INTS11

Summary

INTS11 (integrator complex subunit 11, HGNC:26052) is a protein-coding gene on chromosome 1p36.33, encoding Integrator complex subunit 11 (Q5TA45). RNA endonuclease component of the integrator complex, a multiprotein complex that terminates RNA polymerase II (Pol II) transcription in the promoter-proximal region of genes. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

The Integrator complex contains at least 12 subunits and associates with the C-terminal domain of RNA polymerase II large subunit (POLR2A; MIM 180660) and mediates the 3-prime end processing of small nuclear RNAs U1 (RNU1; MIM 180680) and U2 (RNU2; MIM 180690). INTS11, or CPSF3L, is the catalytic subunit of the Integrator complex (Baillat et al., 2005 [PubMed 16239144]).

Source: NCBI Gene 54973 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 6
• Clinical variants (ClinVar): 185 total — 3 pathogenic, 4 likely-pathogenic
• Phenotypes (HPO): 47
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_017871

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:26052
Approved symbol	INTS11
Name	integrator complex subunit 11
Location	1p36.33
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20542, RC-68, CPSF73L, INT11
Ensembl gene	ENSG00000127054
Ensembl biotype	protein_coding
OMIM	611354
Entrez	54973

Gene structure

Transcript identifiers

Ensembl transcripts: 54 — 20 protein_coding, 19 retained_intron, 10 nonsense_mediated_decay, 5 protein_coding_CDS_not_defined

ENST00000323275, ENST00000411962, ENST00000419704, ENST00000421495, ENST00000429572, ENST00000430786, ENST00000434694, ENST00000435064, ENST00000450926, ENST00000458452, ENST00000461514, ENST00000462432, ENST00000467408, ENST00000470030, ENST00000470679, ENST00000478641, ENST00000485710, ENST00000488042, ENST00000490853, ENST00000493534, ENST00000496353, ENST00000497304, ENST00000498173, ENST00000498476, ENST00000525164, ENST00000525285, ENST00000525603, ENST00000525769, ENST00000526113, ENST00000526332, ENST00000526797, ENST00000526904, ENST00000527098, ENST00000527383, ENST00000527719, ENST00000528879, ENST00000530031, ENST00000530233, ENST00000531019, ENST00000531020, ENST00000531292, ENST00000531377, ENST00000532772, ENST00000532952, ENST00000533916, ENST00000534345, ENST00000540437, ENST00000545578, ENST00000620829, ENST00000891836, ENST00000891837, ENST00000931667, ENST00000931668, ENST00000941695

RefSeq mRNA: 5 — MANE Select: NM_017871 NM_001256456, NM_001256460, NM_001256462, NM_001256463, NM_017871

CCDS: CCDS21, CCDS57959, CCDS57960, CCDS57961, CCDS72678

Canonical transcript exons

ENST00000435064 — 17 exons

Exon	Start	End
ENSE00001606556	1311600	1311924
ENSE00003480282	1312787	1312949
ENSE00003481468	1314301	1314365
ENSE00003493216	1312593	1312700
ENSE00003521162	1313035	1313124
ENSE00003522925	1319296	1319524
ENSE00003524405	1312226	1312368
ENSE00003562382	1315404	1315438
ENSE00003568595	1313732	1313921
ENSE00003580641	1312018	1312147
ENSE00003594178	1320996	1321093
ENSE00003604585	1314824	1314962
ENSE00003625354	1315520	1315618
ENSE00003642378	1312440	1312501
ENSE00003666435	1320456	1320529
ENSE00003692932	1313509	1313592
ENSE00003899545	1324581	1324660

Expression profiles

Bgee: expression breadth ubiquitous, 134 present calls, max score 99.15.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 67.3820 / max 454.0314, expressed in 1824 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
9754	64.0763	1824
9753	2.6889	1576
9752	0.4166	210
9751	0.2002	82

