likely pathogenic
2433997	NM_001048166.1(STIL):c.3538_3541del (p.Asn1180fs)	Likely pathogenic
2504292	NM_001048166.1(STIL):c.785+1_785+3del	Likely pathogenic
2631704	NM_001048166.1(STIL):c.187C>T (p.Arg63Ter)	Likely pathogenic
3675677	NM_001048166.1(STIL):c.1249-2A>G	Likely pathogenic
3910651	NM_001048166.1(STIL):c.44+1G>T	Likely pathogenic
402198	NM_001048166.1(STIL):c.1226G>C (p.Ser409Thr)	Likely pathogenic
451761	NM_001048166.1(STIL):c.453+5G>T	Likely pathogenic
4538620	NM_001048166.1(STIL):c.239del (p.Leu80fs)	Likely pathogenic
817814	NM_001048166.1(STIL):c.2289_2290del (p.Gln764fs)	Likely pathogenic
977229	NM_001048166.1(STIL):c.2344_2347del (p.Leu782fs)	Likely pathogenic

SpliceAI

3001 predictions. Top by Δscore:

Variant	Effect	Δscore
1:47251919:CACA:C	acceptor_gain	1.0000
1:47251921:CA:C	acceptor_gain	1.0000
1:47251923:C:CC	acceptor_gain	1.0000
1:47260284:GTTA:G	donor_loss	1.0000
1:47260285:TTA:T	donor_loss	1.0000
1:47260286:TACCT:T	donor_loss	1.0000
1:47260288:C:T	donor_loss	1.0000
1:47262897:TCTTA:T	donor_loss	1.0000
1:47262898:CTTA:C	donor_loss	1.0000
1:47262899:TTA:T	donor_loss	1.0000
1:47262900:TA:T	donor_loss	1.0000
1:47262901:A:AC	donor_gain	1.0000
1:47262902:C:CC	donor_gain	1.0000
1:47263113:GCTGC:G	acceptor_gain	1.0000
1:47263114:CTGCT:C	acceptor_gain	1.0000
1:47269630:CTTA:C	donor_loss	1.0000
1:47269631:TTA:T	donor_loss	1.0000
1:47269633:A:AC	donor_gain	1.0000
1:47269633:AC:A	donor_loss	1.0000
1:47269634:C:CC	donor_gain	1.0000
1:47272072:TTA:T	donor_loss	1.0000
1:47272073:TA:T	donor_loss	1.0000
1:47272074:ACC:A	donor_loss	1.0000
1:47272097:CA:C	donor_gain	1.0000
1:47272240:ATC:A	acceptor_loss	1.0000
1:47272241:TC:T	acceptor_loss	1.0000
1:47272242:C:CC	acceptor_gain	1.0000
1:47281205:GAAAT:G	acceptor_gain	1.0000
1:47281207:AATC:A	acceptor_loss	1.0000
1:47281209:TC:T	acceptor_loss	1.0000

AlphaMissense

8569 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:47251794:A:G	L1069P	0.999
1:47251797:G:T	A1068D	0.998
1:47251804:C:G	A1066P	0.998
1:47251810:C:G	A1064P	0.998
1:47295825:C:G	R242P	0.998
1:47304941:A:G	W34R	0.998
1:47304941:A:T	W34R	0.998
1:47251785:A:G	L1072S	0.997
1:47251817:G:C	S1061R	0.997
1:47251817:G:T	S1061R	0.997
1:47251819:T:G	S1061R	0.997
1:47280260:A:G	L733P	0.997
1:47293543:A:G	W263R	0.997
1:47293543:A:T	W263R	0.997
1:47295768:C:T	G261E	0.997
1:47295769:C:G	G261R	0.997
1:47295769:C:T	G261R	0.997
1:47299968:G:T	A213D	0.997
1:47251789:A:C	Y1071D	0.996
1:47281187:A:T	V424D	0.996
1:47301718:C:G	R99P	0.996
1:47304939:C:A	W34C	0.996
1:47304939:C:G	W34C	0.996
1:47251617:A:G	L1128P	0.995
1:47251798:C:G	A1068P	0.995
1:47251800:A:T	I1067K	0.995
1:47295798:T:C	D251G	0.995
1:47251636:A:C	Y1122D	0.994
1:47260361:A:G	L1002P	0.994
1:47269859:G:C	S797R	0.994

dbSNP variants (sampled 300 via entrez): RS1000006337 (1:47299392 A>G), RS1000042563 (1:47271153 T>A,C), RS1000164272 (1:47276922 T>C), RS1000234864 (1:47302900 A>T), RS1000274819 (1:47258079 C>T), RS1000373140 (1:47295346 G>A), RS1000410670 (1:47290496 G>C), RS1000456561 (1:47275521 T>C), RS1000581372 (1:47256516 G>A,C), RS1000595597 (1:47296569 C>A,T), RS1000608639 (1:47301038 C>A,T), RS1000633780 (1:47256216 A>G), RS1000656575 (1:47252443 A>G), RS1000713509 (1:47304160 CTTATT>C), RS1000749405 (1:47303408 C>T)

