DISC1

Summary

DISC1 (DISC1 scaffold protein, HGNC:2888) is a protein-coding gene on chromosome 1q42.2, encoding Disrupted in schizophrenia 1 protein (Q9NRI5). Involved in the regulation of multiple aspects of embryonic and adult neurogenesis.

This gene encodes a protein with multiple coiled coil motifs which is located in the nucleus, cytoplasm and mitochondria. The protein is involved in neurite outgrowth and cortical development through its interaction with other proteins. This gene is disrupted in a t(1;11)(q42.1;q14.3) translocation which segregates with schizophrenia and related psychiatric disorders in a large Scottish family. Alternate transcriptional splice variants, encoding different isoforms, have been characterized.

Source: NCBI Gene 27185 — RefSeq curated summary.

At a glance

• GWAS associations: 15
• Clinical variants (ClinVar): 173 total — 2 likely-pathogenic
• Phenotypes (HPO): 1
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_018662

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2888
Approved symbol	DISC1
Name	DISC1 scaffold protein
Location	1q42.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000162946
Ensembl biotype	protein_coding
OMIM	605210
Entrez	27185

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 12 protein_coding, 7 nonsense_mediated_decay, 2 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000295051, ENST00000317586, ENST00000366632, ENST00000366633, ENST00000366636, ENST00000366637, ENST00000422590, ENST00000427560, ENST00000439617, ENST00000468399, ENST00000535944, ENST00000535983, ENST00000537876, ENST00000539444, ENST00000602281, ENST00000602600, ENST00000602700, ENST00000602713, ENST00000602822, ENST00000602873, ENST00000622252, ENST00000628350

RefSeq mRNA: 21 — MANE Select: NM_018662 NM_001012957, NM_001012958, NM_001012959, NM_001164537, NM_001164538, NM_001164539, NM_001164540, NM_001164541, NM_001164542, NM_001164544, NM_001164545, NM_001164546, NM_001164547, NM_001164548, NM_001164549, NM_001164551, NM_001164553, NM_001164554, NM_001164555, NM_001164556, NM_018662

CCDS: CCDS31055, CCDS31056, CCDS53482, CCDS53483, CCDS53484, CCDS53485, CCDS59205, CCDS59206, CCDS59207, CCDS86058, CCDS86059

Canonical transcript exons

ENST00000439617 — 13 exons

Exon	Start	End
ENSE00000000139	231626790	231626934
ENSE00001070086	232008785	232009049
ENSE00001442223	232036692	232041272
ENSE00003478345	231693826	231694805
ENSE00003499659	231800108	231800210
ENSE00003501785	231818329	231818517
ENSE00003503221	231958828	231958888
ENSE00003565649	231767140	231767269
ENSE00003569598	231795242	231795296
ENSE00003596335	231749926	231750076
ENSE00003617157	231770835	231771070
ENSE00003649595	231701955	231702024
ENSE00003818469	232026435	232026552

Expression profiles

Bgee: expression breadth ubiquitous, 207 present calls, max score 94.84.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 3.4970 / max 134.3970, expressed in 1060 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
9057	2.6775	947
9056	0.7675	328
9058	0.0520	19

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	94.84	gold quality
sural nerve	UBERON:0015488	92.49	gold quality
decidua	UBERON:0002450	87.75	gold quality
monocyte	CL:0000576	78.97	gold quality
mononuclear cell	CL:0000842	78.75	gold quality
leukocyte	CL:0000738	78.53	gold quality
calcaneal tendon	UBERON:0003701	78.04	gold quality
blood	UBERON:0000178	77.99	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	76.82	gold quality
placenta	UBERON:0001987	76.65	gold quality
germinal epithelium of ovary	UBERON:0001304	74.93	silver quality
adrenal tissue	UBERON:0018303	74.84	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	74.55	gold quality
granulocyte	CL:0000094	74.02	gold quality
bone marrow cell	CL:0002092	73.99	gold quality
colonic epithelium	UBERON:0000397	73.94	gold quality
nerve	UBERON:0001021	72.70	gold quality
tibial nerve	UBERON:0001323	72.70	gold quality
stromal cell of endometrium	CL:0002255	72.33	gold quality
corpus callosum	UBERON:0002336	72.28	gold quality
hindlimb stylopod muscle	UBERON:0004252	71.26	gold quality
choroid plexus epithelium	UBERON:0003911	70.22	silver quality
gall bladder	UBERON:0002110	69.98	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	69.80	gold quality
amygdala	UBERON:0001876	69.69	gold quality
ovary	UBERON:0000992	69.63	gold quality
endothelial cell	CL:0000115	69.59	silver quality
right ovary	UBERON:0002118	69.41	gold quality
left ovary	UBERON:0002119	69.10	gold quality
ganglionic eminence	UBERON:0004023	69.06	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-180759	yes	2395.30
E-HCAD-35	yes	58.71
E-HCAD-25	yes	17.42
E-MTAB-6075	no	197.85
E-ANND-3	no	5.97

