THOC2

Summary

THOC2 (THO complex subunit 2, HGNC:19073) is a protein-coding gene on chromosome Xq25, encoding THO complex subunit 2 (Q8NI27). Component of the THO subcomplex of the TREX complex which is thought to couple mRNA transcription, processing and nuclear export, and which specifically associates with spliced mRNA and not with unspliced pre-mRNA. It is a common-essential gene (DepMap: required in 99.1% of cancer cell lines).

The TREX multiprotein complex binds specifically to spliced mRNAs to facilitate mRNA export. The protein encoded by this gene is a member of the THO complex, a subset of the TREX complex. The encoded protein interacts with the THOC1 protein.

Source: NCBI Gene 57187 — RefSeq curated summary.

At a glance

• Gene–disease (curated): X-linked complex neurodevelopmental disorder (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 1
• Clinical variants (ClinVar): 587 total — 8 pathogenic, 13 likely-pathogenic
• Phenotypes (HPO): 83
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 99.1% of screened cell lines (common-essential)
• MANE Select transcript: NM_001081550

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19073
Approved symbol	THOC2
Name	THO complex subunit 2
Location	Xq25
Locus type	gene with protein product
Status	Approved
Aliases	THO2, dJ506G2.1
Ensembl gene	ENSG00000125676
Ensembl biotype	protein_coding
OMIM	300395
Entrez	57187

Gene structure

Transcript identifiers

Ensembl transcripts: 21 — 10 protein_coding, 6 retained_intron, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000245838, ENST00000355725, ENST00000416618, ENST00000419789, ENST00000432353, ENST00000433883, ENST00000438358, ENST00000441692, ENST00000448128, ENST00000455053, ENST00000459945, ENST00000464161, ENST00000464604, ENST00000464982, ENST00000464992, ENST00000491737, ENST00000492203, ENST00000496830, ENST00000497887, ENST00000618150, ENST00000931863

RefSeq mRNA: 1 — MANE Select: NM_001081550 NM_001081550

CCDS: CCDS43988

Canonical transcript exons

ENST00000245838 — 39 exons

Exon	Start	End
ENSE00001537798	123600569	123601338
ENSE00002700240	123732952	123733052
ENSE00003516348	123671669	123671761
ENSE00003520667	123703454	123703505
ENSE00003528531	123613639	123613708
ENSE00003528571	123611440	123611516
ENSE00003544996	123610918	123610963
ENSE00003556009	123696021	123696154
ENSE00003614298	123613399	123613556
ENSE00003631304	123614052	123614189
ENSE00003644252	123622758	123622860
ENSE00003655894	123686548	123686714
ENSE00003659811	123619401	123619436
ENSE00003674538	123624060	123624191
ENSE00003888891	123638934	123639027
ENSE00003888921	123665642	123665837
ENSE00003889126	123625912	123626069
ENSE00003889566	123644779	123644909
ENSE00003889679	123638043	123638123
ENSE00003890321	123712850	123712908
ENSE00003890379	123623105	123623283
ENSE00003890581	123632861	123633040
ENSE00003890683	123697681	123697751
ENSE00003891306	123627693	123627968
ENSE00003891615	123667106	123667278
ENSE00003892015	123631688	123631852
ENSE00003892209	123668159	123668314
ENSE00003892304	123645334	123645375
ENSE00003892371	123636079	123636175
ENSE00003893204	123621157	123621587
ENSE00003893645	123624541	123624669
ENSE00003893834	123633953	123634070
ENSE00003894240	123623787	123623971
ENSE00003894520	123696721	123696842
ENSE00003894623	123640538	123640622
ENSE00003894692	123626521	123626662
ENSE00003894918	123644575	123644676
ENSE00003895400	123620907	123620965
ENSE00003896240	123706858	123706949

Expression profiles

Bgee: expression breadth ubiquitous, 297 present calls, max score 99.20.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 33.8049 / max 818.1560, expressed in 1805 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
200388	32.1036	1803
200386	1.7013	771