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right hemisphere of cerebellum	UBERON:0014890	99.15	gold quality
cerebellar hemisphere	UBERON:0002245	99.13	gold quality
cerebellum	UBERON:0002037	99.12	gold quality
cerebellar cortex	UBERON:0002129	99.12	gold quality
right uterine tube	UBERON:0001302	98.95	gold quality
body of uterus	UBERON:0009853	98.83	gold quality
right ovary	UBERON:0002118	98.61	gold quality
left ovary	UBERON:0002119	98.58	gold quality
endocervix	UBERON:0000458	98.50	gold quality
pituitary gland	UBERON:0000007	98.32	gold quality
muscle layer of sigmoid colon	UBERON:0035805	98.32	gold quality
ovary	UBERON:0000992	98.31	gold quality
left uterine tube	UBERON:0001303	98.28	gold quality
fundus of stomach	UBERON:0001160	98.24	gold quality
ectocervix	UBERON:0012249	98.23	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	98.23	gold quality
lower esophagus muscularis layer	UBERON:0035833	98.22	gold quality
lower esophagus	UBERON:0013473	98.21	gold quality
apex of heart	UBERON:0002098	98.17	gold quality
right lobe of thyroid gland	UBERON:0001119	98.14	gold quality
adenohypophysis	UBERON:0002196	98.09	gold quality
myometrium	UBERON:0001296	98.06	gold quality
left testis	UBERON:0004533	98.02	gold quality
vagina	UBERON:0000996	97.98	gold quality
popliteal artery	UBERON:0002250	97.98	gold quality
tibial artery	UBERON:0007610	97.97	gold quality
right testis	UBERON:0004534	97.96	gold quality
left lobe of thyroid gland	UBERON:0001120	97.92	gold quality
prostate gland	UBERON:0002367	97.92	gold quality
body of stomach	UBERON:0001161	97.82	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-110499	no	127.66
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

5 targeting INTS11, 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-548AN	99.97	70.91	2817
HSA-MIR-6764-5P	99.75	67.89	2304
HSA-MIR-1915-3P	99.58	66.79	1988
HSA-MIR-1911-5P	98.92	67.53	325
HSA-MIR-3649	96.85	64.10	340

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 7)

• The specific heterodimeric interaction between IntS9 and IntS11 is mediated by a discrete domain present at the extreme C terminus of IntS9 and within the C terminus of IntS11, adjacent to the predicted active site of this endonuclease. (PMID:22252320)
• Functional studies demonstrate that the IntS9-IntS11 interaction is crucial for the role of INT in snRNA 3’-end processing. (PMID:28396433)
• INTS4 is a specific and conserved interaction partner of INTS9/11 that does not interact with either subunit individually. (PMID:29471365)
• NACK and INTEGRATOR act coordinately to activate Notch-mediated transcription in tumorigenesis. (PMID:34551776)
• An examination of the metal ion content in the active sites of human endonucleases CPSF73 and INTS11. (PMID:36822327)
• A homozygous variant in INTS11 links mitosis and neurogenesis defects to a severe neurodevelopmental disorder. (PMID:37980560)
• Human promoter directionality is determined by transcriptional initiation and the opposing activities of INTS11 and CDK9. (PMID:38976490)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ints11	ENSDARG00000025212
mus_musculus	Ints11	ENSMUSG00000029034
rattus_norvegicus	Ints11	ENSRNOG00000019712
drosophila_melanogaster	IntS11	FBGN0039691
caenorhabditis_elegans		WBGENE00008642

Paralogs (3): INTS9 (ENSG00000104299), CPSF3 (ENSG00000119203), CPSF2 (ENSG00000165934)

Protein

Protein identifiers

Integrator complex subunit 11 — Q5TA45 (reviewed: Q5TA45)

Alternative names: Cleavage and polyadenylation-specific factor 3-like protein, Protein related to CPSF subunits of 68 kDa

All UniProt accessions (21): Q5TA45, A0A087WXT8, A0A087WYI0, C9IYS7, C9J979, E9PI75, E9PIG1, E9PIL7, E9PIS0, E9PIX9, E9PJG0, E9PKA4, E9PMA2, E9PNH9, E9PNS4, E9PQF0, H0YDB1, H0YE15, H0YEQ9, H7C247, J3QRY6