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATF4, ATF5, HOXB13, NRXN1, TBX18, TBX5

miRNA regulators (miRDB)

176 targeting DISC1, 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-6873-3P	100.00	71.42	2626
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426
HSA-MIR-548AR-5P	99.94	71.28	3515

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Mutant truncation prevents binding to NudE-like (NUDEL) and inhibits neurite outgrowth (PMID:12506198)
• DISC1 is a multifunctional protein whose truncation contributes to schizophrenia susceptibility by disrupting intracellular transport, neurite architecture and/or neuronal migration (PMID:12812986)
• DISC1 interacts with FEZ1 through a binding site at AA 446-633. (PMID:12874605)
• Disc1 was genotyped using snps to determine its association to schizophrenia. (PMID:14532331)
• The cellular roles of the proteins identified implicate DISC1 in several aspects of central nervous system development and function, including gene transcription, mitochondrial function, modulation of the actin cytoskeleton, and neuronal migration. (PMID:14623284)
• Mitochondria are the predominant site of DISC1 expression with additional nuclear, cytoplasmic, and actin-associated locations evident. (PMID:15121183)
• subjects with schizophrenia who carry the t (1;11) translocation have similar phenotype to unrelated subjects with schizophrenia and a normal karyotype. (PMID:15184103)
• Variation at the DISC1 locus predisposes individuals to a variety of psychiatric disorders. (PMID:15386212)
• DISC1 inhibits NUDEL-oligopeptidase activity in a competitive fashion. (PMID:15728732)
• This is first direct evidence that DISC1 is localized to mitochondria in cultured cortical neurons that are dependent on an intact cytoskeleton. (PMID:15797709)
• Results provide further supporting evidence for DISC1 as a susceptibility factor for both bipolar disorder and schizophrenia. (PMID:15838535)
• Allelic variation within DISC1, either at Ser704Cys or haplotypes monitored by it, increases the risk for schizophrenia through the involvement of structural and functional alterations in the hippocampal formation. (PMID:15939883)
• Possibility that mutations in the DISC1 gene can increase the risk for schizophrenia and related disorders. (PMID:15940305)
• Variation in DISC1 may therefore affect cognitive aging especially in women. (PMID:16054297)
• These data suggest that DISC1 is associated with neurocognitive functioning in schizophrenia. (PMID:16056147)
• Results provide genetic support that the DISC1 gene contributes to sensitivity to schizophrenia and associated disturbances and affects short-term visual memory functions. (PMID:16103888)
• DISC1 over-expression produces striking mitochondrial reorganization in some cells, with formation of mitochondrial ring-like structures, indicating a potential involvement of DISC1 in mitochondrial fusion and/or fission. (PMID:16209927)
• Furthermore, we found that overexpression of DISC1 in SH-SY5Y cells induces the assembly of eIF3- and TIA-1-positive stress granules (SGs), discrete cytoplasmic granules formed in response to environmental stresses. (PMID:16243297)
• a mechanistic model whereby DISC1 sequesters phosphodiesterase 4B in resting cells and releases it in an activated state in response to elevated cAMP (PMID:16293762)
• Results further strengthen the candidacy of DISC1 as a risk factor for schizophrenia in the general population, and suggest that more intensive searching for causative variants is justified. (PMID:16389590)
• We found no difference in the expression of DISC1 or reelin mRNA in schizophrenia and no association with previously identified risk DISC1 SNPs (PMID:16510495)
• DISC1 immunoreactivity was examined in frontal and parietal cortex in normal adult human brain. DICS1 is prevalent throughout the cortical layers in neurons, axon terminals, and postsynaptic targets. (PMID:16736468)
• Decreased mRNA levels of DISC1 expression, associating with the risk haplotype, may be implicated in the pathophysiology of bipolar disorder. (PMID:16814263)
• DISC1 has emerged as a key molecular player in the etiology of major mental illness and in normal brain processes–{REVIEW} (PMID:16843095)
• Located on chromosome 1, a region implicated in schizophrenia, and bipolar disorders. (PMID:16936759)
• Study found that Cys704 allele of the Ser704Cys single-nucleotide polymorphism (SNP) was associated with an increased risk of developing major depressive disorder and strong evidence for association in a multi-marker haplotype analysis with this SNP. (PMID:16959794)
• chromosome 1q42.1 harbors GNPAT and DISC1 as candidate genes for schizophrenia, and DISC1 is associated with sustained attention deficits. (PMID:16997000)
• SNPs in RGS4, G72, GRM3, and DISC1 showed evidence for significant statistical epistasis with COMT. (PMID:17006672)
• DISC1 looks to have a protein interaction profile consistent with that of an essential synaptic protein (PMID:17043677)
• these data suggest involvement of genetically linked abnormalities in the DISC1 molecular pathway in the pathophysiology of schizophrenia–{REVIEW} (PMID:17117617)
• Two additional loci displayed an evidence of linkage (LOD > 3) and included a locus on 16p13, proximal to the gene encoding NDE1, which has been shown to biologically interact with DISC1. (PMID:17185386)
• Further evidence for DISC1 as a predisposing gene involved in schizophrenia in the Chinese Han Population. (PMID:17286247)
• The involvement of DISC1 gene in the etiopathogenesis of autism and Asperger syndrome. (PMID:17579608)
• Allelic heterogeneity within DISC1 leading to heterogeneity in psychotic and bipolar spectrum disorders. (PMID:17673452)
• Altered DISC1-PDE4B interaction may thus underlie the symptoms of some cases of schizophrenia and depression.(Review) (PMID:17823207)
• DISC1 is a hub protein in a multidimensional risk pathway for major mental illness, and studies of this pathway are opening up opportunities for a better understanding of causality and possible mechanisms of intervention [review]. (PMID:17912248)
• DISC1 may be a susceptibility gene for poor concentration among Korean patients with schizophrenia. (PMID:17997036)
• Single nuleotide polymorphism in the 5’ upstream region is not associated with mood disorders. (PMID:18075479)
• these findings implicate DISC1 in variations of prefrontal cortical volume confeing increased risk for schizophrenia (PMID:18078707)
• We conclude that ultra-rare structural variants in DISC1 are associated with an attributable risk of about 2% for schizophrenia. We also confirm that two common structural variants (Q264R and S704C) elevate the risk for schizophrenia slightly. (PMID:18164685)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	disc1	ENSDARG00000021895
mus_musculus	Disc1	ENSMUSG00000043051
rattus_norvegicus	Disc1	ENSRNOG00000019779

