Bipolar disorder

Summary

Bipolar disorder (MONDO:0004985) is a disease (an umbrella term covering 12 Mondo subtypes) with 75 cohort genes (1,617 GWAS associations across 162 studies) and 1,375 clinical trials. The dominant Reactome pathway is Bicarbonate transporters (3 cohort genes). Top therapeutic interventions include ziprasidone, valproic acid, and olanzapine.

At a glance

• Umbrella term: 12 Mondo subtypes
• Cohort genes: 75
• GWAS associations: 1,617
• ClinVar variants: 2
• Clinical trials: 1,375

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	bipolar disorder
Mondo ID	MONDO:0004985
MeSH	D001714
DOID	DOID:3312
ICD-10-CM	F31
NCIT	C34423
SNOMED CT	13746004
UMLS	C0005586
MedGen	2649
Is cancer (heuristic)	no

Also known as: bipolar depression · bipolar disorder · bipolar disorder manic phase · MAFD · major affective disorder · manic bipolar affective disorder · manic bipolar I disorder · manic depression · manic depressive disorder · manic disorder · manic-depression · mixed bipolar disorder

Data availability: 2 ClinVar variants · 1,617 GWAS associations (162 studies) · 1 GenCC gene-disease record · 222 cell lines.

Disease family

An umbrella term covering 12 Mondo subtypes.

Classification path: disease › human disease › disease by developmental or physiological process › psychiatric disorder › mental disorder › mood disorder › bipolar disorder

Related subtypes (4): dysthymic disorder, atypical depressive disorder, depressive disorder, cyclothymic disorder

Subtypes (12): bipolar II disorder, bipolar I disorder, major affective disorder 1, major affective disorder 3, major affective disorder 4, major affective disorder 5, major affective disorder 6, major affective disorder 8, major affective disorder 7, major affective disorder 9, manic bipolar affective disorder, bipolar depression

Genetics & variants

GWAS landscape

1,617 GWAS associations across 162 studies. Top hits map to 37 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs13217619	1e-27	ZSCAN31	?
rs1516725	1e-24	ETV5, DGKG	T	0.05
rs3888190	1e-24	ATP2A1-AS1	A	0.03
rs12552	1e-23	OLFM4	A	1.04
rs68188794	2e-21	ZSCAN16, ZSCAN16-AS1	T	0.21
rs34706883	7e-20	H2AC15	?
rs144447022	7e-20	LINC03003	?
rs4298967	8e-20	CACNA1C, CACNA1C-IT3	?
rs151181	3e-19	CLN3	T	0.03
rs67981811	5e-19	ZSCAN12	C	8.91
rs75782365	3e-18	BTN3A1	?
rs145410455	7e-18	LINC00533	G	1.06
rs144373461	1e-17	HLA-F-AS1	A
rs9834970	2e-17	HSPD1P6 - LINC02033	?
rs12129573	5e-17	RN7SKP19 - LINC01360	?
rs4481150	5e-17	ITIH3	?
rs7531118	1e-16	LINC02796	C	1.04
rs12658451	2e-16	NIHCOLE - RNU6-334P	?
rs12658032	2e-16	NIHCOLE - RNU6-334P	A	1.04
rs1702294	3e-16	MIR137HG	?
rs7085104	3e-16	BORCS7-ASMT	?
rs30266	1e-15	NIHCOLE - RNU6-334P	A	7.99
rs4129585	2e-15	TSNARE1	?
rs10968576	3e-15	LINGO2	A	0.03
rs8037355	4e-15	Metazoa_SRP - TMCO5A	C	1.03
rs61867293	8e-15	SORCS3	?
rs11688767	2e-14	EIF2S2P7 - ACTG1P22	?
rs10883832	3e-14	NT5C2	?
rs71395455	5e-14	ZSCAN2-AS1, ZSCAN2	?
rs5758265	5e-14	L3MBTL2-AS1, L3MBTL2	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST003962	Charney AW	2017	13,903	19,279	Evidence for genetic heterogeneity between clinical subtypes of bipolar disorder.
GCST002385	Muhleisen TW	2014	9,747	14,278	Genome-wide association study reveals two new risk loci for bipolar disorder.
GCST004001	van Hulzen KJE	2016	9,650	16,325	Genetic Overlap Between Attention-Deficit/Hyperactivity Disorder and Bipolar Disorder: Evidence From Genome-wide Association Study Meta-analysis.
GCST003724	Hou L	2016	7,647	27,303	Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder.
GCST004139	Ikeda M	2017	7,481	61,887	A genome-wide association study identifies two novel susceptibility loci and trans population polygenicity associated with bipolar disorder.
GCST001241	Sklar P	2011	7,481	9,250	Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4.
GCST001877	Smoller JW	2013	6,990	27,888	Identification of risk loci with shared effects on five major psychiatric disorders: a genome-wide analysis.
GCST001358	Chen DT	2011	5,568	7,187	Genome-wide association study meta-analysis of European and Asian-ancestry samples identifies three novel loci associated with bipolar disorder.
GCST004002	van Hulzen KJE	2016	5,167	16,325	Genetic Overlap Between Attention-Deficit/Hyperactivity Disorder and Bipolar Disorder: Evidence From Genome-wide Association Study Meta-analysis.
GCST006668	Qi G	2018	4,949	27,888	Heritability informed power optimization (HIPO) leads to enhanced detection of genetic associations across multiple traits.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	2
Tier 3: regulatory	2
Tier 4: intronic/intergenic	46

MAF distribution

Bucket	Variants
common (>=0.05)	48
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	2

Functional consequences

Consequence	Count
intron_variant	41
intergenic_variant	3
non_coding_transcript_exon_variant	2
3_prime_UTR_variant	2
regulatory_region_variant	2

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs13217619	6	28338894	T>C	0.05	intron_variant	ZSCAN31	1e-27	Tier 4: intronic/intergenic
rs1516725	3	186106215	T>A,C,G	0.05	intron_variant	ETV5, DGKG	1e-24	Tier 4: intronic/intergenic
rs3888190	16	28878165	C>A,G,T	0.05	non_coding_transcript_exon_variant	ATP2A1-AS1	1e-24	Tier 4: intronic/intergenic
rs12552	13	53051646	A>C,G,T	0.05	3_prime_UTR_variant	OLFM4	1e-23	Tier 2: splice/UTR
rs68188794	6	28112999	T>C	0.069	intron_variant	ZSCAN16, ZSCAN16-AS1	2e-21	Tier 4: intronic/intergenic
rs34706883	6	27837477	A>C,T	0.05	intergenic_variant	H2AC15	7e-20	Tier 4: intronic/intergenic
rs144447022	6	29276442	G>C,T	0.05	intron_variant	LINC03003	7e-20	Tier 4: intronic/intergenic
rs4298967	12	2299028	A>C,G,T	0.05	intron_variant	CACNA1C, CACNA1C-IT3	8e-20	Tier 4: intronic/intergenic
rs151181	16	28479196	T>A,C,G	0.05	intron_variant	CLN3	3e-19	Tier 4: intronic/intergenic
rs67981811	6	28387058	C>G	0.05	3_prime_UTR_variant	ZSCAN12	5e-19	Tier 2: splice/UTR
rs75782365	6	26408323	T>G	0.05	intron_variant	BTN3A1	3e-18	Tier 4: intronic/intergenic
rs145410455	6	28706221			intron_variant	LINC00533	7e-18	Tier 4: intronic/intergenic
rs144373461	6	29783228			intron_variant	HLA-F-AS1	1e-17	Tier 4: intronic/intergenic
rs9834970	3	36814539	T>C	0.05	regulatory_region_variant	HSPD1P6 - LINC02033	2e-17	Tier 3: regulatory
rs12129573	1	73302683	C>A	0.05	intron_variant	RN7SKP19 - LINC01360	5e-17	Tier 4: intronic/intergenic
rs4481150	3	52803777	T>C,G	0.05	intron_variant	ITIH3	5e-17	Tier 4: intronic/intergenic
rs7531118	1	72371556	T>C	0.05	intron_variant	LINC02796	1e-16	Tier 4: intronic/intergenic
rs12658451	5	104568336	T>C	0.05	intron_variant	NIHCOLE - RNU6-334P	2e-16	Tier 4: intronic/intergenic
rs12658032	5	104568525	A>G,T	0.05	intron_variant	NIHCOLE - RNU6-334P	2e-16	Tier 4: intronic/intergenic
rs1702294	1	98036428	T>A,C,G	0.05	intron_variant	MIR137HG	3e-16	Tier 4: intronic/intergenic
rs7085104	10	102869116	A>G	0.05	intron_variant	BORCS7-ASMT	3e-16	Tier 4: intronic/intergenic
rs30266	5	104636656	G>A,C	0.05	intron_variant	NIHCOLE - RNU6-334P	1e-15	Tier 4: intronic/intergenic
rs4129585	8	142231572	A>C,G,T	0.05	intron_variant	TSNARE1	2e-15	Tier 4: intronic/intergenic
rs10968576	9	28414341	A>G	0.05	intron_variant	LINGO2	3e-15	Tier 4: intronic/intergenic
rs8037355	15	37351630	C>T	0.05	intron_variant	Metazoa_SRP - TMCO5A	4e-15	Tier 4: intronic/intergenic
rs61867293	10	104804166	C>T	0.05	intron_variant	SORCS3	8e-15	Tier 4: intronic/intergenic
rs11688767	2	57761059	A>G,T	0.05	intron_variant	EIF2S2P7 - ACTG1P22	2e-14	Tier 4: intronic/intergenic
rs10883832	10	103111522	T>A,G	0.05	intron_variant	NT5C2	3e-14	Tier 4: intronic/intergenic
rs71395455	15	84610573	A>C,G,T	0.05	intron_variant	ZSCAN2-AS1, ZSCAN2	5e-14	Tier 4: intronic/intergenic
rs5758265	22	41221893	G>A,C,T	0.05	intron_variant	L3MBTL2-AS1, L3MBTL2	5e-14	Tier 4: intronic/intergenic