Disease associations

OMIM: gene MIM:181590 | disease phenotypes: MIM:612703

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive primary microcephaly	Definitive	Autosomal recessive
microcephaly 7, primary, autosomal recessive	Strong	Autosomal recessive
holoprosencephaly	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
autosomal recessive primary microcephaly	Definitive	AR

Mondo (5): microcephaly 7, primary, autosomal recessive (MONDO:0012989), myoepithelial tumor (MONDO:0002380), intellectual disability (MONDO:0001071), autosomal recessive primary microcephaly (MONDO:0016660), holoprosencephaly (MONDO:0016296)

Orphanet (2): Autosomal recessive primary microcephaly (Orphanet:2512), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

109 total (30 of 109 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000076	Vesicoureteral reflux
HP:0000119	Abnormality of the genitourinary system
HP:0000122	Unilateral renal agenesis
HP:0000161	Median cleft upper lip
HP:0000175	Cleft palate
HP:0000193	Bifid uvula
HP:0000218	High palate
HP:0000219	Thin upper lip vermilion
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000340	Sloping forehead
HP:0000407	Sensorineural hearing impairment
HP:0000448	Prominent nose
HP:0000457	Depressed nasal ridge
HP:0000478	Abnormality of the eye
HP:0000582	Upslanted palpebral fissure
HP:0000601	Hypotelorism
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0000736	Short attention span
HP:0000737	Irritability
HP:0000739	Anxiety
HP:0000741	Apathy
HP:0000772	Abnormal rib morphology
HP:0000818	Abnormality of the endocrine system
HP:0000824	Decreased response to growth hormone stimulation test
HP:0000826	Precocious puberty
HP:0000830	Anterior hypopituitarism

GWAS associations

10 associations (top):

Study	Trait	p-value
GCST002595_12	Clozapine-induced agranulocytosis	2.000000e-06
GCST010696_1	Cortical thickness (min-P)	7.000000e-09
GCST010697_11	Cortical surface area (min-P)	3.000000e-10
GCST010698_70	Subcortical volume (min-P)	1.000000e-14
GCST010699_77	Brain morphology (min-P)	4.000000e-17
GCST010700_17	Cortical thickness (MOSTest)	4.000000e-12
GCST010701_126	Cortical surface area (MOSTest)	1.000000e-10
GCST010702_41	Subcortical volume (MOSTest)	2.000000e-10
GCST010703_86	Brain morphology (MOSTest)	2.000000e-103
GCST012227_1400	Hip circumference adjusted for BMI	3.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0008039	BMI-adjusted hip circumference

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D016142	Holoprosencephaly	C05.660.207.410; C10.500.034.875; C16.131.077.410; C16.131.260.380; C16.131.621.207.410; C16.131.666.034.875; C16.320.180.380
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D009208	Myoepithelioma	C04.557.435.585
C579935	Autosomal Recessive Primary Microcephaly (supp.)
C567198	Microcephaly, Primary Autosomal Recessive, 7 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Tetrachlorodibenzodioxin	affects expression, decreases expression	4
Resveratrol	increases expression, decreases expression, affects cotreatment	3
Benzo(a)pyrene	affects methylation, decreases expression, increases expression	3
bisphenol A	decreases expression, increases methylation	2
Estradiol	increases expression	2
Cyclosporine	decreases expression	2
aristolochic acid I	decreases expression	1
3-((6-(2-methoxyphenyl)pyrimidin-4-yl)amino)phenyl)methane sulfonamide	decreases expression	1
SP2509	decreases expression	1
beta-lapachone	decreases expression	1
arsenite	affects binding, decreases reaction	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
zinc chromate	decreases expression, increases abundance	1
2,3-bis(3’-hydroxybenzyl)butyrolactone	affects cotreatment, increases expression	1
diallyl trisulfide	decreases expression	1
chromium hexavalent ion	decreases expression, increases abundance	1
perfluorooctane sulfonic acid	decreases expression	1
2-palmitoylglycerol	increases expression	1
palbociclib	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, decreases expression	1
incobotulinumtoxinA	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Dasatinib	decreases expression	1
Sunitinib	decreases expression	1
Troglitazone	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, decreases expression	1
Azathioprine	decreases expression	1
Calcitriol	decreases expression, affects cotreatment	1
Catechin	affects cotreatment, decreases expression	1