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
secondary oocyte	CL:0000655	99.20	gold quality
calcaneal tendon	UBERON:0003701	98.40	gold quality
oocyte	CL:0000023	98.23	gold quality
sural nerve	UBERON:0015488	97.92	gold quality
ventricular zone	UBERON:0003053	96.56	gold quality
colonic epithelium	UBERON:0000397	96.42	gold quality
adrenal tissue	UBERON:0018303	96.03	gold quality
right lung	UBERON:0002167	95.35	gold quality
lower esophagus muscularis layer	UBERON:0035833	95.31	gold quality
lower esophagus	UBERON:0013473	95.30	gold quality
visceral pleura	UBERON:0002401	95.10	gold quality
tendon	UBERON:0000043	94.99	gold quality
left ovary	UBERON:0002119	94.74	gold quality
mucosa of stomach	UBERON:0001199	94.72	gold quality
body of pancreas	UBERON:0001150	94.66	gold quality
right ovary	UBERON:0002118	94.66	gold quality
ganglionic eminence	UBERON:0004023	94.66	gold quality
monocyte	CL:0000576	94.60	gold quality
mononuclear cell	CL:0000842	94.55	gold quality
tonsil	UBERON:0002372	94.55	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.49	gold quality
pylorus	UBERON:0001166	94.46	gold quality
body of uterus	UBERON:0009853	94.37	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.37	gold quality
skin of abdomen	UBERON:0001416	94.30	gold quality
leukocyte	CL:0000738	94.27	gold quality
esophagus	UBERON:0001043	94.25	gold quality
upper lobe of left lung	UBERON:0008952	94.24	gold quality
left lobe of thyroid gland	UBERON:0001120	94.15	gold quality
small intestine Peyer’s patch	UBERON:0003454	94.13	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	12.96

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

110 targeting THOC2, 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-4673	100.00	66.64	1490
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-1229-3P	99.97	66.49	906
HSA-MIR-7152-3P	99.97	67.47	849
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-493-5P	99.96	72.47	2382

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.1% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 4)

• recruitment of the human TREX complex to spliced mRNA is not directly coupled to transcription, but is instead coupled to transcription indirectly through splicing (PMID:15998806)
• THOC2 mutations implicate mRNA-export pathway in X-linked intellectual disability. (PMID:26166480)
• Study presents detailed clinical assessment and functional studies on a de novo variant in a female with an epileptic encephalopathy and discuss an additional four families with rare variants in THOC2 with supportive evidence for pathogenicity. (PMID:29851191)
• THOC2 reduction repressed melanoma cell proliferation and invasion, and induced cell apoptosis. (PMID:31680623)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	thoc2	ENSDARG00000037503
mus_musculus	Thoc2	ENSMUSG00000037475
mus_musculus	Thoc2l	ENSMUSG00000097392
rattus_norvegicus	Thoc2	ENSRNOG00000007315
rattus_norvegicus	Thoc2l	ENSRNOG00000042340
drosophila_melanogaster	tho2	FBGN0031390
caenorhabditis_elegans		WBGENE00015813

Protein

Protein identifiers

THO complex subunit 2 — Q8NI27 (reviewed: Q8NI27)

Alternative names: hTREX120

All UniProt accessions (9): Q8NI27, A0A0C4DG98, B7ZB98, B7ZBA0, F2Z2V2, H0Y594, H0Y7U4, H0Y815, H7C477

UniProt curated annotations — full annotation on UniProt →

Function. Component of the THO subcomplex of the TREX complex which is thought to couple mRNA transcription, processing and nuclear export, and which specifically associates with spliced mRNA and not with unspliced pre-mRNA. Required for efficient export of polyadenylated RNA and spliced mRNA. The THOC1-THOC2-THOC3 core complex alone is sufficient to bind export factor NXF1-NXT1 and promote ATPase activity of DDX39B; in the complex THOC2 is the only component that directly interacts with DDX39B. TREX is recruited to spliced mRNAs by a transcription-independent mechanism, binds to mRNA upstream of the exon-junction complex (EJC) and is recruited in a splicing- and cap-dependent manner to a region near the 5’ end of the mRNA where it functions in mRNA export to the cytoplasm via the TAP/NXF1 pathway. Required for NXF1 localization to the nuclear rim. THOC2 (and probably the THO complex) is involved in releasing mRNA from nuclear speckle domains. (Microbial infection) The TREX complex is essential for the export of Kaposi’s sarcoma-associated herpesvirus (KSHV) intronless mRNAs and infectious virus production.