ClinVar germline variants

2 retrieved; paginated sample, class counts are floors:

2 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
267971	46;X;inv(X)(q27q28)		Uncertain significance	criteria provided, single submitter
523471	NM_004366.6(CLCN2):c.740G>T (p.Gly247Val)	CLCN2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 69 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
SYNGR1	Limited	Autosomal dominant	bipolar disorder	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RMRP	Orphanet:175	Cartilage-hair hypoplasia
RMRP	Orphanet:39041	Omenn syndrome
RMRP	Orphanet:93347	Anauxetic dysplasia
ROR2	Orphanet:1507	Autosomal recessive Robinow syndrome
ROR2	Orphanet:572385	Brachydactyly type B1
ROS1	Orphanet:251579	Giant cell glioblastoma
ROS1	Orphanet:70567	Cholangiocarcinoma
CNNM2	Orphanet:620363	Primary hypomagnesemia-generalized seizures-intellectual disability-obesity syndrome
RPL13	Orphanet:370015	Spondyloepimetaphyseal dysplasia, Isidor-Toutain type
RPL18	Orphanet:124	Diamond-Blackfan anemia
RYR2	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
RYR2	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
RYR2	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
RYR2	Orphanet:3286	Catecholaminergic polymorphic ventricular tachycardia
CNNM4	Orphanet:1873	Jalili syndrome
SAR1B	Orphanet:71	Chylomicron retention disease
ATXN7	Orphanet:94147	Spinocerebellar ataxia type 7
SCN2A	Orphanet:140927	Self-limited neonatal-infantile epilepsy
SCN2A	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
SCN2A	Orphanet:2131	Alternating hemiplegia of childhood
SCN2A	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
SCN2A	Orphanet:306	Self-limited infantile epilepsy
SCN2A	Orphanet:33069	Dravet syndrome
SCN2A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN2A	Orphanet:697160	Infantile epileptic spasms syndrome
SDCCAG8	Orphanet:110	Bardet-Biedl syndrome
SDCCAG8	Orphanet:3156	Senior-Loken syndrome
SEMA3A	Orphanet:130	Brugada syndrome
SEMA3A	Orphanet:478	Kallmann syndrome
SGCG	Orphanet:353	Gamma-sarcoglycan-related limb-girdle muscular dystrophy R5
BRAF	Orphanet:1340	Cardiofaciocutaneous syndrome
BRAF	Orphanet:146	Differentiated thyroid carcinoma
BRAF	Orphanet:251615	Pilomyxoid astrocytoma
BRAF	Orphanet:389	Langerhans cell histiocytosis
BRAF	Orphanet:500	Noonan syndrome with multiple lentigines
BRAF	Orphanet:54595	Craniopharyngioma
BRAF	Orphanet:58017	Classic hairy cell leukemia
BRAF	Orphanet:626	Large/giant congenital melanocytic nevus
BRAF	Orphanet:648	Noonan syndrome
BRAF	Orphanet:840	Syringocystadenoma papilliferum
BRAF	Orphanet:96253	Cushing disease
SLC4A1	Orphanet:3202	Dehydrated hereditary stomatocytosis
SLC4A1	Orphanet:398088	Hereditary cryohydrocytosis with normal stomatin
SLC4A1	Orphanet:822	Hereditary spherocytosis
SLC4A1	Orphanet:93608	Autosomal dominant distal renal tubular acidosis
SLC4A1	Orphanet:93610	Distal renal tubular acidosis with anemia
SLC4A1	Orphanet:98868	Southeast Asian ovalocytosis
SMARCA2	Orphanet:3051	Nicolaides-Baraitser syndrome
SMARCA2	Orphanet:637013	SMARCA2-related blepharophimosis-intellectual disability syndrome
SMC1A	Orphanet:199	Cornelia de Lange syndrome