Protein

Protein identifiers

Disrupted in schizophrenia 1 protein — Q9NRI5 (reviewed: Q9NRI5)

All UniProt accessions (7): C4P092, C4P093, C4P0A0, C4P0B0, C4P0B1, Q9NRI5, H0Y7U2

UniProt curated annotations — full annotation on UniProt →

Function. Involved in the regulation of multiple aspects of embryonic and adult neurogenesis. Required for neural progenitor proliferation in the ventrical/subventrical zone during embryonic brain development and in the adult dentate gyrus of the hippocampus. Participates in the Wnt-mediated neural progenitor proliferation as a positive regulator by modulating GSK3B activity and CTNNB1 abundance. Plays a role as a modulator of the AKT-mTOR signaling pathway controlling the tempo of the process of newborn neurons integration during adult neurogenesis, including neuron positioning, dendritic development and synapse formation. Inhibits the activation of AKT-mTOR signaling upon interaction with CCDC88A. Regulates the migration of early-born granule cell precursors toward the dentate gyrus during the hippocampal development. Inhibits ATF4 transcription factor activity in neurons by disrupting ATF4 dimerization and DNA-binding. Plays a role, together with PCNT, in the microtubule network formation.

Subunit / interactions. Interacts with NDEL1. Interacts with CCDC88A (via C-terminus); the interaction is direct. Interacts with GSK3B. Interacts with tubulin alpha, ACTN2, ANKHD1, ATF4, ATF5, CEP63, EIF3S3, MAP1A, NDEL1, PAFAH1B1, RANBP9, SPTBN4, SYNE1 and TRAF3IP1. Interaction with microtubules may be mediated in part by TRAF3IP1. Interacts (via C-terminal) with PCNT. Interacts with CHCHD6. Interacts with CCDC141. Interacts with FBXW7, the substrate-recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex; the interaction targets DISC1 for proteasomal degradation. Interacts with ZNF365. Interacts with ATF4; inhibiting ATF4 transcription factor activity by disrupting ATF4 dimerization and DNA-binding. Interacts with PDE4B (isoform PDE4B5).

Subcellular location. Cytoplasm. Cytoskeleton. Mitochondrion. Microtubule organizing center. Centrosome. Postsynaptic density.

Tissue specificity. Ubiquitous. Highly expressed in the dentate gyrus of the hippocampus. Also expressed in the temporal and parahippocampal cortices and cells of the white matter.

Post-translational modifications. Ubiquitinated. Ubiquitination with ‘Lys-48’-linked polyubiquitin chains leads to its proteasomal degradation.

Disease relevance. A chromosomal aberration involving DISC1 segregates with schizophrenia and related psychiatric disorders in a large Scottish family. Translocation t(1;11)(q42.1;q14.3). The truncated DISC1 protein produced by this translocation is unable to interact with ATF4, ATF5 and NDEL1. Schizophrenia 9 (SCZD9) [MIM:604906] A complex, multifactorial psychotic disorder or group of disorders characterized by disturbances in the form and content of thought (e.g. delusions, hallucinations), in mood (e.g. inappropriate affect), in sense of self and relationship to the external world (e.g. loss of ego boundaries, withdrawal), and in behavior (e.g bizarre or apparently purposeless behavior). Although it affects emotions, it is distinguished from mood disorders in which such disturbances are primary. Similarly, there may be mild impairment of cognitive function, and it is distinguished from the dementias in which disturbed cognitive function is considered primary. Some patients manifest schizophrenic as well as bipolar disorder symptoms and are often given the diagnosis of schizoaffective disorder. Disease susceptibility is associated with variants affecting the gene represented in this entry.