Subunit / interactions. Component of the THO subcomplex, which is composed of THOC1, THOC2, THOC3, THOC5, THOC6 and THOC7. The THO subcomplex interacts with DDX39B to form the THO-DDX39B complex which multimerizes into a 28-subunit tetrameric assembly. Component of the transcription/export (TREX) complex at least composed of ALYREF/THOC4, DDX39B, SARNP/CIP29, CHTOP and the THO subcomplex; in the complex interacts with THOC1, THOC3, THOC5, THOC7 and DDX39B. TREX seems to have a dynamic structure involving ATP-dependent remodeling. Interacts with POLDIP3 and ZC3H11A.

Subcellular location. Nucleus. Nucleus speckle. Cytoplasm.

Tissue specificity. Expressed in the hippocampus and the cerebral cortex.

Disease relevance. Intellectual developmental disorder, X-linked, syndromic, Kumar type (MRXSK) [MIM:300957] A form of intellectual disability, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked forms, while syndromic forms present with associated physical, neurological and/or psychiatric manifestations. MRXSK patients manifest variable degrees of intellectual disability. Commonly observed features included speech delay, elevated BMI, short stature, seizure disorders, gait disturbance, and tremors. The disease is caused by variants affecting the gene represented in this entry. Arthrogryposis multiplex congenita 7, X-linked (AMC7) [MIM:301127] A form of arthrogryposis multiplex congenita, a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. AMC7 is an X-linked recessive, severe form with onset in utero. Affected fetuses may also have subcutaneous edema and dysmorphic facial features. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the THOC2 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8NI27-1	1	yes
Q8NI27-2	2

RefSeq proteins (1): NP_001075019* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR021418	THO_THOC2_C	Domain
IPR021726	THO_THOC2_N	Domain
IPR032302	THOC2_N	Domain
IPR040007	Tho2	Family

Pfam: PF11262, PF11732, PF16134

UniProt features (121 total): helix 56, sequence variant 19, compositionally biased region 9, modified residue 9, region of interest 7, strand 7, sequence conflict 4, turn 4, mutagenesis site 2, chain 1, splice variant 1, coiled-coil region 1, short sequence motif 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
7APK	ELECTRON MICROSCOPY	3.3
7ZNL	ELECTRON MICROSCOPY	3.45
7ZNK	ELECTRON MICROSCOPY	3.9
8R7L	ELECTRON MICROSCOPY	4.12

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8NI27-F1	72.83	0.33

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 (9): 1222, 1385, 1390, 1393, 1417, 1443, 1450, 1486, 1516

Mutagenesis-validated functional residues (2):

Position	Phenotype
551–558	impairs interaction with ddx39b. abolishes interaction with ddx39b; when associated with 589-a–a-592.
589–592	impairs interaction with ddx39b. abolishes interaction with ddx39b; when associated with 551-a–s-558.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-159236	Transport of Mature mRNA derived from an Intron-Containing Transcript
R-HSA-72187	mRNA 3’-end processing
R-HSA-73856	RNA Polymerase II Transcription Termination
R-HSA-72202	Transport of Mature Transcript to Cytoplasm
R-HSA-72203	Processing of Capped Intron-Containing Pre-mRNA
R-HSA-73857	RNA Polymerase II Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-8953854	Metabolism of RNA

MSigDB gene sets: 381 (showing top): RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, BROWNE_HCMV_INFECTION_6HR_DN, YAGI_AML_WITH_INV_16_TRANSLOCATION, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_NEUROGENESIS, MORF_HDAC2, GOBP_REGULATION_OF_NUCLEOBASE_CONTAINING_COMPOUND_TRANSPORT, GOBP_NEGATIVE_REGULATION_OF_CELLULAR_COMPONENT_ORGANIZATION, GOBP_NUCLEAR_TRANSPORT, MODULE_331, GOBP_STEM_CELL_DIVISION, GOBP_REGULATION_OF_CELL_PROJECTION_ORGANIZATION, GOBP_IN_UTERO_EMBRYONIC_DEVELOPMENT, GOBP_REGULATION_OF_NUCLEOCYTOPLASMIC_TRANSPORT