UniProt curated annotations — full annotation on UniProt →

Function. RNA endonuclease component of the integrator complex, a multiprotein complex that terminates RNA polymerase II (Pol II) transcription in the promoter-proximal region of genes. The integrator complex provides a quality checkpoint during transcription elongation by driving premature transcription termination of transcripts that are unfavorably configured for transcriptional elongation: the complex terminates transcription by (1) catalyzing dephosphorylation of the C-terminal domain (CTD) of Pol II subunit POLR2A/RPB1 and SUPT5H/SPT5, (2) degrading the exiting nascent RNA transcript via endonuclease activity and (3) promoting the release of Pol II from bound DNA. The integrator complex is also involved in terminating the synthesis of non-coding Pol II transcripts, such as enhancer RNAs (eRNAs), small nuclear RNAs (snRNAs), telomerase RNAs and long non-coding RNAs (lncRNAs). Within the integrator complex, INTS11 constitutes the RNA endonuclease subunit that degrades exiting nascent RNA transcripts. Mediates recruitment of cytoplasmic dynein to the nuclear envelope, probably as component of the integrator complex.

Subunit / interactions. Component of the Integrator complex, composed of core subunits INTS1, INTS2, INTS3, INTS4, INTS5, INTS6, INTS7, INTS8, INTS9/RC74, INTS10, INTS11/CPSF3L, INTS12, INTS13, INTS14 and INTS15. The core complex associates with protein phosphatase 2A subunits PPP2CA and PPP2R1A, to form the Integrator-PP2A (INTAC) complex. INTS11 is part of the RNA endonuclease subcomplex, composed of INTS4, INTS9, INTS11 and inositol hexakisphosphate (InsP6). Interacts with WDR73; interaction is required for the assembly of the RNA endonuclease subcomplex in the cytoplasm. Interacts with BRAT1; interaction is required for the assembly of the RNA endonuclease subcomplex and inhibits the endonuclease activity of INTS11 before formation of mature integrator complex.

Subcellular location. Nucleus. Cytoplasm.

Post-translational modifications. Sumoylated; sumoylation regulates its subcellular location and is required for integrator complex integrity.

Disease relevance. Neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities (NEDMLOB) [MIM:620428] An autosomal recessive disorder apparent from infancy or early childhood, and characterized by global developmental delay, intellectual disability, motor and speech impairment, and brain abnormalities. Specifically, brain imaging shows progressive cortical atrophy, cortical gyral simplification, and delayed myelination affecting cerebrum and cerebellum. Ocular defects can include optic atrophy, nystagmus, strabismus, and retinal dystrophy. Disease severity is variable and some patients may die in childhood. The disease may be caused by variants affecting the gene represented in this entry.

Activity regulation. The RNA endonuclease activity is inhibited by BRAT1 that forms hydrogen bond and hydrophobic interactions with the active site.

Similarity. Belongs to the metallo-beta-lactamase superfamily. RNA-metabolizing metallo-beta-lactamase-like family. INTS11 subfamily.

Isoforms (5)

UniProt ID	Names	Canonical?
Q5TA45-1	1	yes
Q5TA45-2	2
Q5TA45-3	3
Q5TA45-4	4
Q5TA45-5	5

RefSeq proteins (5): NP_001243385, NP_001243389, NP_001243391, NP_001243392, NP_060341* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001279	Metallo-B-lactamas	Domain
IPR011108	RMMBL	Domain
IPR022712	Beta_Casp	Domain
IPR036866	RibonucZ/Hydroxyglut_hydro	Homologous_superfamily
IPR041897	INTS11-like_MBL-fold	Domain
IPR048662	IntS11_C	Domain
IPR050698	MBL	Family

Pfam: PF07521, PF10996, PF16661, PF21386

UniProt features (120 total): strand 41, helix 23, sequence variant 14, mutagenesis site 14, binding site 9, turn 4, splice variant 4, sequence conflict 4, cross-link 3, short sequence motif 2, chain 1, active site 1

Structure

Experimental structures (PDB)

15 structures.