Miscellaneous. Non-canonical donor and acceptor splice sites for the last 2 exons. Non-canonical donor and acceptor splice sites for the last 2 exons.

Isoforms (11)

UniProt ID	Names	Canonical?
Q9NRI5-1	1, L	yes
Q9NRI5-2	2, LV
Q9NRI5-3	3, S
Q9NRI5-4	4, ES
Q9NRI5-5	5, 26
Q9NRI5-6	6
Q9NRI5-7	7
Q9NRI5-8	8
Q9NRI5-9	9
Q9NRI5-10	10
Q9NRI5-11	11

RefSeq proteins (21): NP_001012975, NP_001012976, NP_001012977, NP_001158009, NP_001158010, NP_001158011, NP_001158012, NP_001158013, NP_001158014, NP_001158016, NP_001158017, NP_001158018, NP_001158019, NP_001158020, NP_001158021, NP_001158023, NP_001158025, NP_001158026, NP_001158027, NP_001158028, NP_061132* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026081	DISC1	Family

UniProt features (52 total): splice variant 19, region of interest 12, sequence variant 8, coiled-coil region 4, compositionally biased region 3, mutagenesis site 3, chain 1, short sequence motif 1, cross-link 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5V4B	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NRI5-F1	64.74	0.28

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 (1): 372

Mutagenesis-validated functional residues (3):

Position	Phenotype
372	reduced ubiquitination.
815	impairs interaction with ndel1; when associated with p-822.
822	impairs interaction with ndel1; when associated with p-815.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 367 (showing top): GOBP_FOREBRAIN_NEURON_DEVELOPMENT, GOBP_DENDRITE_DEVELOPMENT, GOBP_PROTEIN_LOCALIZATION_TO_CYTOSKELETON, GOBP_SENSORY_PERCEPTION_OF_TEMPERATURE_STIMULUS, GOBP_RESPONSE_TO_ELECTRICAL_STIMULUS, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, GOBP_REGULATION_OF_SYNAPTIC_TRANSMISSION_GLUTAMATERGIC, GOBP_DENDRITIC_SPINE_DEVELOPMENT, GOCC_KINESIN_COMPLEX, GOBP_GROWTH, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, GOBP_NEUROGENESIS, GOBP_REGULATION_OF_WNT_SIGNALING_PATHWAY, GOBP_REGULATION_OF_NERVOUS_SYSTEM_DEVELOPMENT

GO Biological Process (29): microtubule cytoskeleton organization (GO:0000226), neuron migration (GO:0001764), positive regulation of cell-matrix adhesion (GO:0001954), positive regulation of neuroblast proliferation (GO:0002052), ubiquitin-dependent protein catabolic process (GO:0006511), positive regulation of neuron projection development (GO:0010976), cell proliferation in forebrain (GO:0021846), pyramidal neuron migration to cerebral cortex (GO:0021852), positive regulation of Wnt signaling pathway (GO:0030177), TOR signaling (GO:0031929), positive regulation of axon extension (GO:0045773), detection of temperature stimulus involved in sensory perception of pain (GO:0050965), mitochondrial calcium ion homeostasis (GO:0051560), response to electrical stimulus (GO:0051602), regulation of synaptic transmission, glutamatergic (GO:0051966), canonical Wnt signaling pathway (GO:0060070), cilium assembly (GO:0060271), regulation of dendritic spine development (GO:0060998), neuron cellular homeostasis (GO:0070050), protein localization to centrosome (GO:0071539), regulation of synapse maturation (GO:0090128), regulation of postsynapse organization (GO:0099175), non-motile cilium assembly (GO:1905515), positive regulation of ubiquitin-dependent protein catabolic process (GO:2000060), nervous system development (GO:0007399), intracellular protein localization (GO:0008104), regulation of neuron projection development (GO:0010975), Wnt signaling pathway (GO:0016055), cerebral cortex radially oriented cell migration (GO:0021799)

GO Molecular Function (5): kinesin binding (GO:0019894), identical protein binding (GO:0042802), protein-containing complex binding (GO:0044877), molecular adaptor activity (GO:0060090), protein binding (GO:0005515)