Cohort genes → proteins

75 cohort genes, 72 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	74
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SYNGR1	HGNC:11498	ENSG00000100321	O43759	Synaptogyrin-1	gencc
RGS6	HGNC:10002	ENSG00000182732	P49758	Regulator of G-protein signaling 6	gwas
RMRP	HGNC:10031	ENSG00000277027		RNA component of mitochondrial RNA processing endoribonuclease	gwas
RNU5D-1	HGNC:10214	ENSG00000200169		RNA, U5D small nuclear 1	gwas
RNU5E-1	HGNC:10215	ENSG00000199347		RNA, U5E small nuclear 1	gwas
PHAX	HGNC:10241	ENSG00000164902	Q9H814	Phosphorylated adapter RNA export protein	gwas
ROR2	HGNC:10257	ENSG00000169071	Q01974	Tyrosine-protein kinase transmembrane receptor ROR2	gwas
ROS1	HGNC:10261	ENSG00000047936	P08922	Proto-oncogene tyrosine-protein kinase ROS	gwas
CNNM2	HGNC:103	ENSG00000148842	Q9H8M5	Metal transporter CNNM2	gwas
RPL13	HGNC:10303	ENSG00000167526	P26373	Large ribosomal subunit protein eL13	gwas
RPL18	HGNC:10310	ENSG00000063177	Q07020	Large ribosomal subunit protein eL18	gwas
CNNM3	HGNC:104	ENSG00000168763	Q8NE01	Metal transporter CNNM3	gwas
RPS6KA2	HGNC:10431	ENSG00000071242	Q15349	Ribosomal protein S6 kinase alpha-2	gwas
RTN1	HGNC:10467	ENSG00000139970	Q16799	Reticulon-1	gwas
RXRG	HGNC:10479	ENSG00000143171	P48443	Retinoic acid receptor RXR-gamma	gwas
RYR2	HGNC:10484	ENSG00000198626	Q92736	Ryanodine receptor 2	gwas
CNNM4	HGNC:105	ENSG00000158158	Q6P4Q7	Metal transporter CNNM4	gwas
SAR1B	HGNC:10535	ENSG00000152700	Q9Y6B6	Small COPII coat GTPase SAR1B	gwas
SART1	HGNC:10538	ENSG00000175467	O43290	U4/U6.U5 tri-snRNP-associated protein 1	gwas
ATXN7	HGNC:10560	ENSG00000163635	O15265	Ataxin-7	gwas
SCAND2P	HGNC:10567	ENSG00000176700	Q9GZW5	Putative SCAN domain-containing protein SCAND2P	gwas
SCN2A	HGNC:10588	ENSG00000136531	Q99250	Sodium channel protein type 2 subunit alpha	gwas
SCTR	HGNC:10608	ENSG00000080293	P47872	Secretin receptor	gwas
SDCCAG8	HGNC:10671	ENSG00000054282	Q86SQ7	Serologically defined colon cancer antigen 8	gwas
SEMA3A	HGNC:10723	ENSG00000075213	Q14563	Semaphorin-3A	gwas
SEMG1	HGNC:10742	ENSG00000124233	P04279	Semenogelin-1	gwas
SEMG2	HGNC:10743	ENSG00000124157	Q02383	Semenogelin-2	gwas
SF3B2	HGNC:10769	ENSG00000087365	Q13435	Splicing factor 3B subunit 2	gwas
ACHE	HGNC:108	ENSG00000087085	P22303	Acetylcholinesterase	gwas
SGCG	HGNC:10809	ENSG00000102683	Q13326	Gamma-sarcoglycan	gwas
SHC1	HGNC:10840	ENSG00000160691	P29353	SHC-transforming protein 1	gwas
SHMT2	HGNC:10852	ENSG00000182199	P34897	Serine hydroxymethyltransferase, mitochondrial	gwas
ST8SIA2	HGNC:10870	ENSG00000140557	Q92186	Alpha-2,8-sialyltransferase 8B	gwas
SLC16A5	HGNC:10926	ENSG00000170190	O15375	Monocarboxylate transporter 6	gwas
BRAF	HGNC:1097	ENSG00000157764	P15056	Serine/threonine-protein kinase B-raf	gwas
SLC25A17	HGNC:10987	ENSG00000100372	O43808	Peroxisomal membrane protein PMP34	gwas
SLC28A1	HGNC:11001	ENSG00000156222	O00337	Sodium/nucleoside cotransporter 1	gwas
SLC29A2	HGNC:11004	ENSG00000174669	Q14542	Equilibrative nucleoside transporter 2	gwas
SLC4A1	HGNC:11027	ENSG00000004939	P02730	Band 3 anion transport protein	gwas
SLC4A9	HGNC:11035	ENSG00000113073	Q96Q91	Anion exchange protein 4	gwas
SLC6A6	HGNC:11052	ENSG00000131389	P31641	Sodium- and chloride-dependent taurine transporter	gwas
BABAM2	HGNC:1106	ENSG00000158019	Q9NXR7	BRISC and BRCA1-A complex member 2	gwas
SLC8A3	HGNC:11070	ENSG00000100678	P57103	Sodium/calcium exchanger 3	gwas
SLIT1	HGNC:11085	ENSG00000187122	O75093	Slit homolog 1 protein	gwas
SLPI	HGNC:11092	ENSG00000124107	P03973	Antileukoproteinase	gwas
SMARCA2	HGNC:11098	ENSG00000080503	P51531	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2	gwas
SMC1A	HGNC:11111	ENSG00000072501	Q14683	Structural maintenance of chromosomes protein 1A	gwas
SNAP23	HGNC:11131	ENSG00000092531	O00161	Synaptosomal-associated protein 23	gwas
SORT1	HGNC:11186	ENSG00000134243	Q99523	Sortilin	gwas
SOX5	HGNC:11201	ENSG00000134532	P35711	Transcription factor SOX-5	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SYNGR1	Synaptogyrin-1	May play a role in regulated exocytosis.
RGS6	Regulator of G-protein signaling 6	Regulates G protein-coupled receptor signaling cascades.
PHAX	Phosphorylated adapter RNA export protein	A phosphoprotein adapter involved in the XPO1-mediated U snRNA export from the nucleus.
ROR2	Tyrosine-protein kinase transmembrane receptor ROR2	Tyrosine-protein kinase receptor which may be involved in the early formation of the chondrocytes.
ROS1	Proto-oncogene tyrosine-protein kinase ROS	Receptor tyrosine kinase (RTK) that plays a role in epithelial cell differentiation and regionalization of the proximal epididymal epithelium.
CNNM2	Metal transporter CNNM2	Divalent metal cation transporter.
RPL13	Large ribosomal subunit protein eL13	Component of the ribosome, a large ribonucleoprotein complex responsible for the synthesis of proteins in the cell.
RPL18	Large ribosomal subunit protein eL18	Component of the large ribosomal subunit.
CNNM3	Metal transporter CNNM3	Probable metal transporter.
RPS6KA2	Ribosomal protein S6 kinase alpha-2	Serine/threonine-protein kinase that acts downstream of ERK (MAPK1/ERK2 and MAPK3/ERK1) signaling and mediates mitogenic and stress-induced activation of transcription factors, regulates translation, and mediates cellular proliferation, su…
RTN1	Reticulon-1	Inhibits amyloid precursor protein processing, probably by blocking BACE1 activity.
RXRG	Retinoic acid receptor RXR-gamma	Receptor for retinoic acid.
RYR2	Ryanodine receptor 2	Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytosol and thereby plays a key role in triggering cardiac muscle contraction.
CNNM4	Metal transporter CNNM4	Probable metal transporter.
SAR1B	Small COPII coat GTPase SAR1B	Small GTPase that cycles between an active GTP-bound and an inactive GDP-bound state and mainly functions in vesicle-mediated endoplasmic reticulum (ER) to Golgi transport.
SART1	U4/U6.U5 tri-snRNP-associated protein 1	Plays a role in mRNA splicing as a component of the U4/U6-U5 tri-snRNP, one of the building blocks of the spliceosome.
ATXN7	Ataxin-7	Acts as a component of the SAGA (aka STAGA) transcription coactivator-HAT complex.
SCN2A	Sodium channel protein type 2 subunit alpha	Mediates the voltage-dependent sodium ion permeability of excitable membranes.
SCTR	Secretin receptor	G protein-coupled receptor activated by secretin (SCT), which is involved in different processes such as regulation of the pH of the duodenal content, food intake and water homeostasis.
SDCCAG8	Serologically defined colon cancer antigen 8	Plays a role in the establishment of cell polarity and epithelial lumen formation.
SEMA3A	Semaphorin-3A	Involved in the development of the olfactory system and in neuronal control of puberty.
SEMG1	Semenogelin-1	Predominant protein in semen.
SEMG2	Semenogelin-2	Participates in the formation of a gel matrix (sperm coagulum) entrapping the accessory gland secretions and ejaculated spermatozoa.
SF3B2	Splicing factor 3B subunit 2	Component of the 17S U2 SnRNP complex of the spliceosome, a large ribonucleoprotein complex that removes introns from transcribed pre-mRNAs.
ACHE	Acetylcholinesterase	Hydrolyzes rapidly the acetylcholine neurotransmitter released into the synaptic cleft allowing to terminate the signal transduction at the neuromuscular junction.
SGCG	Gamma-sarcoglycan	Component of the sarcoglycan complex, a subcomplex of the dystrophin-glycoprotein complex which forms a link between the F-actin cytoskeleton and the extracellular matrix.
SHC1	SHC-transforming protein 1	Signaling adapter that couples activated growth factor receptors to signaling pathways.
SHMT2	Serine hydroxymethyltransferase, mitochondrial	Catalyzes the cleavage of serine to glycine accompanied with the production of 5,10-methylenetetrahydrofolate, an essential intermediate for purine biosynthesis.
ST8SIA2	Alpha-2,8-sialyltransferase 8B	Catalyzes the transfer of a sialic acid from a CMP-linked sialic acid donor onto a terminal alpha-2,3-, alpha-2,6-, or alpha-2,8-linked sialic acid of an N-linked glycan acceptor through alpha-2,8-linkages.
SLC16A5	Monocarboxylate transporter 6	Proton-linked monocarboxylate transporter.
BRAF	Serine/threonine-protein kinase B-raf	Protein kinase involved in the transduction of mitogenic signals from the cell membrane to the nucleus.
SLC25A17	Peroxisomal membrane protein PMP34	Peroxisomal transporter for multiple cofactors like coenzyme A (CoA), flavin adenine dinucleotide (FAD), flavin mononucleotide (FMN) and nucleotide adenosine monophosphate (AMP), and to a lesser extent for nicotinamide adenine dinucleotide…
SLC28A1	Sodium/nucleoside cotransporter 1	Sodium and pyrimidine nucleoside symporter of the plasma membrane that imports uridine, thymidine and cytidine into cells by coupling their transport to the transmembrane sodium electrochemical gradient.
SLC29A2	Equilibrative nucleoside transporter 2	Bidirectional uniporter involved in the facilitative transport of nucleosides and nucleobases, and contributes to maintaining their cellular homeostasis.
SLC4A1	Band 3 anion transport protein	Functions both as a transporter that mediates electroneutral anion exchange across the cell membrane and as a structural protein.
SLC4A9	Anion exchange protein 4	Electroneutral Cl(-)/HCO3(-) antiporter that favors chloride ion entry and efflux of hydrogencarbonate and sodium ion across the basolateral membrane and may participate in salivary secretion.
SLC6A6	Sodium- and chloride-dependent taurine transporter	Mediates sodium- and chloride-dependent transport of taurine.
BABAM2	BRISC and BRCA1-A complex member 2	Component of the BRCA1-A complex, a complex that specifically recognizes ‘Lys-63’-linked ubiquitinated histones H2A and H2AX at DNA lesions sites, leading to target the BRCA1-BARD1 heterodimer to sites of DNA damage at double-strand breaks…
SLC8A3	Sodium/calcium exchanger 3	Mediates the electrogenic exchange of Ca(2+) against Na(+) ions across the cell membrane, and thereby contributes to the regulation of cytoplasmic Ca(2+) levels and Ca(2+)-dependent cellular processes.
SLIT1	Slit homolog 1 protein	Thought to act as molecular guidance cue in cellular migration, and function appears to be mediated by interaction with roundabout homolog receptors.
SLPI	Antileukoproteinase	Acid-stable proteinase inhibitor with strong affinities for trypsin, chymotrypsin, elastase, and cathepsin G.
SMARCA2	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2	ATPase involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
SMC1A	Structural maintenance of chromosomes protein 1A	Involved in chromosome cohesion during cell cycle and in DNA repair.
SNAP23	Synaptosomal-associated protein 23	Essential component of the high affinity receptor for the general membrane fusion machinery and an important regulator of transport vesicle docking and fusion.
SORT1	Sortilin	Functions as a sorting receptor in the Golgi compartment and as a clearance receptor on the cell surface.
SOX5	Transcription factor SOX-5	Transcription factor involved in chondrocytes differentiation and cartilage formation.
SP4	Transcription factor Sp4	Binds to GT and GC boxes promoters elements.
SPA17	Sperm surface protein Sp17	Sperm surface zona pellucida binding protein.
KLF9	Krueppel-like factor 9	Transcription factor that binds to GC box promoter elements.
SPTBN2	Spectrin beta chain, non-erythrocytic 2	Probably plays an important role in neuronal membrane skeleton.