GO Biological Process (13): cell morphogenesis (GO:0000902), blastocyst development (GO:0001824), mRNA processing (GO:0006397), mRNA export from nucleus (GO:0006406), RNA splicing (GO:0008380), regulation of gene expression (GO:0010468), regulation of mRNA export from nucleus (GO:0010793), negative regulation of neuron projection development (GO:0010977), poly(A)+ mRNA export from nucleus (GO:0016973), stem cell division (GO:0017145), neuron development (GO:0048666), generation of neurons (GO:0048699), mRNA transport (GO:0051028)

GO Molecular Function (3): mRNA binding (GO:0003729), RNA binding (GO:0003723), protein binding (GO:0005515)

GO Cellular Component (8): transcription export complex (GO:0000346), THO complex (GO:0000347), THO complex part of transcription export complex (GO:0000445), nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), nuclear speck (GO:0016607), chromosome, telomeric region (GO:0000781)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Processing of Capped Intron-Containing Pre-mRNA	2
Transport of Mature Transcript to Cytoplasm	1
RNA Polymerase II Transcription	1
Metabolism of RNA	1
Gene expression (Transcription)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA processing	2
gene expression	2
mRNA export from nucleus	2
nuclear protein-containing complex	2
cellular anatomical structure	2
anatomical structure morphogenesis	1
in utero embryonic development	1
anatomical structure development	1
mRNA metabolic process	1
RNA export from nucleus	1
mRNA transport	1
regulation of macromolecule biosynthetic process	1
regulation of RNA export from nucleus	1
regulation of ribonucleoprotein complex localization	1
regulation of neuron projection development	1
neuron projection development	1
negative regulation of cell projection organization	1
cell division	1
neuron differentiation	1
cell development	1
neurogenesis	1
RNA transport	1
RNA binding	1
nucleic acid binding	1
binding	1
transcription export complex	1
THO complex	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
intracellular anatomical structure	1
nuclear ribonucleoprotein granule	1
chromosomal region	1

Protein interactions and networks

STRING

2800 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
THOC2	THOC1	Q96FV9	999
THOC2	THOC3	Q96J01	999
THOC2	DDX39B	Q13838	998
THOC2	THOC5	Q13769	997
THOC2	THOC7	Q6I9Y2	997
THOC2	THOC6	Q86W42	997
THOC2	GLI2	P10070	992
THOC2	ALYREF	Q86V81	992
THOC2	CYLD	Q9NQC7	992
THOC2	RAE1	P78406	860
THOC2	NXF1	Q9UBU9	827
THOC2	SARNP	P82979	763
THOC2	FYTTD1	Q96QD9	733
THOC2	ZC3H18	Q86VM9	713
THOC2	NCBP3	Q53F19	688

IntAct

108 interactions, top by confidence:

A	B	Type	Score
THOC1	THOC5	psi-mi:“MI:0914”(association)	0.930
MED4	MED19	psi-mi:“MI:0914”(association)	0.900
MED20	MED19	psi-mi:“MI:0914”(association)	0.840
DDX39B	THOC5	psi-mi:“MI:0915”(physical association)	0.800
DDX39B	ALYREF	psi-mi:“MI:0914”(association)	0.770
THOC2	THOC5	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
ALYREF	THOC5	psi-mi:“MI:0914”(association)	0.710
THOC5	ALYREF	psi-mi:“MI:0914”(association)	0.710
MOB1A	LATS1	psi-mi:“MI:0914”(association)	0.670
THOC1	EIF4A3	psi-mi:“MI:0914”(association)	0.660
CHTOP	THOC5	psi-mi:“MI:0914”(association)	0.660
THOC1	DDX39A	psi-mi:“MI:0914”(association)	0.640
KPNB1	POM121C	psi-mi:“MI:0914”(association)	0.530
THOC3	CLUH	psi-mi:“MI:0914”(association)	0.530
NCBP3	SAP18	psi-mi:“MI:0914”(association)	0.530
THOC5	EIF4A3	psi-mi:“MI:0914”(association)	0.530
VCAM1	PSMD11	psi-mi:“MI:0914”(association)	0.530
	EIF4A3	psi-mi:“MI:0915”(physical association)	0.490
THOC2	CRK	psi-mi:“MI:0915”(physical association)	0.400
HLCS	THOC2	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (343): THOC2 (Affinity Capture-MS), THOC2 (Affinity Capture-MS), THOC2 (Affinity Capture-MS), THOC2 (Affinity Capture-MS), THOC2 (Affinity Capture-MS), THOC2 (Affinity Capture-MS), PDCD4 (Co-fractionation), THOC1 (Co-fractionation), THOC2 (Co-fractionation), THOC2 (Co-fractionation), THOC6 (Co-fractionation), THOC7 (Co-fractionation), USP7 (Co-fractionation), THOC2 (Affinity Capture-MS), THOC2 (Affinity Capture-MS)