PDB	Method	Resolution (Å)
5V8W	X-RAY DIFFRACTION	2.1
8RC4	ELECTRON MICROSCOPY	3.1
8R23	ELECTRON MICROSCOPY	3.2
8UIB	ELECTRON MICROSCOPY	3.21
7CUN	ELECTRON MICROSCOPY	3.5
7BFP	ELECTRON MICROSCOPY	3.56
7PKS	ELECTRON MICROSCOPY	3.6
8RBZ	ELECTRON MICROSCOPY	3.7
8R22	ELECTRON MICROSCOPY	3.9
8R2D	ELECTRON MICROSCOPY	3.9
8RBX	ELECTRON MICROSCOPY	4.1
8YJB	ELECTRON MICROSCOPY	4.1
7BFQ	ELECTRON MICROSCOPY	4.15
7YCX	ELECTRON MICROSCOPY	4.18
9VD9	ELECTRON MICROSCOPY	4.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q5TA45-F1	90.82	0.67

Functional residue map

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

Catalytic / active sites (1): 203

Ligand- & substrate-binding residues (9): 178; 414; 462; 68; 70; 72; 73; 157; 178

Post-translational modifications (3): 381, 462, 475

Mutagenesis-validated functional residues (14):

Position	Phenotype
38–43	in gr2e mutant; abolished interaction with brat1.
72–73	abolished rna endonuclease activity.
127–131	abolished interaction with brat1.
203	abolished rna endonuclease activity. abolishes the ability of the integrator complex to process u1 and u2 snrna genes. d
210	decreased nuclear localization of brat1.
381	abolished sumoylation, leading to impaired integrator complex integrity; when associated with r-462 and r-475.
449–502	in ctd1-delta mutant; decreased processing activity of the integrator complex.
462	decreased processing activity of the integrator complex.
462	abolished sumoylation, leading to impaired integrator complex integrity; when associated with r-381 and r-475.
474–475	decreased localization in the nucleus.
475	abolished sumoylation, leading to impaired integrator complex integrity; when associated with r-381 and r-462.
503–600	in ctd2-delta mutant; decreased processing activity of the integrator complex.
509–511	abolished interaction with ints9.
510–512	abolished interaction with ints9.

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6807505	RNA polymerase II transcribes snRNA genes
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)

MSigDB gene sets: 188 (showing top): GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, GOMF_NUCLEASE_ACTIVITY, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, CHANDRAN_METASTASIS_DN, MODULE_313, GOBP_RNA_SURVEILLANCE, GOMF_RNA_ENDONUCLEASE_ACTIVITY, GOBP_DNA_TEMPLATED_TRANSCRIPTION_INITIATION, GOBP_TRANSCRIPTION_INITIATION_AT_RNA_POLYMERASE_II_PROMOTER, LASTOWSKA_NEUROBLASTOMA_COPY_NUMBER_DN, GOBP_SNRNA_PROCESSING, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_UP, GOBP_REGULATION_OF_DNA_TEMPLATED_TRANSCRIPTION_ELONGATION, CHANDRAN_METASTASIS_TOP50_DN

GO Biological Process (6): snRNA processing (GO:0016180), regulation of transcription elongation by RNA polymerase II (GO:0034243), snRNA 3’-end processing (GO:0034472), RNA polymerase II transcription initiation surveillance (GO:0160240), transcription by RNA polymerase II (GO:0006366), transcription elongation by RNA polymerase II (GO:0006368)

GO Molecular Function (4): RNA endonuclease activity (GO:0004521), hydrolase activity (GO:0016787), metal ion binding (GO:0046872), protein binding (GO:0005515)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), integrator complex (GO:0032039), blood microparticle (GO:0072562), INTAC complex (GO:0160232)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
RNA Polymerase II Transcription	1
Gene expression (Transcription)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
nuclear protein-containing complex	2
RNA processing	1
snRNA metabolic process	1
transcription elongation by RNA polymerase II	1
regulation of DNA-templated transcription elongation	1
snRNA processing	1
RNA 3’-end processing	1
transcription initiation at RNA polymerase II promoter	1
nuclear RNA surveillance	1
DNA-templated transcription	1
DNA-templated transcription elongation	1
transcription by RNA polymerase II	1
endonuclease activity	1
RNA nuclease activity	1
catalytic activity	1
cation binding	1
binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
cytoplasm	1
extracellular region	1
integrator complex	1