Protein-family classification

Druggable: 24 · Difficult: 10 · Unknown: 41 · Druggable fraction: 0.32

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	8	3.0×	0.055
Nuclear receptor	1	5.2×	0.573
Ion channel	2	3.0×	0.573
Transporter	2	2.1×	0.573
Enzyme (other)	8	1.3×	0.573
Other/Unknown	41	1.0×	0.918
Transcription factor	7	0.8×	0.918
Scaffold/PPI	3	0.7×	0.918
GPCR	2	0.6×	0.918
Antibody/Immunoglobulin	1	0.4×	0.927

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SYNGR1	Other/Unknown	no		Marvel, Synaptogyrin
RGS6	Other/Unknown	no		DEP_dom, G-protein_gamma-like_dom, RGS
RMRP	Other/Unknown	no
RNU5D-1	Other/Unknown	no
RNU5E-1	Other/Unknown	no
PHAX	Other/Unknown	no		PHAX_RNA-binding_domain, PHAX_RNA-binding_sf, PHAX
ROR2	Kinase	yes	2.7.10.1	Kringle, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
ROS1	Kinase	yes	2.7.10.1	LDLR_classB_rpt, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
CNNM2	Other/Unknown	no		CBS_dom, CNNM, RmlC-like_jellyroll
RPL13	Other/Unknown	no		Ribosomal_eL13, Ribosomal_eL13_CS
RPL18	Other/Unknown	no		Ribosomal_eL18, Ribosomal_uL15/eL18, Ribosomal_eL18/eL18-A/B/_CS
CNNM3	Other/Unknown	no		CBS_dom, CNNM, Ion_transp-like_CBS
RPS6KA2	Kinase	yes	2.7.11.1	Prot_kinase_dom, AGC-kinase_C, Ser/Thr_kinase_AS
RTN1	Other/Unknown	no		Reticulon, RTN1-4
RXRG	Nuclear receptor	yes		Retinoid-X_rcpt/HNF4, Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt
RYR2	Ion channel	yes		RIH_dom, B30.2/SPRY, EF_hand_dom
CNNM4	Enzyme (other)	yes	7.2.2.14	cNMP-bd_dom, CBS_dom, CNNM
SAR1B	Other/Unknown	no		Small_GTP-bd, Small_GTPase_SAR1, Small_GTPase_ARF/SAR
SART1	Other/Unknown	no		SNU66/SART1, HIND
ATXN7	Other/Unknown	no		SCA7_dom, Ataxin-7-like_regulator
SCAND2P	Transcription factor	no		SCAN_dom, SCAN_sf, SCAN-C2H2_zinc_finger
SCN2A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
SCTR	GPCR	yes		GPCR_2_secretin-like, GPCR_2_extracellular_dom, GPCR_2_secretin_rcpt
SDCCAG8	Other/Unknown	no		SDCCAG8
SEMA3A	Antibody/Immunoglobulin	yes		Semap_dom, Ig_sub, Ig-like_dom
SEMG1	Other/Unknown	no		Semenogelin
SEMG2	Other/Unknown	no		Semenogelin
SF3B2	Other/Unknown	no		SAP_dom, PSP_pro-rich, DUF382
ACHE	Enzyme (other)	yes	3.1.1.7	Cholinesterase, CarbesteraseB, AChE_tetra
SGCG	Other/Unknown	no		Sarcoglycan, Sarcoglycan_gamma/delta/zeta
SHC1	Scaffold/PPI	no		SH2, PID_Shc-like, PTB/PI_dom
SHMT2	Enzyme (other)	yes	2.1.2.1	Ser_HO-MeTrfase, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase_small
ST8SIA2	Enzyme (other)	yes	2.4.99.8	Glyco_trans_29, Sialyl_trans, GT29-like_sf
SLC16A5	Transporter	yes		MCT, MFS, MFS_dom
BRAF	Kinase	yes	2.7.10.2	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, PKC_DAG/PE
SLC25A17	Other/Unknown	no		MCP, MCP_transmembrane, MCP_dom_sf
SLC28A1	Other/Unknown	no		CNT_N_dom, C_nuclsd_transpt, Gate_dom
SLC29A2	Transporter	yes		Eqnu_transpt, ENT1/ENT2, MFS_trans_sf
SLC4A1	Other/Unknown	no		Anion_exchange, Anion_exchange_1, HCO3_transpt_euk
SLC4A9	Other/Unknown	no		HCO3_transpt_euk, Na/HCO3_transpt, HCO3_transpt-like_TM_dom
SLC6A6	Other/Unknown	no		Na/ntran_symport, Na/ntran_symport_taurine, SNS_sf
BABAM2	Other/Unknown	no		BRE
SLC8A3	Other/Unknown	no		Calx_beta, Na_Ca_Ex, NaCa_Exmemb
SLIT1	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, LRRNT, Cys-rich_flank_reg_C
SLPI	Other/Unknown	no		WAP_dom, Elafin-like_sf, WAP_four-disulfide_core
SMARCA2	Other/Unknown	no		SNF2_N, Bromodomain, Helicase_C-like
SMC1A	Other/Unknown	no		RecF/RecN/SMC_N, SMC_hinge, SMC
SNAP23	Other/Unknown	no		T_SNARE_dom, SNAP-25_dom
SORT1	Scaffold/PPI	no		VPS10, WD40/YVTN_repeat-like_dom_sf, Sortilin_C
SOX5	Transcription factor	no		HMG_box_dom, HMG_box_dom_sf, SOX/SOX-like_TF

Expression context

Cohort genes with no expression data: 0.

67 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	75
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	9
calcaneal tendon	9
sural nerve	5
colonic epithelium	5
buccal mucosa cell	5
endothelial cell	5
cerebellar hemisphere	4
left ovary	4
right ovary	4
sperm	4
ventricular zone	4
bronchial epithelial cell	4
right hemisphere of cerebellum	3
middle temporal gyrus	3
corpus epididymis	3
gastrocnemius	3
muscle of leg	3
pons	3
hindlimb stylopod muscle	3
mucosa of transverse colon	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SYNGR1	298	ubiquitous	marker	Brodmann (1909) area 10, right hemisphere of cerebellum, cerebellar hemisphere
RGS6	185	broad	marker	cortical plate, sural nerve, middle temporal gyrus
RMRP	128	ubiquitous	yes	corpus callosum, colonic epithelium, bone marrow cell
RNU5D-1	100		marker	primordial germ cell in gonad, calcaneal tendon, adult mammalian kidney
RNU5E-1	79	broad	yes	sural nerve, adrenal tissue, liver
PHAX	262	ubiquitous	marker	buccal mucosa cell, calcaneal tendon, endothelial cell
ROR2	188	ubiquitous	marker	muscle layer of sigmoid colon, mucosa of stomach, body of uterus
ROS1	79	tissue_specific	marker	upper lobe of left lung, upper lobe of lung, corpus epididymis
CNNM2	234	ubiquitous	marker	secondary oocyte, oocyte, right adrenal gland
RPL13	311	ubiquitous	marker	right uterine tube, right ovary, left ovary
RPL18	304	ubiquitous	marker	nipple, penis, adult organism
CNNM3	250	ubiquitous	marker	gastrocnemius, muscle of leg, cerebellar hemisphere
RPS6KA2	295	ubiquitous	marker	inferior olivary complex, lower lobe of lung, medial globus pallidus
RTN1	270	broad	marker	Brodmann (1909) area 23, endothelial cell, pons
RXRG	170	broad	marker	hindlimb stylopod muscle, adenohypophysis, muscle of leg
RYR2	210	broad	marker	heart right ventricle, left ventricle myocardium, myocardium
CNNM4	189	ubiquitous	marker	mucosa of transverse colon, rectum, ileal mucosa
SAR1B	287	ubiquitous	marker	jejunal mucosa, skeletal muscle tissue of rectus abdominis, biceps brachii
SART1	292	ubiquitous	marker	tendon of biceps brachii, lower esophagus mucosa, apex of heart
ATXN7	290	ubiquitous	marker	mucosa of paranasal sinus, jejunal mucosa, superficial temporal artery
SCAND2P	189	ubiquitous	yes	buccal mucosa cell, sural nerve, right uterine tube
SCN2A	187	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, cerebellar vermis
SCTR	159		marker	body of pancreas, metanephros cortex, pancreas
SDCCAG8	134	ubiquitous	marker	corpus callosum, calcaneal tendon, thyroid gland
SEMA3A	194	ubiquitous	marker	stromal cell of endometrium, cortical plate, colonic epithelium
SEMG1	62	tissue_specific	marker	seminal vesicle, sperm, male germ cell
SEMG2	45	tissue_specific	marker	seminal vesicle, sperm, male germ cell
SF3B2	292	ubiquitous	marker	ventricular zone, left testis, right testis
ACHE	202	ubiquitous	marker	hindlimb stylopod muscle, right hemisphere of cerebellum, cerebellar hemisphere
SGCG	184	broad	marker	skeletal muscle tissue of rectus abdominis, gluteal muscle, triceps brachii

Protein interactions among cohort

Intra-cohort edges: 11.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BRAF	7,394
SHMT2	5,293
SMC1A	5,246
RPL18	4,722
RPL13	4,612
TAGLN2	4,271
SMARCA2	4,237
SHC1	3,993
SF3B2	3,906
SRPK2	3,839

Intra-cohort edges

A	B	Sources
ATXN7	SPTBN2	string_interaction
BABAM2	SHMT2	biogrid_interaction, intact
BRAF	ROS1	intact
NEK4	SDCCAG8	string_interaction
RPL13	RPL18	biogrid_interaction
SEMA3A	SLIT1	string_interaction
SEMG1	SEMG2	string_interaction
SEMG1	SLPI	string_interaction
SEMG2	SLPI	string_interaction
SLC28A1	SLC29A2	string_interaction
TCF7L1	TCF7L2	string_interaction

Structural data

PDB: 47 · AlphaFold-only: 25 · No structure: 3

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RPL18	Q07020	196
RPL13	P26373	191
BRAF	P15056	131
ACHE	P22303	79
SLC4A1	P02730	54
SF3B2	Q13435	50
SLC6A6	P31641	45
SMARCA2	P51531	32
SHMT2	P34897	27
RYR2	Q92736	26
SART1	O43290	26
SMC1A	Q14683	18
SORT1	Q99523	17
SPTLC1	O15269	17
STK4	Q13043	16
TACR1	P25103	15
SHC1	P29353	11
MED22	Q15528	11
CNNM2	Q9H8M5	7
CNNM3	Q8NE01	7
STAT6	P42226	7
ROR2	Q01974	6
TMEM258	P61165	6
ROS1	P08922	5
ATXN7	O15265	5
SCN2A	Q99250	5
TARS1	P26639	5
TCF4	P15884	5
SAR1B	Q9Y6B6	4
SEMG1	P04279	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ST8SIA2	Q92186	85.70
SLC25A17	O43808	85.31
SEMA3A	Q14563	84.50
SLC29A2	Q14542	84.48
SRMS	Q9H3Y6	83.99
ST13	P50502	82.20
SLC28A1	O00337	81.94
SLC16A5	O15375	80.56
SLIT1	O75093	80.28
SGCG	Q13326	80.24
SDCCAG8	Q86SQ7	78.67
RPS6KA2	Q15349	77.37
SLC8A3	P57103	76.87
ELP4	Q96EB1	74.49
SLC4A9	Q96Q91	72.50
DAGLA	Q9Y4D2	63.87
KLF9	Q13886	63.69
SOX5	P35711	58.95
NEK4	P51957	58.95
SCAND2P	Q9GZW5	55.63
TCF7L1	Q9HCS4	52.59
RTN1	Q16799	48.88
SP4	Q02446	39.58
TCF20	Q9UGU0	39.03
SEMG2	Q02383	30.69

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 689. Enrichment computed across 250 evidence-associated genes (171 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 171 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Bicarbonate transporters	3	20.0×	0.089	SLC4A1, SLC4A9, SLC4A10
Negative regulation of activity of TFAP2 (AP-2) family transcription factors	3	20.0×	0.089	TFAP2B, WWOX, TFAP2D
NCAM signaling for neurite out-growth	5	8.0×	0.089	ST8SIA2, SPTBN2, CACNA1C, CACNA1I, CACNB2
Activation of the TFAP2 (AP-2) family of transcription factors	3	16.7×	0.113	TFAP2B, WWOX, TFAP2D
Repression of WNT target genes	3	12.5×	0.221	TCF7L1, TCF7L2, TLE4
Binding of TCF/LEF:CTNNB1 to target gene promoters	2	13.4×	0.376	TCF7L1, TCF7L2
RUNX3 regulates WNT signaling	2	13.4×	0.376	TCF7L1, TCF7L2
WNT ligand biogenesis and trafficking	3	7.4×	0.376	WNT1, WNT10B, WNT11
Notch-HLH transcription pathway	3	7.2×	0.376	HDAC4, HDAC7, HDAC5
NCAM1 interactions	4	5.8×	0.376	ST8SIA2, CACNA1C, CACNA1I, CACNB2
NOTCH1 Intracellular Domain Regulates Transcription	4	5.6×	0.376	TLE4, HDAC4, HDAC7, HDAC5
Deactivation of the beta-catenin transactivating complex	4	5.5×	0.376	TCF7L1, TCF7L2, TLE4, KMT2B
Transcriptional regulation by RUNX1	5	4.3×	0.376	SMARCA2, ITCH, AUTS2, KMT2B, CCNH
Muscle contraction	7	3.2×	0.376	RYR2, SCN2A, SLC8A3, CACNA1C, CACNA1I, CACNB2, ACTN3
SLC-mediated transmembrane transport	8	2.8×	0.376	SLC28A1, SLC29A2, SLC4A1, SLC4A9, SLC6A6, SLC8A3, SLC4A10, SLC2A8
Axon guidance	10	2.6×	0.376	RPS6KA2, SCN2A, SEMA3A, SHC1, ST8SIA2, SLIT1, SPTBN2, CACNA1C (+2 more)
Nervous system development	10	2.5×	0.376	RPS6KA2, SCN2A, SEMA3A, SHC1, ST8SIA2, SLIT1, SPTBN2, CACNA1C (+2 more)
R-HSA-425393	5	3.8×	0.392	SLC4A1, SLC4A9, SLC6A6, SLC8A3, SLC4A10
Presynaptic depolarization and calcium channel opening	2	11.1×	0.399	CACNA1B, CACNB2
Transport of nucleosides and free purine and pyrimidine bases across the plasma membrane	2	11.1×	0.399	SLC28A1, SLC29A2
Positive Regulation of CDH1 Gene Transcription	2	11.1×	0.399	KLF9, FOXP2
Phase 0 - rapid depolarisation	3	6.1×	0.399	SCN2A, CACNA1C, CACNB2
Class B/2 (Secretin family receptors)	4	4.5×	0.399	SCTR, WNT1, WNT10B, WNT11
Formation of the beta-catenin:TCF transactivating complex	5	3.5×	0.400	TCF4, TCF7L1, TCF7L2, TLE4, KMT2B
Defective SLC4A1 causes hereditary spherocytosis type 4 (HSP4), distal renal tubular acidosis (dRTA) and dRTA with hemolytic anemia (dRTA-HA)	1	66.8×	0.413	SLC4A1
Phase 2 - plateau phase	2	8.9×	0.431	CACNA1C, CACNB2
Defective B3GALTL causes PpS	3	5.4×	0.431	ADAMTS12, ADAMTSL3, ADAMTS19
PCP/CE pathway	3	5.3×	0.431	ROR2, WNT1, WNT11
O-glycosylation of TSR domain-containing proteins	3	5.3×	0.431	ADAMTS12, ADAMTSL3, ADAMTS19
Beta-catenin independent WNT signaling	3	5.1×	0.431	ROR2, TCF7L1, TCF7L2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 231 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
coagulation	2	73.0×	0.130	SEMG1, SEMG2
membrane depolarization during atrial cardiac muscle cell action potential	2	48.6×	0.130	CACNA1C, CACNB2
positive regulation of serine-type endopeptidase activity	2	48.6×	0.130	SEMG1, SEMG2
negative regulation of flagellated sperm motility	2	48.6×	0.130	SEMG1, SEMG2
magnesium ion homeostasis	3	24.3×	0.130	CNNM2, CNNM3, CNNM4
calcium ion transport into cytosol	3	15.6×	0.130	RYR2, SLC8A3, CACNA1C
calcium ion import across plasma membrane	4	9.4×	0.130	SLC8A3, CACNA1B, CACNA1C, CACNA1I
positive regulation of stress fiber assembly	5	6.8×	0.130	BRAF, TACR1, ARHGEF15, RAPGEF3, CD47
canonical Wnt signaling pathway	7	4.6×	0.130	RECK, STK4, TCF7L1, TCF7L2, WNT1, WNT10B, WNT11
cytidine transport	2	36.5×	0.139	SLC28A1, SLC29A2
meiotic chromosome segregation	2	36.5×	0.139	SMC4, NUF2
kinetochore organization	2	29.2×	0.140	SMC4, NUF2
pyrimidine-containing compound transmembrane transport	2	29.2×	0.140	SLC28A1, SLC29A2
membrane depolarization during AV node cell action potential	2	29.2×	0.140	CACNA1C, CACNB2
regulation of MAPK cascade	4	7.9×	0.140	STK4, VRK2, ULK4, PAK6
positive regulation of T cell differentiation	4	7.9×	0.140	SMARCA2, WNT10B, ZAP70, ZMIZ1
positive regulation of DNA-templated transcription	18	2.2×	0.140	ATXN7, SHC1, SMARCA2, NEK4, TCF4, TFAP2B, MYRF, NSD3 (+10 more)
positive regulation of transcription by RNA polymerase II	28	1.8×	0.140	RXRG, SMARCA2, STAT6, TCF20, TCF4, TCF7L2, TFAP2B, TFEC (+20 more)
uridine transmembrane transport	2	24.3×	0.170	SLC28A1, SLC29A2
nucleoside transmembrane transport	2	24.3×	0.170	SLC28A1, SLC29A2
purine nucleobase transmembrane transport	2	24.3×	0.170	SLC28A1, SLC29A2
bicarbonate transport	3	10.4×	0.170	SLC4A1, SLC4A9, SLC4A10
TORC1 signaling	3	10.4×	0.170	RPS6KA2, PPDPF, CARD11
synapse assembly	5	5.0×	0.188	ACHE, SPTBN2, NLGN1, SHANK2, PCDHB16
transition between fast and slow fiber	2	20.8×	0.192	TNNC1, ACTN3
response to denervation involved in regulation of muscle adaptation	2	20.8×	0.192	HDAC4, ACTN3
positive regulation of muscle contraction	2	20.8×	0.192	CACNA1C, CACNB2
maturation of 5S rRNA	1	73.0×	0.211	SART1
obsolete regulation of glutamine family amino acid metabolic process	1	73.0×	0.211	SIRT4
columnar/cuboidal epithelial cell development	1	73.0×	0.211	ROS1

Therapeutics

Drugs indicated for this disease

9 approved, 42 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Aripiprazole	Approved (phase 4)
Asenapine	Approved (phase 4)
Carbamazepine	Approved (phase 4)
Lamotrigine	Approved (phase 4)
Lithium Carbonate	Approved (phase 4)
Loxapine	Approved (phase 4)
Olanzapine	Approved (phase 4)
Risperidone	Approved (phase 4)
Valproic Acid	Approved (phase 4)
Allopurinol	Phase 3 (in late-stage trials)
Aspirin	Phase 3 (in late-stage trials)
Bifeprunox	Phase 3 (in late-stage trials)
Brexpiprazole	Phase 3 (in late-stage trials)
Cannabidiol	Phase 3 (in late-stage trials)
Cariprazine	Phase 3 (in late-stage trials)
Celecoxib	Phase 3 (in late-stage trials)
Clozapine	Phase 3 (in late-stage trials)
Dextromethorphan	Phase 3 (in late-stage trials)
Doconexent	Phase 3 (in late-stage trials)
Endoxifen	Phase 3 (in late-stage trials)
Escitalopram	Phase 3 (in late-stage trials)
Fluoxetine	Phase 3 (in late-stage trials)
Haloperidol	Phase 3 (in late-stage trials)
Icosapent	Phase 3 (in late-stage trials)
Iloperidone	Phase 3 (in late-stage trials)
Insulin Human	Phase 3 (in late-stage trials)
Ketamine	Phase 3 (in late-stage trials)
Licarbazepine	Phase 3 (in late-stage trials)
Liothyronine	Phase 3 (in late-stage trials)
Liraglutide	Phase 3 (in late-stage trials)
Lisdexamfetamine	Phase 3 (in late-stage trials)
Lithium	Phase 3 (in late-stage trials)
Lumateperone	Phase 3 (in late-stage trials)
Lurasidone	Phase 3 (in late-stage trials)
Maltose	Phase 3 (in late-stage trials)
Meglumine Antimonate	Phase 3 (in late-stage trials)
Memantine	Phase 3 (in late-stage trials)
Metformin	Phase 3 (in late-stage trials)
Methylphenidate	Phase 3 (in late-stage trials)
Miltefosine	Phase 3 (in late-stage trials)
Minocycline	Phase 3 (in late-stage trials)
Paliperidone	Phase 3 (in late-stage trials)
Paroxetine	Phase 3 (in late-stage trials)
Quetiapine	Phase 3 (in late-stage trials)
Ramelteon	Phase 3 (in late-stage trials)
Sertraline	Phase 3 (in late-stage trials)
Tianeptine	Phase 3 (in late-stage trials)
Topiramate	Phase 3 (in late-stage trials)
Trehalose	Phase 3 (in late-stage trials)
Verapamil	Phase 3 (in late-stage trials)
Ziprasidone	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Acetylcarnitine, Acetylcysteine, Alcohol, Amisulpride, Bezafibrate, Bifidobacterium Spp., Calcium, Cannabinol, Ceftriaxone, Citalopram, Creatine, Curcumin, Cycloserine, Ebselen, Eslicarbazepine Acetate, Felbamate, Glycine, Infliximab, Isradipine, Levetiracetam, Levothyroxine, Lipoic Acid, Alpha, Melatonin, Midazolam, Mifepristone, Nitrous Oxide, OMEGA-3 FATTY ACIDS, OMEGA-3-ACID ETHYL ESTERS, Palmidrol, Pentazocine, Pramipexole, Psilocybin, Riluzole, Scopolamine, Simvastatin, Sodium Chloride, Tamoxifen, Taurine, Ubidecarenone, Valacyclovir, Vortioxetine.

Drug target analysis

Approved (phase 4): 19 · Phase ≥3: 21 · Phased (≥1): 25 · Undrugged: 50

Druggability breadth: 94 of 250 evidence-associated genes (38%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ROS1	LORLATINIB
RPL13	GENTAMICIN SULFATE
RPL18	GENTAMICIN SULFATE
RPS6KA2	FEDRATINIB
RXRG	BEXAROTENE
SCN2A	BEPRIDIL
SCTR	SECRETIN
ACHE	ISOFLUROPHATE
SHMT2	OXAPROZIN
BRAF	VEMURAFENIB
SLC28A1	ADENOSINE
SMC1A	SELUMETINIB
SRMS	FEDRATINIB
SRPK2	FEDRATINIB
STAT6	THIORIDAZINE HYDROCHLORIDE
NEK4	FEDRATINIB
STK4	AXITINIB
TACR1	CLOTRIMAZOLE
DAGLA	ORLISTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ACHE	153	4
SCN2A	99	4
BRAF	48	4
TACR1	42	4
ROS1	41	4
STK4	38	4
RPS6KA2	29	4
SRMS	19	4
SRPK2	11	4
STAT6	11	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
LORLATINIB	4	ACHE, ROS1
BRIGATINIB	4	ROS1, RPS6KA2
REPOTRECTINIB	4	ROS1
CRIZOTINIB	4	ROS1, STK4
FEDRATINIB	4	BRAF, NEK4, ROS1, RPS6KA2, SRMS, SRPK2
AXITINIB	4	ROS1, STK4
ALECTINIB	4	ROS1, SRPK2
INFIGRATINIB PHOSPHATE	4	BRAF, ROS1
INFIGRATINIB	4	BRAF, ROS1
ENTRECTINIB	4	ROS1
CERITINIB	4	ROS1
GILTERITINIB	4	ROS1
LAROTRECTINIB	4	ROS1
PAZOPANIB	4	ACHE, BRAF, ROS1, SRMS
NINTEDANIB	4	ROS1, RPS6KA2, SRPK2, STK4
MITOXANTRONE	4	ROS1
MIDOSTAURIN	4	ROS1, RPS6KA2, SRPK2, STK4
GENTAMICIN SULFATE	4	RPL13, RPL18
RUXOLITINIB	4	BRAF, RPS6KA2
NERATINIB	4	RPS6KA2, STK4
TOFACITINIB CITRATE	4	RPS6KA2
TOFACITINIB	4	RPS6KA2
BOSUTINIB	4	ACHE, RPS6KA2, SRMS, STK4, TACR1
SUNITINIB	4	ACHE, RPS6KA2, SRPK2, STK4
BEXAROTENE	4	RXRG
OXAPROZIN	4	RXRG, SHMT2
TRETINOIN	4	RXRG
ALITRETINOIN	4	RXRG
BEPRIDIL	4	SCN2A
DIBUCAINE	4	SCN2A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 15.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ACHE	2,563	Binding:2513, ADMET:27, Functional:22, Toxicity:1
BRAF	1,442	Binding:1400, Functional:37, ADMET:5
TACR1	620	Binding:506, Functional:111, ADMET:3
ROS1	461	Binding:459, Functional:2
RPS6KA2	448	Binding:446, ADMET:1, Functional:1
STK4	362	Binding:362
SMARCA2	311	Binding:274, Functional:25, ADMET:12
SRPK2	221	Binding:221
SCN2A	203	Binding:172, Functional:20, ADMET:10, Toxicity:1
RXRG	193	Binding:169, Functional:24
SRMS	179	Binding:178, Functional:1
NEK4	171	Binding:170, Functional:1
RPL13	90	Binding:90
RPL18	90	Binding:90
STAT6	81	Binding:77, Functional:4
TARS1	53	Binding:53
DAGLA	48	Binding:48
TCF4	31	Binding:31
TCF7L2	22	Binding:22
SCTR	20	Functional:16, Binding:4
SF3B2	20	Binding:20
SORT1	17	Binding:15, ADMET:2
RYR2	15	Binding:15
SHC1	10	Binding:10
SMC1A	10	Binding:10
SLC28A1	7	Binding:5, ADMET:2
SLC29A2	7	Binding:4, ADMET:3
SHMT2	6	Binding:6
ATXN7	5	Binding:5
SLC6A6	5	Binding:4, Functional:1
ROR2	4	Binding:4
SPTLC1	4	Binding:4
PHAX	1	Binding:1
SLC25A17	1	Binding:1
SNAP23	1	Binding:1
TAGLN2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ROR2	2.7.10.1	receptor protein-tyrosine kinase
ROS1	2.7.10.1	receptor protein-tyrosine kinase
RPS6KA2	2.7.11.1	non-specific serine/threonine protein kinase
CNNM4	7.2.2.14	P-type Mg2+ transporter
ACHE	3.1.1.7, 3.5.1.13	acetylcholinesterase, aryl-acylamidase
SHMT2	2.1.2.1	glycine hydroxymethyltransferase
ST8SIA2	2.4.99.8	alpha-N-acetylneuraminate alpha-2,8-sialyltransferase
BRAF	2.7.10.2, 2.7.11.1	non-specific protein-tyrosine kinase, non-specific serine/threonine protein kinase
SPTLC1	2.3.1.50	serine C-palmitoyltransferase
SRMS	2.7.10.2	non-specific protein-tyrosine kinase
STK4	2.7.11.1	non-specific serine/threonine protein kinase
TARS1	6.1.1.3	threonine-tRNA ligase
TCF4	7.6.2.3	ABC-type glutathione-S-conjugate transporter
TMEM258	2.4.99.18	dolichyl-diphosphooligosaccharide-protein glycotransferase
DAGLA	3.1.1.116	sn-1-specific diacylglycerol lipase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
ROS1	461
RPS6KA2	448
RXRG	193
SCN2A	203
ACHE	2,563
BRAF	1,442
SMARCA2	311
SRMS	179
SRPK2	221
NEK4	171
STK4	362
TACR1	620

Pharmacogenomics

Cohort genes with a PharmGKB record: 73; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
LORLATINIB	4	ACHE, ROS1
BRIGATINIB	4	ROS1, RPS6KA2
REPOTRECTINIB	4	ROS1
CRIZOTINIB	4	ROS1, STK4
FEDRATINIB	4	BRAF, NEK4, ROS1, RPS6KA2, SRMS, SRPK2
AXITINIB	4	ROS1, STK4
ALECTINIB	4	ROS1, SRPK2
INFIGRATINIB PHOSPHATE	4	BRAF, ROS1
INFIGRATINIB	4	BRAF, ROS1
ENTRECTINIB	4	ROS1
CERITINIB	4	ROS1
GILTERITINIB	4	ROS1
LAROTRECTINIB	4	ROS1
PAZOPANIB	4	ACHE, BRAF, ROS1, SRMS
NINTEDANIB	4	ROS1, RPS6KA2, SRPK2, STK4
MITOXANTRONE	4	ROS1
MIDOSTAURIN	4	ROS1, RPS6KA2, SRPK2, STK4
GENTAMICIN SULFATE	4	RPL13, RPL18
RUXOLITINIB	4	BRAF, RPS6KA2
NERATINIB	4	RPS6KA2, STK4
TOFACITINIB CITRATE	4	RPS6KA2
TOFACITINIB	4	RPS6KA2
BOSUTINIB	4	ACHE, RPS6KA2, SRMS, STK4, TACR1
SUNITINIB	4	ACHE, RPS6KA2, SRPK2, STK4
BEXAROTENE	4	RXRG
OXAPROZIN	4	RXRG, SHMT2
TRETINOIN	4	RXRG
ALITRETINOIN	4	RXRG
BEPRIDIL	4	SCN2A
DIBUCAINE	4	SCN2A

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	19	ROS1, RPL13, RPL18, RPS6KA2, RXRG, SCN2A, SCTR, ACHE, SHMT2, BRAF (+9 more)
B	Phased (≥1) drug, not yet approved	6	RYR2, SF3B2, SLC6A6, SMARCA2, SORT1, TCF4
C	Druggable family + PDB, no drug	5	ROR2, CNNM4, SPTLC1, TARS1, TMEM258
D	Druggable family + AlphaFold only, no drug	4	SEMA3A, ST8SIA2, SLC16A5, SLC29A2
E	Difficult family or no structure, no drug	41	SYNGR1, RGS6, RMRP, RNU5D-1, RNU5E-1, PHAX, CNNM2, CNNM3, RTN1, SAR1B (+31 more)

Undrugged target profiles

50 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC29A2	7	SLC28A1
SYNGR1	0	—
RGS6	0	—
RMRP	0	—
RNU5D-1	0	—
RNU5E-1	0	—
PHAX	1	—
ROR2	4	—
CNNM2	0	—
CNNM3	0	—
RTN1	0	—
CNNM4	0	—
SAR1B	0	—
SART1	0	—
ATXN7	5	—
SCAND2P	0	—
SDCCAG8	0	—
SEMA3A	0	—
SEMG1	0	—
SEMG2	0	—
SGCG	0	—
SHC1	10	—
ST8SIA2	0	—
SLC16A5	0	—
SLC25A17	1	—
SLC4A1	0	—
SLC4A9	0	—
BABAM2	0	—
SLC8A3	0	—
SLIT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1,375.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	526
PHASE4	195
PHASE3	185
PHASE2	99
PHASE1	49
PHASE2/PHASE3	18
PHASE1/PHASE2	18
EARLY_PHASE1	10

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05044611	PHASE4	ACTIVE_NOT_RECRUITING	AMIloride for the Treatment of Nephrogenic Diabetes Insipidus for Patients With Bipolar Disorder Treated With Lithium
NCT06417437	PHASE4	RECRUITING	Non-invasive BCI and Application Verification for Depressed People
NCT06662526	PHASE4	NOT_YET_RECRUITING	Lithium for Prevention of Cognitive Declining in Mood Illnesses
NCT07026461	PHASE4	RECRUITING	Right-sided 1-Hz Repetitive Transcranial Magnetic Stimulation (rTMS) Versus Left-sided Intermittent Theta Burst Stimulation (iTBS) in Patients With Depression
NCT07105111	PHASE4	RECRUITING	A Study to Evaluate the Effectiveness of Valbenazine in Adult Participants With Tardive Dyskinesia (TD) Who Remain Symptomatic While Receiving or After Stopping a Vesicular Monoamine Transporter 2 (VMAT2) Inhibitor
NCT07266545	PHASE4	RECRUITING	RNA Editing as a Biomarker of Antidepressant Response in Unipolar and Bipolar Depression (EDIT-ANDRE)
NCT00034580	PHASE4	COMPLETED	Olanzapine Versus Active Comparator in the Treatment of Bipolar I Disorder
NCT00044187	PHASE4	COMPLETED	The Assessment of a Weight-Gain Agent for the Treatment of Olanzapine-Associated Anti-Obesity Agent in Patients With Schizophrenia, Schizophreniform Disorder, Schizoaffective Disorder, and Bipolar I Disorder
NCT00044616	PHASE4	COMPLETED	Relapse Prevention for Bipolar Type-II Disorder
NCT00045916	PHASE4	COMPLETED	Optimizing Electroconvulsive Therapy for Depression
NCT00047567	PHASE4	TERMINATED	Open-label Adjunctive Zonisamide for Bipolar Disorder
NCT00048802	PHASE4	COMPLETED	Treatment and Outcome of Early Onset Bipolar Disorder
NCT00050206	PHASE4	COMPLETED	Olanzapine Versus Placebo in the Treatment of Mania in Adolescents With Bipolar I Disorder
NCT00067938	PHASE4	COMPLETED	Bipolar Study in Adults at Least 18 Years of Age
NCT00071253	PHASE4	TERMINATED	Depakote Monotherapy, Olanzapine Monotherapy, and Combination Therapy of Depakote Plus Olanzapine in Stable Subjects During the Maintenance Phase of Bipolar Illness
NCT00094549	PHASE4	COMPLETED	Olanzapine vs. Comparator and Placebo in the Treatment of Patients With Bipolar I Disorder
NCT00139074	PHASE4	TERMINATED	Seroquel in Acute Mania: Study to Investigate if Valproate Add-On Therapy is Superior to Quetiapine Monotherapy in Acutely Manic Patients
NCT00139594	PHASE4	COMPLETED	Open Label Extension Study of Licarbazepine in the Treatment of Manic Episodes of Bipolar I Disorder
NCT00154323	PHASE4	COMPLETED	The Efficacy and Safety of Oral Oxcarbazepine 300-1200 mg/Day as Adjuvant Therapy in the Treatment of Bipolar Disorder I or II This Study is Not Being Conducted in the United States.
NCT00167479	PHASE4	COMPLETED	A Study of Risperidone Monotherapy in Bipolar Anxiety
NCT00177567	PHASE4	COMPLETED	Treatment of Geriatric Bipolar Mood Disorders: A Pilot Study
NCT00181727	PHASE4	COMPLETED	Study of Depakote ER for the Treatment of Mania in Children Ages 6-12 With Bipolar Disorder
NCT00181779	PHASE4	COMPLETED	Aripiprazole for the Treatment of Mania in Children and Adolescents With Bipolar Disorder
NCT00181844	PHASE4	COMPLETED	Lamotrigine for the Treatment of Mania in Youth Ages 6-17 With Bipolar Disorder
NCT00181870	PHASE4	COMPLETED	Equetro for the Treatment of Mania in Children Ages 6-12 With Bipolar Disorder
NCT00181883	PHASE4	COMPLETED	Quetiapine for Mania In Preschool Children 4 to 6 Years of Age With Bipolar Disorder
NCT00181896	PHASE4	TERMINATED	Bupropion SR for Major Depression and Depression NOS in Children and Adolescents With Bipolar Disorder
NCT00181922	PHASE4	COMPLETED	Ziprasidone for the Treatment of Mania in Children and Adolescents With Bipolar Disorder
NCT00181935	PHASE4	COMPLETED	Risperidone Versus Olanzapine for Mania in Preschool Children 4 to 6 Years of Age With Bipolar Disorder
NCT00181987	PHASE4	COMPLETED	Concerta in the Treatment of ADHD in Youth and Adults With Bipolar Disorder
NCT00183469	PHASE4	COMPLETED	Maintenance Treatment of Bipolar Depression
NCT00186017	PHASE4	COMPLETED	Short Term Rescue Study of Olanzapine
NCT00188643	PHASE4	COMPLETED	Venlafaxine Versus Lamotrigine in the Treatment of Bipolar I/II Depression
NCT00190892	PHASE4	COMPLETED	Olanzapine Plus Carbamazepine in the Treatment of Bipolar I Mania
NCT00191997	PHASE4	COMPLETED	Optimal Length of Treatment Continuation With Olanzapine After Remission of Manic or Mixed Episode
NCT00194038	PHASE4	COMPLETED	Aripiprazole in Late Life Bipolar Disorder
NCT00195845	PHASE4	COMPLETED	A Double-Blind, Placebo-Controlled Study of Galantamine to Improve Cognitive Dysfunction in Bipolar Disorder
NCT00198198	PHASE4	COMPLETED	Aripiprazole Treatment of Bipolar Depression
NCT00199966	PHASE4	COMPLETED	Safety And Efficacy Study Of Depakote ER To Treat Pediatric Bipolar Disorder
NCT00202293	PHASE4	COMPLETED	Comparison of Combination Olanzapine+Lithium or Chlorpromazine+Lithium in Treatment of First Manic Episode With Psychotic Features

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ZIPRASIDONE	4	77
VALPROIC ACID	4	66
OLANZAPINE	4	39
QUETIAPINE	4	38
LURASIDONE	4	35
LAMOTRIGINE	4	27
VENLAFAXINE	4	21
CARIPRAZINE	4	18
FLUOXETINE	4	18
LITHIUM CARBONATE	4	14
ASENAPINE	4	13
ARIPIPRAZOLE	4	12
BUPROPION	4	10
ESCITALOPRAM	4	10
RISPERIDONE	4	10
KETAMINE	4	9
TOPIRAMATE	4	9
CARBAMAZEPINE	4	6
CLOZAPINE	4	6
LUMATEPERONE	4	6
VARENICLINE	4	6
PRAMIPEXOLE	4	5
MEMANTINE	4	4
MINOCYCLINE	4	4
OXCARBAZEPINE	4	4
PALIPERIDONE	4	4
RILUZOLE	4	4
ACETYLCYSTEINE	4	3
CYCLOSERINE	4	3
HALOPERIDOL	4	3