ESM2 similar proteins: A0A3Q1LSX9, A2APV2, A2AT37, A2VD00, A4II09, B0KWH8, B1AZI6, B1MTK1, B2KI97, B3MS75, B3NU52, B4GW22, B4I0W6, B4JM29, B4L2J8, B4NC41, B4Q034, C0H906, C1FXW9, F4IUX6, Q09161, Q16UN6, Q1LUC1, Q1LXC9, Q29G82, Q2L4X1, Q3UYV9, Q4R6R4, Q56A27, Q5R7L4, Q5ZJZ6, Q5ZL42, Q5ZLT7, Q5ZMW3, Q6DDM4, Q6DIE2, Q6GQ80, Q6GQD0, Q6P2Z0, Q6P7P5

Diamond homologs: B0KWH8, B1AZI6, B1MTK1, B2KI97, C1FXW9, F4IAT2, Q09779, Q8NI27

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
THOC2	“form complex”	“TREX complex”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 109 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
mRNA 3’-end processing	12	32.4×	3e-13
Transport of Mature Transcript to Cytoplasm	6	31.3×	2e-06
Transport of Mature mRNA derived from an Intron-Containing Transcript	13	27.1×	3e-13
RNA Polymerase II Transcription Termination	7	21.1×	2e-06
Processing of Capped Intron-Containing Pre-mRNA	14	15.8×	3e-11
mRNA Splicing	9	13.5×	2e-06
mRNA Splicing - Major Pathway	14	10.5×	6e-09
Metabolism of RNA	14	8.0×	2e-07

GO biological processes:

GO term	Partners	Fold	FDR
RNA export from nucleus	5	50.9×	7e-06
negative regulation of mRNA splicing, via spliceosome	5	41.6×	1e-05
mRNA export from nucleus	12	38.6×	1e-13
positive regulation of transcription elongation by RNA polymerase II	6	19.6×	6e-05
RNA splicing	14	13.4×	8e-10
mRNA processing	12	10.3×	5e-07
mRNA splicing, via spliceosome	10	10.0×	1e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	8
Likely pathogenic	13
Uncertain significance	200
Likely benign	31
Benign	21

Top pathogenic / likely-pathogenic (21)