Protein interactions and networks

STRING

1464 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
INTS11	INTS4	Q96HW7	983
INTS11	INTS12	Q96CB8	976
INTS11	INTS1	Q8N201	970
INTS11	INTS5	Q6P9B9	963
INTS11	INTS7	Q9NVH2	962
INTS11	INTS10	Q9NVR2	955
INTS11	INTS9	Q9NV88	951
INTS11	INTS8	Q75QN2	950
INTS11	INTS6	Q9UL03	945
INTS11	INTS2	Q9H0H0	913
INTS11	INTS3	Q68E01	872
INTS11	POLR2A	P24928	788
INTS11	INTS13	Q9NVM9	732
INTS11	INIP	Q9NRY2	729
INTS11	LACTB	P83096	679

IntAct

166 interactions, top by confidence:

A	B	Type	Score
INTS11	INTS9	psi-mi:“MI:0407”(direct interaction)	0.940
INTS11	INTS9	psi-mi:“MI:0915”(physical association)	0.940
INTS9	INTS11	psi-mi:“MI:0915”(physical association)	0.940
INTS9	INTS11	psi-mi:“MI:0914”(association)	0.940
PPP2R1A	STRN	psi-mi:“MI:0914”(association)	0.880
INTS11	INTS4	psi-mi:“MI:0915”(physical association)	0.860
INTS10	INTS11	psi-mi:“MI:0915”(physical association)	0.740
INTS13	INTS11	psi-mi:“MI:0915”(physical association)	0.690
INTS13	INTS11	psi-mi:“MI:0914”(association)	0.690
KPNA1	TCERG1	psi-mi:“MI:0914”(association)	0.640

BioGRID (153): CPSF3L (Affinity Capture-MS), CPSF3L (Affinity Capture-MS), CPSF3L (Two-hybrid), CPSF3L (Two-hybrid), CPSF3L (Two-hybrid), CPSF3L (Co-fractionation), CPSF3L (Co-fractionation), CPSF3L (Co-fractionation), CPSF3L (Affinity Capture-MS), CPSF3L (Affinity Capture-MS), CPSF3L (Affinity Capture-MS), CPSF3L (Affinity Capture-MS), CPSF3L (Affinity Capture-MS), CPSF3L (Affinity Capture-MS), CPSF3L (Affinity Capture-MS)

ESM2 similar proteins: A4FV08, A4IHW6, A5PJI5, G3V9T7, O43681, O54984, O94973, P16298, P17427, P18484, P20651, P48452, P48453, P63328, P63329, Q08209, Q08211, Q0IIZ2, Q0P5E2, Q0VCK5, Q17QL1, Q28141, Q2KJ61, Q2YDH6, Q2YDM2, Q3MHC2, Q503E1, Q5HZM6, Q5NVE6, Q5R5S4, Q5R874, Q5RIC0, Q5TA45, Q5ZHS1, Q5ZIH0, Q6GNQ1, Q6IQE5, Q6NVL5, Q6R518, Q7RTP6

Diamond homologs: A0A0F8XYN9, A0RXV0, O27271, O50112, Q2YDM2, Q3MHC2, Q503E1, Q57626, Q58633, Q5JH24, Q5NVE6, Q5SLP1, Q5TA45, Q5ZIH0, Q60355, Q6C2Z7, Q6LZD5, Q86A79, Q8GUU3, Q8PZ03, Q980D0, Q9CWS4, Q9V0P0, Q9VAH9, A0QVT2, B9XZG7, M4MR97, O31760, P47385, P54122, P54123, P56185, P75497, P9WGZ8, P9WGZ9, Q2FHG3, Q2FHZ1, Q2FZ19, Q2FZG9, Q2YX35

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
INTS11	“form complex”	“Integrator complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 103 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
FGFR2 mutant receptor activation	6	74.9×	3e-09
Signaling by FGFR2 IIIa TM	6	59.1×	1e-08
Abortive elongation of HIV-1 transcript in the absence of Tat	7	57.0×	1e-09
Pausing and recovery of Tat-mediated HIV elongation	8	48.3×	3e-10
Tat-mediated HIV elongation arrest and recovery	8	48.3×	3e-10
RNA Pol II CTD phosphorylation and interaction with CE during HIV infection	7	46.8×	3e-09
Signaling by FGFR2	7	46.8×	3e-09
RNA Pol II CTD phosphorylation and interaction with CE	7	46.8×	3e-09