GO Cellular Component (22): mitochondrion (GO:0005739), centrosome (GO:0005813), microtubule organizing center (GO:0005815), cytosol (GO:0005829), kinesin complex (GO:0005871), microtubule (GO:0005874), synaptic vesicle (GO:0008021), postsynaptic density (GO:0014069), dynein complex (GO:0030286), ciliary basal body (GO:0036064), cell body (GO:0044297), intermediate filament cytoskeleton (GO:0045111), perinuclear region of cytoplasm (GO:0048471), central region of growth cone (GO:0090724), ciliary base (GO:0097546), presynapse (GO:0098793), glutamatergic synapse (GO:0098978), GABA-ergic synapse (GO:0098982), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), axon (GO:0030424), synapse (GO:0045202)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	8
binding	3
cytoplasm	3
synapse	3
Wnt signaling pathway	2
microtubule organizing center	2
microtubule cytoskeleton	2
microtubule associated complex	2
cilium	2
cytoskeleton organization	1
microtubule-based process	1
cell migration	1
generation of neurons	1
regulation of cell-matrix adhesion	1
cell-matrix adhesion	1
positive regulation of cell-substrate adhesion	1
neuroblast proliferation	1
positive regulation of neurogenesis	1
regulation of neuroblast proliferation	1
positive regulation of neural precursor cell proliferation	1
protein ubiquitination	1
modification-dependent protein catabolic process	1
regulation of neuron projection development	1
neuron projection development	1
positive regulation of cell projection organization	1
forebrain development	1
neural precursor cell proliferation	1
cerebral cortex radial glia-guided migration	1
pyramidal neuron development	1
radial glia-guided pyramidal neuron migration	1
positive regulation of signal transduction	1
regulation of Wnt signaling pathway	1
intracellular signal transduction	1
positive regulation of cell growth	1
regulation of axon extension	1
positive regulation of developmental growth	1
axon extension	1
positive regulation of axonogenesis	1
sensory perception of pain	1
detection of temperature stimulus involved in sensory perception	1

Protein interactions and networks

STRING

2246 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DISC1	NDEL1	Q9GZM8	998
DISC1	PDE4B	Q07343	998
DISC1	NDE1	Q9NXR1	997
DISC1	PDE4A	P27815	993
DISC1	GSK3B	P49841	969
DISC1	PCNT	O95613	963
DISC1	DIXDC1	Q155Q3	957
DISC1	DTNBP1	Q96EV8	953
DISC1	YWHAE	P29360	932
DISC1	DRD2	P14416	932
DISC1	TSNAX	Q99598	904
DISC1	TRAK1	Q9UPV9	879
DISC1	ZNF365	Q70YC5	876
DISC1	APP	P05067	873
DISC1	IFT54	Q8TDR0	868

IntAct

809 interactions, top by confidence:

A	B	Type	Score
DISC1	SYNM	psi-mi:“MI:0915”(physical association)	0.370
ACTG1	DISC1	psi-mi:“MI:0915”(physical association)	0.000
AGTPBP1	DISC1	psi-mi:“MI:0915”(physical association)	0.000
ARIH2	DISC1	psi-mi:“MI:0915”(physical association)	0.000
BICD1	DISC1	psi-mi:“MI:0915”(physical association)	0.000
PCNX4	DISC1	psi-mi:“MI:0915”(physical association)	0.000
RTRAF	DISC1	psi-mi:“MI:0915”(physical association)	0.000
MPPED1	DISC1	psi-mi:“MI:0915”(physical association)	0.000
MEMO1	DISC1	psi-mi:“MI:0915”(physical association)	0.000
CEP57L1	DISC1	psi-mi:“MI:0915”(physical association)	0.000
CLU	DISC1	psi-mi:“MI:0915”(physical association)	0.000
CRNKL1	DISC1	psi-mi:“MI:0915”(physical association)	0.000
DCTN1	DISC1	psi-mi:“MI:0915”(physical association)	0.000
DCTN2	DISC1	psi-mi:“MI:0915”(physical association)	0.000
CCDC136	DISC1	psi-mi:“MI:0915”(physical association)	0.000
DNAJC7	DISC1	psi-mi:“MI:0915”(physical association)	0.000
DYNC1H1	DISC1	psi-mi:“MI:0915”(physical association)	0.000
DPYSL2	DISC1	psi-mi:“MI:0915”(physical association)	0.000
DPYSL3	DISC1	psi-mi:“MI:0915”(physical association)	0.000
DISC1	DST	psi-mi:“MI:0915”(physical association)	0.000
EEF2	DISC1	psi-mi:“MI:0915”(physical association)	0.000
GNB1	DISC1	psi-mi:“MI:0915”(physical association)	0.000
GPRASP2	DISC1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (518): DISC1 (Affinity Capture-MS), DISC1 (Affinity Capture-MS), MYH7 (Two-hybrid), EIF3H (Affinity Capture-Western), DISC1 (Affinity Capture-MS), DISC1 (Affinity Capture-MS), DISC1 (Affinity Capture-MS), DISC1 (Affinity Capture-MS), DISC1 (Affinity Capture-MS), DISC1 (Affinity Capture-MS), DISC1 (Affinity Capture-MS), DISC1 (Affinity Capture-MS), DISC1 (Affinity Capture-MS), DISC1 (Affinity Capture-MS), DISC1 (Affinity Capture-MS)

ESM2 similar proteins: A0A494C1R9, A2AKB4, A2APT9, A6NKD2, A8MT33, B0BN44, E9PGG2, F5GYI3, O19110, O88852, P0CV98, P0CV99, P0CW00, P0CW01, Q01534, Q03386, Q0P5N2, Q12967, Q14684, Q2M329, Q3U3N0, Q5F267, Q5I0E2, Q5R5G8, Q5R866, Q5SYB0, Q5VTJ3, Q60953, Q69ZB3, Q6ZUX3, Q7TQI8, Q80VJ8, Q80VR2, Q86VY4, Q8BSI6, Q8IZJ4, Q8N831, Q8VD63, Q95LS7, Q96FG2