Variant ID	HGVS	Classification
208523	NM_001081550.2(THOC2):c.1313T>C (p.Leu438Pro)	Pathogenic
208524	NM_001081550.2(THOC2):c.937C>T (p.Leu313Phe)	Pathogenic
208525	NM_001081550.2(THOC2):c.3034T>C (p.Ser1012Pro)	Pathogenic
208526	NM_001081550.2(THOC2):c.2399T>C (p.Ile800Thr)	Pathogenic
3362897	THOC2, 2.4-KB DEL, EX37-38DEL	Pathogenic
3362900	THOC2, 4-BP DEL, 2482GTCA	Pathogenic
488431	NM_001081550.2(THOC2):c.2138G>A (p.Gly713Asp)	Pathogenic
488434	NM_001081550.2(THOC2):c.4450-2A>G	Pathogenic
1527937	NM_001081550.2(THOC2):c.1844G>A (p.Cys615Tyr)	Likely pathogenic
1700225	NM_001081550.2(THOC2):c.34T>C (p.Trp12Arg)	Likely pathogenic
1700228	NM_001081550.2(THOC2):c.2695T>C (p.Tyr899His)	Likely pathogenic
1801970	NM_001081550.2(THOC2):c.2788C>T (p.Arg930Cys)	Likely pathogenic
2314312	NM_001081550.2(THOC2):c.2818G>A (p.Glu940Lys)	Likely pathogenic
3342610	NM_001081550.2(THOC2):c.2482-1_2484del	Likely pathogenic
3349329	NM_001081550.2(THOC2):c.3215C>T (p.Thr1072Ile)	Likely pathogenic
488433	NM_001081550.2(THOC2):c.3503+4A>C	Likely pathogenic
488437	NM_001081550.2(THOC2):c.3323C>T (p.Ser1108Leu)	Likely pathogenic
804356	NM_001081550.2(THOC2):c.2642A>G (p.Tyr881Cys)	Likely pathogenic
807709	NM_001081550.2(THOC2):c.149A>C (p.Tyr50Ser)	Likely pathogenic
982367	NM_001081550.2(THOC2):c.1942G>T (p.Ala648Ser)	Likely pathogenic
984647	NM_001081550.2(THOC2):c.3305A>G (p.Tyr1102Cys)	Likely pathogenic

SpliceAI

6313 predictions. Top by Δscore:

Variant	Effect	Δscore
X:123611452:T:TA	donor_gain	1.0000
X:123612217:ATAG:A	donor_gain	1.0000
X:123612217:ATAGC:A	donor_gain	1.0000
X:123613552:CCCCA:C	acceptor_gain	1.0000
X:123613553:CCCA:C	acceptor_gain	1.0000
X:123613553:CCCAC:C	acceptor_gain	1.0000
X:123613554:CCA:C	acceptor_gain	1.0000
X:123613554:CCAC:C	acceptor_gain	1.0000
X:123613555:CAC:C	acceptor_gain	1.0000
X:123613557:C:CC	acceptor_gain	1.0000
X:123613637:A:AC	donor_gain	1.0000
X:123613638:C:CC	donor_gain	1.0000
X:123614050:AC:A	donor_gain	1.0000
X:123614051:CC:C	donor_gain	1.0000
X:123614066:T:A	donor_gain	1.0000
X:123614190:C:CC	acceptor_gain	1.0000
X:123615309:A:AC	donor_gain	1.0000
X:123615310:T:C	donor_gain	1.0000
X:123620966:C:CC	acceptor_gain	1.0000
X:123621589:T:C	acceptor_gain	1.0000
X:123621589:T:TC	acceptor_gain	1.0000
X:123622752:TCCTA:T	donor_loss	1.0000
X:123622753:CCTAC:C	donor_loss	1.0000
X:123622754:CTA:C	donor_loss	1.0000
X:123622755:TAC:T	donor_loss	1.0000
X:123622756:ACC:A	donor_loss	1.0000
X:123622757:CCTGT:C	donor_loss	1.0000
X:123622856:TTTAT:T	acceptor_gain	1.0000
X:123622857:TTAT:T	acceptor_gain	1.0000
X:123622858:TAT:T	acceptor_gain	1.0000

AlphaMissense

10588 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:123623228:G:C	H1187D	1.000
X:123623229:A:C	F1186L	1.000
X:123623229:A:T	F1186L	1.000
X:123623230:A:G	F1186S	1.000
X:123623231:A:G	F1186L	1.000
X:123623275:C:T	G1171E	1.000
X:123623793:G:T	A1166D	1.000
X:123623794:C:G	A1166P	1.000
X:123623868:C:T	G1141D	1.000
X:123623886:G:T	P1135Q	1.000
X:123623887:G:A	P1135S	1.000
X:123623910:A:G	L1127P	1.000
X:123623955:A:G	L1112P	1.000
X:123624067:A:G	L1104P	1.000
X:123624080:A:G	W1100R	1.000
X:123624080:A:T	W1100R	1.000
X:123624081:T:A	K1099N	1.000
X:123624081:T:G	K1099N	1.000
X:123624082:T:A	K1099I	1.000
X:123624083:T:C	K1099E	1.000
X:123624086:G:C	H1098D	1.000
X:123624091:A:T	V1096D	1.000
X:123624097:C:G	R1094P	1.000
X:123624100:A:G	F1093S	1.000
X:123624115:A:G	L1088S	1.000
X:123624168:G:C	F1070L	1.000
X:123624168:G:T	F1070L	1.000
X:123624170:A:G	F1070L	1.000
X:123624172:C:T	G1069E	1.000
X:123624173:C:G	G1069R	1.000

dbSNP variants (sampled 300 via entrez): RS1000011782 (X:123656098 A>G), RS1000018433 (X:123728270 C>T), RS1000047919 (X:123654055 C>T), RS1000049051 (X:123720935 A>G), RS1000053335 (X:123640748 A>G), RS1000071868 (X:123658657 G>A), RS1000124839 (X:123639925 C>T), RS1000130298 (X:123718925 C>T), RS1000156599 (X:123682492 G>A), RS1000192990 (X:123733488 TTCTCCC>T,TTCTCCCTCTCCC), RS1000198446 (X:123688567 C>A), RS1000228637 (X:123719284 A>C), RS1000229470 (X:123614397 C>A), RS1000291732 (X:123663625 T>C,G), RS1000318879 (X:123646098 G>A)

Disease associations

OMIM: gene MIM:300395 | disease phenotypes: MIM:300957, MIM:620977, MIM:209850, MIM:301127

GenCC curated gene-disease

Disease	Classification	Inheritance
X-linked intellectual disability-short stature-overweight syndrome	Strong	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
X-linked complex neurodevelopmental disorder	Definitive	XL

Mondo (6): intellectual disability (MONDO:0001071), X-linked intellectual disability-short stature-overweight syndrome (MONDO:0010496), neurodevelopmental disorder (MONDO:0700092), immunodeficiency 127 (MONDO:0975832), autism (MONDO:0005260), arthrogryposis multiplex congenita 7, X-linked (MONDO:0975826)

Orphanet (2): X-linked intellectual disability-short stature-overweight syndrome (Orphanet:457240), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

83 total (30 of 83 shown, HPO-id order):

HPO	Term
HP:0000028	Cryptorchidism
HP:0000054	Micropenis
HP:0000202	Orofacial cleft
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000256	Macrocephaly
HP:0000316	Hypertelorism
HP:0000337	Broad forehead
HP:0000347	Micrognathia
HP:0000348	High forehead
HP:0000400	Macrotia
HP:0000407	Sensorineural hearing impairment
HP:0000463	Anteverted nares
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000577	Exotropia
HP:0000639	Nystagmus
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0000729	Autistic behavior
HP:0000733	Motor stereotypy
HP:0000739	Anxiety
HP:0000742	Self-mutilation
HP:0000750	Delayed speech and language development
HP:0000824	Decreased response to growth hormone stimulation test
HP:0000954	Single transverse palmar crease
HP:0001188	Hand clenching
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001252	Hypotonia

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST90002381_503	Eosinophil count	2.000000e-10

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004842	eosinophil count

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066378 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.69	Kd	2050	nM	CHEMBL5653589
5.69	ED50	2050	nM	CHEMBL5653589
5.08	Kd	8402	nM	CHEMBL3752910
5.08	ED50	8402	nM	CHEMBL3752910

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149582: Binding affinity to human THOC2 incubated for 45 mins by Kinobead based pull down assay	kd	2.0497	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149582: Binding affinity to human THOC2 incubated for 45 mins by Kinobead based pull down assay	kd	8.4024	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression	2
sodium arsenite	decreases expression, increases expression	2
Valproic Acid	decreases expression, increases methylation	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
bisphenol F	affects cotreatment, increases expression	1
TAK-243	decreases sumoylation	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
titanium dioxide	increases methylation	1
decabromobiphenyl ether	increases expression	1
beta-lapachone	decreases expression	1
methylparaben	increases expression	1
tetrabromobisphenol A	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
aflatoxin B2	increases methylation	1
coumarin	decreases phosphorylation	1
methacrylaldehyde	increases abundance, affects cotreatment, increases oxidation	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
jinfukang	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Sunitinib	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5652624	Binding	Binding affinity to human THOC2 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

298 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
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
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
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
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
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
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)
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
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