GO biological processes:

GO term	Partners	Fold	FDR
RNA polymerase II transcription initiation surveillance	7	71.4×	2e-09
snRNA processing	5	60.5×	2e-06
regulation of transcription elongation by RNA polymerase II	6	55.3×	2e-07
transcription by RNA polymerase II	8	6.5×	4e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	4
Uncertain significance	122
Likely benign	18
Benign	5

Top pathogenic / likely-pathogenic (7)

Variant ID	HGVS	Classification
2506979	NM_017871.6(INTS11):c.1240C>T (p.His414Tyr)	Pathogenic
2506980	NM_017871.6(INTS11):c.412C>T (p.Leu138Phe)	Pathogenic
2506983	NM_017871.6(INTS11):c.50G>T (p.Arg17Leu)	Pathogenic
3359221	NM_017871.6(INTS11):c.1652_1653del (p.Val551fs)	Likely pathogenic
3359222	NM_017871.6(INTS11):c.1652T>A (p.Val551Glu)	Likely pathogenic
3376978	NM_017871.6(INTS11):c.1560_1561del (p.Arg521fs)	Likely pathogenic
4845903	NM_017871.6(INTS11):c.510_511insAA (p.Glu171fs)	Likely pathogenic

SpliceAI

3273 predictions. Top by Δscore:

Variant	Effect	Δscore
1:1312014:TTA:T	donor_loss	1.0000
1:1312017:C:CA	donor_loss	1.0000
1:1312143:GGACG:G	acceptor_gain	1.0000
1:1312144:GACG:G	acceptor_gain	1.0000
1:1312145:ACG:A	acceptor_gain	1.0000
1:1312145:ACGC:A	acceptor_loss	1.0000
1:1312146:CG:C	acceptor_gain	1.0000
1:1312146:CGC:C	acceptor_gain	1.0000
1:1312147:GC:G	acceptor_loss	1.0000
1:1312148:C:CC	acceptor_gain	1.0000
1:1312148:CT:C	acceptor_loss	1.0000
1:1312149:T:C	acceptor_loss	1.0000
1:1312220:GCCCA:G	donor_loss	1.0000
1:1312221:CCCA:C	donor_loss	1.0000
1:1312222:CCAC:C	donor_loss	1.0000
1:1312223:CACCT:C	donor_loss	1.0000
1:1312224:A:AT	donor_loss	1.0000
1:1312225:CCT:C	donor_gain	1.0000
1:1312227:T:TA	donor_gain	1.0000
1:1312364:AAGTT:A	acceptor_gain	1.0000
1:1312365:AGTT:A	acceptor_gain	1.0000
1:1312366:GTT:G	acceptor_gain	1.0000
1:1312367:TT:T	acceptor_gain	1.0000
1:1312368:TC:T	acceptor_loss	1.0000
1:1312369:C:CC	acceptor_gain	1.0000
1:1312369:C:CG	acceptor_loss	1.0000
1:1312370:T:G	acceptor_loss	1.0000
1:1312438:A:AC	donor_gain	1.0000
1:1312439:C:CC	donor_gain	1.0000
1:1312439:CG:C	donor_gain	1.0000

AlphaMissense

3962 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:1312813:A:G	L423P	1.000
1:1312837:C:A	G415V	1.000
1:1312837:C:T	G415D	1.000
1:1312839:A:C	H414Q	1.000
1:1312839:A:T	H414Q	1.000
1:1312841:G:C	H414D	1.000
1:1312841:G:T	H414N	1.000
1:1312892:C:G	G397R	1.000
1:1312905:G:C	H392Q	1.000
1:1312905:G:T	H392Q	1.000
1:1312906:T:C	H392R	1.000
1:1312907:G:A	H392Y	1.000
1:1312907:G:C	H392D	1.000
1:1312907:G:T	H392N	1.000
1:1312911:G:C	S390R	1.000
1:1312911:G:T	S390R	1.000
1:1312913:T:G	S390R	1.000
1:1312914:G:C	F389L	1.000
1:1312914:G:T	F389L	1.000
1:1312915:A:G	F389S	1.000
1:1312916:A:G	F389L	1.000
1:1313087:C:T	G360D	1.000
1:1313088:C:G	G360R	1.000
1:1313104:G:C	C354W	1.000
1:1313111:C:T	G352D	1.000
1:1313114:G:T	P351H	1.000
1:1313532:A:G	W340R	1.000
1:1313532:A:T	W340R	1.000
1:1313552:G:A	S333F	1.000
1:1313558:C:T	G331E	1.000