Cellosaurus cell lines

7 cell lines: 7 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_1667	RPMI-8402	Cancer cell line	Female
CVCL_1859	CCRF-HSB-2	Cancer cell line	Male
CVCL_1Y12	HSB2/GS	Cancer cell line	Male
CVCL_2878	CPT-K5	Cancer cell line	Female
CVCL_A0DR	HSB.2-A7-D2	Cancer cell line	Male
CVCL_A0DS	HSB.2-A7-D9	Cancer cell line	Male
CVCL_A0DT	HSB.2-C5-B2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT03600649	PHASE1	UNKNOWN	Clinical Trial of SP-2577 (Seclidemstat) in Patients With Relapsed or Refractory Ewing or Ewing-related Sarcomas
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT00005016	Not specified	COMPLETED	Study of the Experiences and Needs of Parents Continuing a Pregnancy Following a Prenatal Diagnosis of Holopresencephaly
NCT00088426	Not specified	COMPLETED	Clinical and Genetic Studies on Holoprosencephaly
NCT00645645	Not specified	COMPLETED	A Study of the Genetic Analysis of Brain Disorders
NCT04691414	Not specified	COMPLETED	Retrospective Study Using Next Generation Sequencing (NGS) on Biological Samples to Improve Genetic Counseling for Patients With Previously Explored Craniofacial Midline Defects.
NCT05266196	PHASE1/PHASE2	UNKNOWN	A Rollover Protocol to Allow for Continued Access to the LSD1 Inhibitor Seclidemstat (SP-2577)
NCT06239272	PHASE1/PHASE2	RECRUITING	NRSTS2021, A Risk Adapted Study Evaluating Maintenance Pazopanib, Limited Margin, Dose-Escalated Radiation Therapy and Selinexor in Non-Rhabdomyosarcoma Soft Tissue Sarcoma (NRSTS)
NCT06625190	PHASE1/PHASE2	RECRUITING	Alpha/Beta T and B Cell Depletion With Zoledronic Acid for Solid Tumors
NCT06244420	Not specified	COMPLETED	Malignant Myoepithelioma of Bone and Soft Tissues: Diagnostic Imaging and Histology in Relation to Prognosis
NCT03479476	PHASE2/PHASE3	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome
NCT02616796	PHASE1/PHASE2	COMPLETED	Effects of Social Gaze Training on Brain and Behavior in Fragile X Syndrome
NCT06860672	EARLY_PHASE1	RECRUITING	Clinical Trial of the Dual Vector Base Editor for the Treatment of the CHD3-R1025W Mutation
NCT00597948	Not specified	COMPLETED	Healthy Lifestyles for People With Intellectual Disabilities
NCT01087320	Not specified	RECRUITING	Genome Medical Sequencing for Gene Discovery
NCT01652963	Not specified	UNKNOWN	Picture-based Computerised Assessment and Training of Cognitive Behaviour Therapy Skills
NCT01695395	Not specified	COMPLETED	Mental Health Care Provision for Adults With Intellectual Disability and a Mental Disorder
NCT01867554	Not specified	COMPLETED	Research and Characterization of New Genes Involved in Intellectual Disability
NCT01915381	Not specified	COMPLETED	Improving Adherence Healthy Lifestyle With a Smartphone Application Based on Adults With Intellectual Disabilities
NCT01988623	Not specified	COMPLETED	Pivotal Response Treatment for Individuals With Intellectual Disabilities
NCT02099773	Not specified	COMPLETED	Support Staff-client Interactions With Augmentative and Alternative Communication
NCT02136849	Not specified	COMPLETED	Inter-regional Project of the Great Western Exploration Approach for Exome Molecular Causes Severe Intellectual Disability Isolated or Syndromic
NCT02225041	Not specified	COMPLETED	Sedation Strategy and Cognitive Outcome After Critical Illness in Early Childhood
NCT02414438	Not specified	COMPLETED	Establishing the Clinical Utility of First StepDx PLUS and NextStepDx PLUS Study
NCT02451761	Not specified	COMPLETED	Apparently Balanced Chromosomal Translocation/ Next-generation Sequencing/ Intellectual Disability
NCT02461420	Not specified	ACTIVE_NOT_RECRUITING	Mapping the Genotype, Phenotype, and Natural History of Phelan-McDermid Syndrome
NCT02461459	Not specified	ACTIVE_NOT_RECRUITING	Autism Spectrum Disorder (ASD) and Intellectual Disability (ID) Determinants in Tuberous Sclerosis Complex (TSC)