Diamond homologs: Q810H6, Q811T9, Q9NRI5

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
DISC1	“up-regulates activity”	KIF5B	binding
DISC1	“up-regulates activity”	NDEL1	binding
DISC1	“up-regulates activity”	PAFAH1B1	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 158 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
Recycling pathway of L1	9	16.1×	1e-06
RHO GTPases activate IQGAPs	5	13.8×	7e-04
COPI-independent Golgi-to-ER retrograde traffic	8	13.3×	1e-05
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	8	12.4×	2e-05
Translocation of SLC2A4 (GLUT4) to the plasma membrane	10	12.3×	2e-06
Intraflagellar transport	7	11.2×	1e-04
RHOU GTPase cycle	5	11.1×	2e-03
MHC class II antigen presentation	15	10.7×	6e-09

GO biological processes:

GO term	Partners	Fold	FDR
intracellular protein localization	9	6.2×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	2
Uncertain significance	99
Likely benign	37
Benign	15

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
148530	GRCh38/hg38 1q42.2(chr1:231432777-231696534)x1	Likely pathogenic
545157	NC_000001.11:g.(?231740970)(231949671_?)del	Likely pathogenic

SpliceAI

3023 predictions. Top by Δscore:

Variant	Effect	Δscore
1:231636421:GAGGA:G	donor_gain	1.0000
1:231701943:A:AG	acceptor_gain	1.0000
1:231701944:A:G	acceptor_gain	1.0000
1:231701945:A:G	acceptor_gain	1.0000
1:231701951:ATAG:A	acceptor_gain	1.0000
1:231701953:AGG:A	acceptor_loss	1.0000
1:231702025:G:GG	donor_gain	1.0000
1:231702026:T:G	donor_loss	1.0000
1:231749911:ATTTT:A	acceptor_gain	1.0000
1:231770824:A:AG	acceptor_gain	1.0000
1:231770825:T:G	acceptor_gain	1.0000
1:231770832:C:G	acceptor_gain	1.0000
1:231770832:CAGA:C	acceptor_loss	1.0000
1:231770833:A:AC	acceptor_loss	1.0000
1:231770833:A:AG	acceptor_gain	1.0000
1:231770834:G:GA	acceptor_gain	1.0000
1:231770834:GAA:G	acceptor_gain	1.0000
1:231770834:GAAA:G	acceptor_gain	1.0000
1:231771067:GGAG:G	donor_gain	1.0000
1:231771068:G:GT	donor_gain	1.0000
1:231771068:G:T	donor_gain	1.0000
1:231818317:A:AG	acceptor_gain	1.0000
1:231818317:AAC:A	acceptor_gain	1.0000
1:231818317:AACGT:A	acceptor_gain	1.0000
1:231818318:A:G	acceptor_gain	1.0000
1:231818319:C:G	acceptor_gain	1.0000
1:231626930:CGCAG:C	donor_loss	0.9900
1:231626932:CAG:C	donor_loss	0.9900
1:231626933:AGG:A	donor_loss	0.9900
1:231626934:GG:G	donor_loss	0.9900

AlphaMissense

5573 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:231694392:T:C	F212L	0.989
1:231694394:T:A	F212L	0.989
1:231694394:T:G	F212L	0.989
1:231694386:T:C	F210L	0.987
1:231694388:T:A	F210L	0.987
1:231694388:T:G	F210L	0.987
1:232026493:T:C	L789P	0.984
1:232026522:G:C	A799P	0.983
1:231694389:A:C	S211R	0.981
1:231694391:C:A	S211R	0.981
1:231694391:C:G	S211R	0.981
1:232036710:T:C	L815P	0.980
1:231818356:T:C	L607P	0.977
1:231694396:T:C	I213T	0.974
1:231800193:A:T	K592I	0.973
1:232036731:T:C	L822P	0.973
1:232026514:T:C	L796P	0.972
1:231767265:T:C	L465P	0.970
1:231800194:A:C	K592N	0.970
1:231800194:A:T	K592N	0.970
1:231694374:T:C	F206L	0.969
1:231694376:T:A	F206L	0.969
1:231694376:T:G	F206L	0.969
1:231818337:T:C	F601L	0.967
1:231818339:C:A	F601L	0.967
1:231818339:C:G	F601L	0.967
1:231800189:G:C	A591P	0.966
1:231701997:G:C	A364P	0.965
1:231767244:T:C	L458P	0.965
1:231800201:G:C	A595P	0.965

dbSNP variants (sampled 300 via entrez): RS1000011166 (1:231766054 C>T), RS1000040600 (1:231630076 G>A,T), RS1000045594 (1:232013503 A>C), RS1000049432 (1:231938836 T>C), RS1000052933 (1:231955619 A>C), RS1000055049 (1:231807728 G>A,C), RS1000057535 (1:231681529 G>C), RS1000091423 (1:231716186 T>A), RS1000096252 (1:231891341 T>C,G), RS1000100131 (1:231938546 T>C), RS1000100139 (1:231661400 C>G,T), RS1000100609 (1:231834042 T>C), RS1000105686 (1:231729313 T>C), RS1000111704 (1:231854813 T>A), RS1000113084 (1:231720724 C>G,T)

Disease associations

OMIM: gene MIM:605210 | disease phenotypes: MIM:209850

GenCC curated gene-disease

Mondo (1): autism (MONDO:0005260)

Orphanet (0):

HPO phenotypes

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

HPO	Term
HP:0000717	Autism

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST000310_3	Alzheimer’s disease	9.000000e-06
GCST000406_2	Amyotrophic lateral sclerosis	8.000000e-06
GCST000635_12	Response to statin therapy	1.000000e-06
GCST001037_1	Neuranatomic and neurocognitive phenotypes	4.000000e-36
GCST001095_2	Response to antineoplastic agents	9.000000e-06
GCST002337_80	Amyotrophic lateral sclerosis (sporadic)	5.000000e-06
GCST003225_14	Pelvic organ prolapse (moderate/severe)	8.000000e-06
GCST003744_1	Chronic periodontitis (mean interproximal clinical attachment level)	8.000000e-09
GCST007059_18	Response to antidepressants (symptom improvement)	4.000000e-06
GCST008151_3	Waist circumference	5.000000e-06
GCST008160_48	Waist circumference	5.000000e-06
GCST008403_32	Arterial stiffness index	5.000000e-06
GCST009391_207	Metabolite levels	1.000000e-06
GCST010316_10	Serum docosahexaenoic fatty acid concentration in metabolic syndrome	3.000000e-06
GCST011354_49	Bell’s palsy	2.000000e-06

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0004346	neuroimaging measurement
EFO:0004785	South Texas Assessment of Neurocognition
EFO:0007780	periodontal measurement
EFO:0004517	arterial stiffness measurement
EFO:0007761	docosahexaenoic acid measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D001321	Autistic Disorder	F03.625.164.113.500

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	increases methylation, affects methylation, decreases expression	5
bisphenol S	decreases expression, affects cotreatment, increases methylation	2
Valproic Acid	increases expression	2
Aflatoxin B1	decreases expression, increases methylation	2
aristolochic acid I	decreases expression	1
FR900359	decreases phosphorylation	1
ethylbenzene	decreases expression, affects cotreatment	1
methyleugenol	decreases expression	1
propionaldehyde	increases expression	1
bisphenol A	affects methylation, affects cotreatment, increases methylation	1
trichostatin A	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression, affects response to substance, increases expression	1
abrine	decreases expression	1
ortho-topolin riboside	affects cotreatment, decreases expression	1
Decitabine	decreases expression, decreases reaction	1
Fulvestrant	affects cotreatment, increases methylation	1
Vorinostat	increases expression	1
Leflunomide	increases expression	1
Cyclic AMP	affects binding, decreases reaction	1
Vehicle Emissions	decreases expression, increases abundance	1
Clozapine	decreases response to substance, affects response to substance	1
Dextroamphetamine	increases response to substance	1
Dopamine	affects metabolic processing, increases uptake	1
Doxorubicin	decreases expression	1
Lipopolysaccharides	decreases expression, affects response to substance, increases expression, affects cotreatment	1
Malathion	increases expression	1
Melatonin	affects cotreatment, decreases expression	1
Naled	affects expression	1

Cellosaurus cell lines

9 cell lines: 8 induced pluripotent stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C4PM	TMOi001-A-5	Induced pluripotent stem cell	Female
CVCL_C4PN	TMOi001-A-6	Induced pluripotent stem cell	Female
CVCL_C640	D1-iPSC-1	Induced pluripotent stem cell	Male
CVCL_C641	D2-iPSC-1	Induced pluripotent stem cell	Female
CVCL_D9DF	Ubigene HEK293 DISC1 KO	Transformed cell line	Female
CVCL_JW69	WISCi004-A-3	Induced pluripotent stem cell	Female
CVCL_JW70	WISCi004-A-4	Induced pluripotent stem cell	Female
CVCL_VL25	D1-iPSC-2	Induced pluripotent stem cell	Male
CVCL_VL26	D2-iPSC-2	Induced pluripotent stem cell	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00211796	PHASE4	COMPLETED	Divalproex Sodium ER in Adult Autism
NCT00391261	PHASE4	COMPLETED	An Open-label Trial of Metformin for Weight Control of Pediatric Patients on Antipsychotic Medications.
NCT00409747	PHASE4	COMPLETED	Minocycline to Treat Childhood Regressive Autism
NCT00576732	PHASE4	COMPLETED	A Study of the Effectiveness and Safety of Two Doses of Risperidone in the Treatment of Children and Adolescents With Autistic Disorder
NCT00844753	PHASE4	COMPLETED	Atomoxetine, Placebo and Parent Management Training in Autism
NCT01028820	PHASE4	COMPLETED	FMRI Brain Activation of Aripiprazole Treatment in Autism Spectrum Disorders
NCT01098383	PHASE4	UNKNOWN	Treatment With Acetyl-Choline Esterase Inhibitors in Children With Autism Spectrum Disorders
NCT01333865	PHASE4	COMPLETED	A Study of Memantine Hydrochloride (Namenda®) for Cognitive and Behavioral Impairment in Adults With Autism Spectrum Disorders
NCT01337700	PHASE4	COMPLETED	Milnacipran in Autism and the Functional Locus Coeruleus and Noradrenergic Model of Autism
NCT01695200	PHASE4	COMPLETED	Omega-3 Fatty Acids in Autism Spectrum Disorders
NCT02069977	PHASE4	UNKNOWN	Study to Evaluate the Efficacy and Safety of Aripiprazole
NCT02096952	PHASE4	COMPLETED	Methylphenidate ER Liquid Formulation in Adults With ASD and ADHD
NCT02199925	PHASE4	UNKNOWN	An Open-Label Study to Evaluate the Efficacy of High-Dose Gammaplex in Children on the Autism Spectrum
NCT02235467	PHASE4	COMPLETED	Multisite Study: Parental Training Using Video Modelling to Develop Social Skills in Children With Autism
NCT02255565	PHASE4	COMPLETED	Dose Response Effects of Quillivant XR in Children With ADHD and Autism: A Pilot Study
NCT02940574	PHASE4	COMPLETED	Neural and Behavioral Effects of Oxytocin in Autism Spectrum Disorders
NCT03333629	PHASE4	COMPLETED	Promoting Positive Outcomes for Individuals With ASD: Linking Early Detection, Treatment, and Long-term Outcomes
NCT03337646	PHASE4	COMPLETED	Evaluation of the Effect and Safety of Lisdexamfetamine in Children Aged 6-12 With ADHD and Autism
NCT03538431	PHASE4	COMPLETED	Improving Driving in Young People With Autism Spectrum Disorders
NCT03757585	PHASE4	COMPLETED	Natural Treatments for the Management of Emotional Dysregulation in Youth With Non-verbal Learning Disability (NVLD) and/or Autism Spectrum Disorders (ASD)
NCT04903353	PHASE4	COMPLETED	Pragmatic Trial Comparing Weight Gain in Children With Autism Taking Risperidone Versus Aripiprazole
NCT05063656	PHASE4	COMPLETED	Biomarker-Driven Pharmacological Treatment of Adolescents With Autism Spectrum Disorder With Gabapentin
NCT05146245	PHASE4	UNKNOWN	Safety and Pharmacokinetics of Antipsychotics in Children 2: Studying TDM in an RCT
NCT05916339	PHASE4	RECRUITING	AWARE: Management of ADHD in Autism Spectrum Disorder
NCT05954052	PHASE4	TERMINATED	A Study of Glutathione in Children With Autism Spectrum Disorder
NCT06853665	PHASE4	RECRUITING	The TEAM Study - Treatment Efficacy for Autism/Attention Using Mixed Amphetamine
NCT07054697	PHASE4	COMPLETED	Pilot-RCT With Individualized Homeopathic Treatment in the Children With Autism Spectrum Disorder
NCT07161804	PHASE4	COMPLETED	Pilot RCT Using Homeopathic Medicines in ASD
NCT07439042	PHASE4	NOT_YET_RECRUITING	Buspirone for Anxiety in Autistic Youth
NCT00036231	PHASE3	TERMINATED	Synthetic Human Secretin in Children With Autism and Gastrointestinal Dysfunction
NCT00036244	PHASE3	COMPLETED	Synthetic Human Secretin in Children With Autism
NCT00065884	PHASE3	UNKNOWN	Valproate Response in Aggressive Autistic Adolescents
NCT00065962	PHASE3	COMPLETED	Secretin for the Treatment of Autism
NCT00252603	PHASE3	COMPLETED	Galantamine Versus Placebo in Childhood Autism
NCT00346736	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00352248	PHASE3	COMPLETED	Randomized Controlled Trial of Acupuncture Versus Sham Acupuncture in Autistic Spectrum Disorder
NCT00352352	PHASE3	COMPLETED	Use of Acupuncture In Children With Autistic Spectrum Disorder
NCT00355329	PHASE3	COMPLETED	Randomized Control Trial of Using Tongue Acupuncture in Autistic Spectrum Disorder Using PET Scan for Clinical Correlation
NCT00498173	PHASE3	COMPLETED	Effectiveness of Atomoxetine in Treating ADHD Symptoms in Children and Adolescents With Autism
NCT00541346	PHASE3	COMPLETED	A Pilot Study of Daytrana TM in Children With Autism Co-Morbid for Attention Deficit Hyperactivity Disorder (ADHD) Symptoms