dbSNP variants (sampled 300 via entrez): RS1000003240 (1:1324638 G>A,T), RS1000073352 (1:1325526 C>A,T), RS1000438273 (1:1324775 G>A), RS1000633999 (1:1317892 G>A,T), RS1000732571 (1:1317752 G>A), RS1001063047 (1:1315899 C>T), RS1001242875 (1:1311218 C>A,G,T), RS1001331534 (1:1325810 C>T), RS1001368795 (1:1314510 G>A), RS1001435385 (1:1315435 C>T), RS1001651729 (1:1324275 G>C), RS1001720675 (1:1323712 G>A), RS1001897383 (1:1318151 T>C,G), RS1001993670 (1:1322804 A>G), RS1002046104 (1:1322431 A>C)

Disease associations

OMIM: gene MIM:611354 | disease phenotypes: MIM:620428

GenCC curated gene-disease

Disease	Classification	Inheritance
neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities	Strong	Autosomal recessive
complex neurodevelopmental disorder	Moderate	Autosomal recessive

Mondo (2): neurodevelopmental disorder with motor and language delay, ocular defects, and brain abnormalities (MONDO:0957386), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (0):

HPO phenotypes

47 total (30 of 47 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000154	Wide mouth
HP:0000189	Narrow palate
HP:0000193	Bifid uvula
HP:0000219	Thin upper lip vermilion
HP:0000252	Microcephaly
HP:0000278	Retrognathia
HP:0000280	Coarse facial features
HP:0000286	Epicanthus
HP:0000316	Hypertelorism
HP:0000325	Triangular face
HP:0000340	Sloping forehead
HP:0000350	Small forehead
HP:0000369	Low-set ears
HP:0000445	Wide nose
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000545	Myopia
HP:0000556	Retinal dystrophy
HP:0000648	Optic atrophy
HP:0000750	Delayed speech and language development
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001270	Motor delay
HP:0001272	Cerebellar atrophy
HP:0001274	Agenesis of corpus callosum
HP:0001321	Cerebellar hypoplasia
HP:0001363	Craniosynostosis
HP:0001511	Intrauterine growth retardation

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST004131_103	Inflammatory bowel disease	2.000000e-07
GCST004133_40	Ulcerative colitis	3.000000e-06
GCST004278_58	Pulse pressure	2.000000e-06
GCST004278_60	Pulse pressure	2.000000e-10
GCST004279_36	Systolic blood pressure	1.000000e-12
GCST007400_7	Systemic lupus erythematosus	1.000000e-07

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005763	pulse pressure measurement
EFO:0006335	systolic blood pressure

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

26 total (human), top 26 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
methacrylaldehyde	increases oxidation, increases abundance, affects cotreatment	2
Acrolein	affects cotreatment, increases oxidation, increases abundance	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, increases expression	2
Ozone	affects cotreatment, increases oxidation, increases abundance	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Smoke	decreases expression, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
TAK-243	increases sumoylation	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases abundance, affects cotreatment, increases oxidation	1
deoxynivalenol	increases expression	1
sodium arsenite	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
14-deoxy-11,12-didehydroandrographolide	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
Arsenic	affects methylation	1
Citrinin	increases expression	1
Demecolcine	decreases expression	1
Diazinon	increases methylation	1
Formaldehyde	decreases expression	1
Ivermectin	decreases expression	1
Valproic Acid	increases expression	1
Vincristine	decreases expression	1
Cyclosporine	decreases methylation	1
Volatile Organic Compounds	affects cotreatment, increases oxidation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder