Restless legs syndrome

Summary

Restless legs syndrome (MONDO:0005391) is a disease with 45 cohort genes (532 GWAS associations across 26 studies) and 233 clinical trials. The dominant Reactome pathway is Post-translational modification: synthesis of GPI-anchored proteins (3 cohort genes). Top therapeutic interventions include ropinirole, pramipexole, and rotigotine.

At a glance

• Cohort genes: 45
• GWAS associations: 532
• ClinVar variants: 1
• Clinical trials: 233

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	restless legs syndrome
Mondo ID	MONDO:0005391
EFO	EFO:0004270
MeSH	D012148
DOID	DOID:0050425
ICD-10-CM	G25.81
ICD-11	1254916765
NCIT	C84501
SNOMED CT	32914008
UMLS	C0035258
MedGen	48427
Is cancer (heuristic)	no

Also known as: restless leg syndrome · RLS · WED

Data availability: 1 ClinVar variant · 532 GWAS associations (26 studies).

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › restless legs syndrome

Related subtypes (71): congenital nervous system disorder, central nervous system disorder, autoimmune disorder of the nervous system, cranial nerve neuropathy, peripheral nervous system disorder, neuronitis, diplegia of upper limb, retinal disorder, developmental disability, movement disorder, toxic encephalopathy, Barre-Lieou syndrome, Gerstmann syndrome, drug-induced akathisia, drug-induced dyskinesia, stiff-person syndrome, Worster-Drought syndrome, corneal-cerebellar syndrome, pachygyria-intellectual disability-epilepsy syndrome, porencephaly-cerebellar hypoplasia-internal malformations syndrome, symmetrical thalamic calcifications, neonatal brainstem dysfunction, primary orthostatic hypotension, rippling muscle disease with myasthenia gravis, periodic paralysis, qualitative or quantitative protein defects in neuromuscular diseases, specific learning disability, cerebellar hypoplasia-tapetoretinal degeneration syndrome, locked-in syndrome, dopa-responsive dystonia, idiopathic recurrent stupor, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids, spontaneous periodic hypothermia, Sydenham chorea, duplication of the pituitary gland, Balint syndrome, paraneoplastic neurologic syndrome, persistent idiopathic facial pain, serotonin syndrome, hypothalamic adipsic hypernatraemia syndrome, exercise-induced malignant hyperthermia, perineural cyst, neuromuscular disease, neuromyelitis optica, AL amyloidosis, AA amyloidosis, neuroleptic malignant syndrome, infectious disorder of the nervous system, central nervous system malformation, synaptopathy, nervous system neoplasm, sensory ganglionopathy, radiculitis, wet beriberi, perceptual disorders, prepubertal anorexia nervosa, neurocutaneous syndrome, neurovascular disorder, Wallerian degeneration, nervous system injury, neurosarcoidosis, neuroendocrine disorder, tubulinopathy, atactic disorder, hereditary neurological disease, meningitis-retention syndrome, KIF1A related neurological disorder, neurological pain disorder, neurodevelopmental disorder, post 5-alpha-reductase inhibitors treatment syndrome, post-selective serotonin reuptake inhibitor sexual dysfunction

Genetics & variants

GWAS landscape

532 GWAS associations across 26 studies. Top hits map to 15 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs868036	9e-288	MAP2K5	A	0.17
rs113851554	2e-280	MEIS1	T	1.92
rs3104769	9e-275	CASC16	T	0.21
rs4714163	2e-220	BTBD9	T	0.3
rs61192259	4e-202	BTBD9	A	1.26
rs1820987	2e-178	LINC01812 - FBXL12P1	T	0.12
rs12044119	1e-164	LINC01677 - MTATP6P14	T	0.12
rs34602324	5e-162	PTPRD	G	0.12
rs113230729	2e-160	UNCX - MICALL2	A	0.22
rs45544231	7e-133	CASC16	C	1.2
rs77276698	1e-115	CCDC148	A	0.12
rs10769894	5e-115	LMO1 - STK33	A	0.1
rs442083	2e-114	MYT1	C	0.12
rs7779363	1e-110	EEF1A1P28 - COX6A1P7	A	0.14
rs6477358	9e-110	PTPRD	T	0.13
rs10458531	1e-104	LINC01677 - MTATP6P14	A	0.13
chr6:38438771	7e-95		T	0.27
rs6920488	4e-93	BTBD9	A	0.28
rs5932706	3e-91	FBLIM1P1 - DCAF12L2	A	0.08
rs113330028	7e-89	CCDC148	A	0.14
rs6439256	3e-80	PIK3R4 - RN7SKP212	T	0.09
rs1389581	1e-78	LINC01304	A	0.09
rs111652004	3e-73	RN7SKP101 - SEMA6D	T	0.14
rs3112626	3e-71	CASC16	A	0.15
rs996064	1e-69	DPH6-DT - LINC02853	A	0.17
rs537670230	2e-69	LMX1B - ZBTB43	A	0.11
rs7620647	8e-69	CRBN - SUMF1	A	0.09
rs4596705	3e-68	PTPRD	T	0.08
rs78593025	2e-66	TOX3	T	0.08
rs11689768	2e-64	CNTNAP5	A	0.09

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90432061	Schormair B	2024	116,647	1,546,466	Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction.
GCST90432063	Schormair B	2024	78,333	844,872	Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction.
GCST90432062	Schormair B	2024	38,314	701,594	Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction.
GCST90475829	Verma A	2024	15,475	428,445	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST005042	Schormair B	2017	15,126	95,725	Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry: a meta-analysis.
GCST011995	Didriksen M	2020	10,257	470,725	Large genome-wide association study identifies three novel risk variants for restless legs syndrome.
GCST90435387	Akcimen F	2024	9,851	38,957	Genomic Analysis Identifies Risk Factors in Restless Legs Syndrome.
GCST90399568	Schormair B	2024	7,248	19,802	Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction.
GCST90399569	Schormair B	2024	4,769	9,380	Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction.
GCST90105080	Tilch E	2022	3,652	5,360	ExomeChip-based rare variant association study in restless legs syndrome.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	1
Tier 3: regulatory	0
Tier 4: intronic/intergenic	49

MAF distribution

Bucket	Variants
common (>=0.05)	50
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	35
intergenic_variant	11
non_coding_transcript_exon_variant	2
unknown	1
3_prime_UTR_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs3112626	16	52591288	A>G,T	0.425	non_coding_transcript_exon_variant	CASC16		Tier 4: intronic/intergenic
rs10947738	6	38501411	A>C,T	0.295	intron_variant	BTBD9		Tier 4: intronic/intergenic
rs113851554	2	66523432	G>A,T	0.059	intron_variant	MEIS1		Tier 4: intronic/intergenic
rs868036	15	67762675	T>A,C	0.329	intron_variant	MAP2K5	9e-288	Tier 4: intronic/intergenic
rs3104769	16	52593319	C>A,G,T	0.422	intron_variant	CASC16	9e-275	Tier 4: intronic/intergenic
rs4714163	6	38470995	T>A,C,G	0.298	intron_variant	BTBD9	2e-220	Tier 4: intronic/intergenic
rs61192259	6	38486186	C>A	0.41	intron_variant	BTBD9	4e-202	Tier 4: intronic/intergenic
rs1820987	2	67842735	C>G,T	0.445	intergenic_variant	LINC01812 - FBXL12P1	2e-178	Tier 4: intronic/intergenic
rs12044119	1	106640104	T>A,C	0.408	intron_variant	LINC01677 - MTATP6P14	1e-164	Tier 4: intronic/intergenic
rs34602324	9	8827308	GA>G,GAA	0.478	intron_variant	PTPRD	5e-162	Tier 4: intronic/intergenic
rs113230729	7	1352865	A>C	0.072	intergenic_variant	UNCX - MICALL2	2e-160	Tier 4: intronic/intergenic
rs45544231	16	52598818	G>C,T	0.42	intron_variant	CASC16	7e-133	Tier 4: intronic/intergenic
rs77276698	2	158393717	G>A	0.247	intron_variant	CCDC148	1e-115	Tier 4: intronic/intergenic
rs10769894	11	8313948	A>C,G	0.448	intergenic_variant	LMO1 - STK33	5e-115	Tier 4: intronic/intergenic
rs442083	20	64162647	G>A,C,T	0.262	intron_variant	MYT1	2e-114	Tier 4: intronic/intergenic
rs7779363	7	88682523	A>G	0.125	intron_variant	EEF1A1P28 - COX6A1P7	1e-110	Tier 4: intronic/intergenic
rs6477358	9	8832394	G>A,C,T	0.485	intron_variant	PTPRD	9e-110	Tier 4: intronic/intergenic
rs10458531	1	106643693	A>G,T	0.41	intron_variant	LINC01677 - MTATP6P14	1e-104	Tier 4: intronic/intergenic
chr6:38438771				0.296			7e-95	Tier 4: intronic/intergenic
rs6920488	6	38476264	A>G,T	0.265	intron_variant	BTBD9	4e-93	Tier 4: intronic/intergenic
rs5932706	X	125762853	G>A	0.307	intergenic_variant	FBLIM1P1 - DCAF12L2	3e-91	Tier 4: intronic/intergenic
rs113330028	2	158416960	A>G	0.247	intron_variant	CCDC148	7e-89	Tier 4: intronic/intergenic
rs6439256	3	130800718	T>C	0.34	intron_variant	PIK3R4 - RN7SKP212	3e-80	Tier 4: intronic/intergenic
rs1389581	2	3969414	A>C,G	0.417	intron_variant	LINC01304	1e-78	Tier 4: intronic/intergenic
rs111652004	15	47068169	G>A,T	0.101	intergenic_variant	RN7SKP101 - SEMA6D	3e-73	Tier 4: intronic/intergenic
rs996064	15	35916797	A>G,T	0.056	intergenic_variant	DPH6-DT - LINC02853	1e-69	Tier 4: intronic/intergenic
rs537670230	9	126758176	A>C	0.155	intergenic_variant	LMX1B - ZBTB43	2e-69	Tier 4: intronic/intergenic
rs7620647	3	3443931	G>A	0.247	intron_variant	CRBN - SUMF1	8e-69	Tier 4: intronic/intergenic
rs4596705	9	9214833	G>C,T	0.393	intron_variant	PTPRD	3e-68	Tier 4: intronic/intergenic
rs78593025	16	52485054	C>A,T	0.328	intron_variant	TOX3	2e-66	Tier 4: intronic/intergenic

ClinVar germline variants

1 retrieved; paginated sample, class counts are floors:

1 likely risk allele

ClinVar	Variant (HGVS)	Gene	Classification	Review
3338473	NM_001105580.3(GABRR3):c.615T>A (p.Tyr205Ter)	GABRR3	Likely risk allele	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 15 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC40A1	Orphanet:647834	SLC40A1-related hemochromatosis
SLC40A1	Orphanet:648562	Ferroportin disease
ATP2C1	Orphanet:2841	Hailey-Hailey disease
NTNG2	Orphanet:528084	Non-specific syndromic intellectual disability
SETBP1	Orphanet:436151	Intellectual disability-expressive aphasia-facial dysmorphism syndrome
SETBP1	Orphanet:798	Schinzel-Giedion syndrome
CLN6	Orphanet:700467	Late infantile CLN6 disease
CLN6	Orphanet:700472	Juvenile CLN6 disease
CLN6	Orphanet:700477	Adult CLN6 disease
CRBN	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
LMO1	Orphanet:635	Neuroblastoma
SMAD3	Orphanet:284984	Aneurysm-osteoarthritis syndrome
SMAD3	Orphanet:60030	Loeys-Dietz syndrome
SMAD3	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
MEIS2	Orphanet:261190	Cleft palate-congenital heart defect-intellectual disability syndrome due to 15q14 microdeletion

Cohort genes → proteins

45 cohort genes, 45 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	44
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RNF8	HGNC:10071	ENSG00000112130	O76064	E3 ubiquitin-protein ligase RNF8	gwas
SLC40A1	HGNC:10909	ENSG00000138449	Q9NP59	Ferroportin	gwas
TOX3	HGNC:11972	ENSG00000103460	O15405	TOX high mobility group box family member 3	gwas
UTRN	HGNC:12635	ENSG00000152818	P46939	Utrophin	gwas
ATP2C1	HGNC:13211	ENSG00000017260	P98194	Calcium-transporting ATPase type 2C member 1	gwas
NTNG2	HGNC:14288	ENSG00000196358	Q96CW9	Netrin-G2	gwas
RANBP17	HGNC:14428	ENSG00000204764	Q9H2T7	Ran-binding protein 17	gwas
SETBP1	HGNC:15573	ENSG00000152217	Q9Y6X0	SET-binding protein	gwas
SEMA6D	HGNC:16770	ENSG00000137872	Q8NFY4	Semaphorin-6D	gwas
GABRR3	HGNC:17969	ENSG00000183185	A8MPY1	Gamma-aminobutyric acid receptor subunit rho-3	clinvar
PRMT6	HGNC:18241	ENSG00000198890	Q96LA8	Protein arginine N-methyltransferase 6	gwas
MDGA1	HGNC:19267	ENSG00000112139	Q8NFP4	MAM domain-containing glycosylphosphatidylinositol anchor protein 1	gwas
LGR6	HGNC:19719	ENSG00000133067	Q9HBX8	Leucine-rich repeat-containing G-protein coupled receptor 6	gwas
ADAM2	HGNC:198	ENSG00000104755	Q99965	Disintegrin and metalloproteinase domain-containing protein 2	gwas
DIS3	HGNC:20604	ENSG00000083520	Q9Y2L1	Exosome complex exonuclease RRP44	gwas
CLN6	HGNC:2077	ENSG00000128973	Q9NWW5	Ceroid-lipofuscinosis neuronal protein 6	gwas
LRRN1	HGNC:20980	ENSG00000175928	Q6UXK5	Leucine-rich repeat neuronal protein 1	gwas
BTBD9	HGNC:21228	ENSG00000183826	Q96Q07	BTB/POZ domain-containing protein 9	gwas
CCDC167	HGNC:21239	ENSG00000198937	Q9P0B6	Coiled-coil domain-containing protein 167	gwas
SKOR1	HGNC:21326	ENSG00000188779	P84550	SKI family transcriptional corepressor 1	gwas
CNTN4	HGNC:2174	ENSG00000144619	Q8IWV2	Contactin-4	gwas
STEAP4	HGNC:21923	ENSG00000127954	Q687X5	Metalloreductase STEAP4	gwas
ZNF804B	HGNC:21958	ENSG00000182348	A4D1E1	Zinc finger protein 804B	gwas
ASTE1	HGNC:25021	ENSG00000034533	Q2TB18	Single-strand DNA endonuclease ASTE1	gwas
CCDC148	HGNC:25191	ENSG00000153237	Q8NFR7	Coiled-coil domain-containing protein 148	gwas
DACH1	HGNC:2663	ENSG00000276644	Q9UI36	Dachshund homolog 1	gwas
APLF	HGNC:28724	ENSG00000169621	Q8IW19	Aprataxin and PNK-like factor	gwas
TANC1	HGNC:29364	ENSG00000115183	Q9C0D5	Protein TANC1	gwas
MICALL2	HGNC:29672	ENSG00000164877	Q8IY33	MICAL-like protein 2	gwas
C1D	HGNC:29911	ENSG00000197223	Q13901	Nuclear nucleic acid-binding protein C1D	gwas
CRBN	HGNC:30185	ENSG00000113851	Q96SW2	Protein cereblon	gwas
DPH6	HGNC:30543	ENSG00000134146	Q7L8W6	Diphthine–ammonia ligase	gwas
PRAC1	HGNC:30591	ENSG00000159182	Q96KF2	Small nuclear protein PRAC1	gwas
DCDC2C	HGNC:32696	ENSG00000214866	A8MYV0	Doublecortin domain-containing protein 2C	gwas
UNCX	HGNC:33194	ENSG00000164853	A6NJT0	Homeobox protein unc-4 homolog	gwas
GLO1	HGNC:4323	ENSG00000124767	Q04760	Lactoylglutathione lyase	gwas
LMO1	HGNC:6641	ENSG00000166407	P25800	Rhombotin-1	gwas
SMAD3	HGNC:6769	ENSG00000166949	P84022	SMAD family member 3	gwas
MAP2K5	HGNC:6845	ENSG00000137764	Q13163	Dual specificity mitogen-activated protein kinase kinase 5	gwas
MEIS1	HGNC:7000	ENSG00000143995	O00470	Homeobox protein Meis1	gwas
MEIS2	HGNC:7001	ENSG00000134138	O14770	Homeobox protein Meis2	gwas
MYT1	HGNC:7622	ENSG00000196132	Q01538	Myelin transcription factor 1	gwas
PKP4	HGNC:9026	ENSG00000144283	Q99569	Plakophilin-4	gwas
PMAIP1	HGNC:9108	ENSG00000141682	Q13794	Phorbol-12-myristate-13-acetate-induced protein 1	gwas
PTPRD	HGNC:9668	ENSG00000153707	P23468	Receptor-type tyrosine-protein phosphatase delta	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RNF8	E3 ubiquitin-protein ligase RNF8	E3 ubiquitin-protein ligase that plays a key role in DNA damage signaling via 2 distinct roles: by mediating the ‘Lys-63’-linked ubiquitination of histones H2A and H2AX and promoting the recruitment of DNA repair proteins at double-strand…
SLC40A1	Ferroportin	Transports Fe(2+) from the inside of a cell to the outside of the cell, playing a key role for maintaining systemic iron homeostasis.
TOX3	TOX high mobility group box family member 3	Transcriptional coactivator of the p300/CBP-mediated transcription complex.
UTRN	Utrophin	May play a role in anchoring the cytoskeleton to the plasma membrane.
ATP2C1	Calcium-transporting ATPase type 2C member 1	ATP-driven pump that supplies the Golgi apparatus with Ca(2+) and Mn(2+) ions, both essential cofactors for processing and trafficking of newly synthesized proteins in the secretory pathway.
NTNG2	Netrin-G2	Involved in controlling patterning and neuronal circuit formation at the laminar, cellular, subcellular and synaptic levels.
RANBP17	Ran-binding protein 17	May function as a nuclear transport receptor.
SEMA6D	Semaphorin-6D	Shows growth cone collapsing activity on dorsal root ganglion (DRG) neurons in vitro.
GABRR3	Gamma-aminobutyric acid receptor subunit rho-3	Rho subunit of the pentameric ligand-gated chloride channels responsible for mediating the effects of gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain.
PRMT6	Protein arginine N-methyltransferase 6	Arginine methyltransferase that can catalyze the formation of both omega-N monomethylarginine (MMA) and asymmetrical dimethylarginine (aDMA), with a strong preference for the formation of aDMA.
MDGA1	MAM domain-containing glycosylphosphatidylinositol anchor protein 1	Required for radial migration of cortical neurons in the superficial layer of the neocortex.
LGR6	Leucine-rich repeat-containing G-protein coupled receptor 6	Receptor for R-spondins that potentiates the canonical Wnt signaling pathway and acts as a marker of multipotent stem cells in the epidermis.
ADAM2	Disintegrin and metalloproteinase domain-containing protein 2	Sperm surface membrane protein that may be involved in sperm-egg plasma membrane adhesion and fusion during fertilization.
DIS3	Exosome complex exonuclease RRP44	Putative catalytic component of the RNA exosome complex which has 3’->5’ exoribonuclease activity and participates in a multitude of cellular RNA processing and degradation events.
SKOR1	SKI family transcriptional corepressor 1	Acts as a transcriptional corepressor of LBX1.
CNTN4	Contactin-4	Contactins mediate cell surface interactions during nervous system development.
STEAP4	Metalloreductase STEAP4	Integral membrane protein that functions as a NADPH-dependent ferric-chelate reductase, using NADPH from one side of the membrane to reduce a Fe(3+) chelate that is bound on the other side of the membrane.
ASTE1	Single-strand DNA endonuclease ASTE1	Structure-specific DNA endonuclease that specifically cleaves single-stranded DNA and 3’ overhang DNA.
DACH1	Dachshund homolog 1	Transcription factor that is involved in regulation of organogenesis.
APLF	Aprataxin and PNK-like factor	Histone chaperone involved in single-strand and double-strand DNA break repair.
TANC1	Protein TANC1	May be a scaffold component in the postsynaptic density.
MICALL2	MICAL-like protein 2	Effector of small Rab GTPases which is involved in junctional complexes assembly through the regulation of cell adhesion molecules transport to the plasma membrane and actin cytoskeleton reorganization.
C1D	Nuclear nucleic acid-binding protein C1D	Plays a role in the recruitment of the RNA exosome complex to pre-rRNA to mediate the 3’-5’ end processing of the 5.8S rRNA; this function may include MPHOSPH6.
CRBN	Protein cereblon	Substrate recognition component of a DCX (DDB1-CUL4-X-box) E3 protein ligase complex that mediates the ubiquitination and subsequent proteasomal degradation of target proteins, such as MEIS2, ILF2 or GLUL.
DPH6	Diphthine–ammonia ligase	Amidase that may catalyze the last step of diphthamide biosynthesis using ammonium and ATP.
UNCX	Homeobox protein unc-4 homolog	Transcription factor involved in somitogenesis and neurogenesis.
GLO1	Lactoylglutathione lyase	Catalyzes the conversion of hemimercaptal, formed from methylglyoxal and glutathione, to S-lactoylglutathione.
LMO1	Rhombotin-1	May be involved in gene regulation within neural lineage cells potentially by direct DNA binding or by binding to other transcription factors.
SMAD3	SMAD family member 3	Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases.
MAP2K5	Dual specificity mitogen-activated protein kinase kinase 5	Acts as a scaffold for the formation of a ternary MAP3K2/MAP3K3-MAP3K5-MAPK7 signaling complex.
MEIS1	Homeobox protein Meis1	Acts as a transcriptional regulator of PAX6.
MEIS2	Homeobox protein Meis2	Involved in transcriptional regulation.
MYT1	Myelin transcription factor 1	Binds to the promoter region of genes encoding proteolipid proteins of the central nervous system.
PKP4	Plakophilin-4	Plays a role as a regulator of Rho activity during cytokinesis.
PMAIP1	Phorbol-12-myristate-13-acetate-induced protein 1	Promotes activation of caspases and apoptosis.
PTPRD	Receptor-type tyrosine-protein phosphatase delta	Can bidirectionally induce pre- and post-synaptic differentiation of neurons by mediating interaction with IL1RAP and IL1RAPL1 trans-synaptically.

Protein-family classification

Druggable: 10 · Difficult: 12 · Unknown: 23 · Druggable fraction: 0.22

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
Transcription factor	10	1.8×	0.399
Antibody/Immunoglobulin	3	1.9×	0.899
Phosphatase	1	1.9×	0.899
Transporter	1	1.7×	0.899
Other/Unknown	23	0.9×	0.899
Protease	1	0.8×	0.899
Scaffold/PPI	2	0.8×	0.899
Kinase	1	0.6×	0.899
Enzyme (other)	2	0.5×	0.899
GPCR	1	0.5×	0.899

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RNF8	Transcription factor	no	2.3.2.27	FHA_dom, Znf_RING, SMAD_FHA_dom_sf
SLC40A1	Transporter	yes		Ferroportin-1, MFS_trans_sf
TOX3	Other/Unknown	no		HMG_box_dom, HMG_box_dom_sf, TOX_HMG-box_domain
UTRN	Transcription factor	no		Znf_ZZ, WW_dom, Actinin_actin-bd_CS
ATP2C1	Transcription factor	no	7.2.2.10	P_typ_ATPase, ATPase_P-typ_cation-transptr_N, ATPase_P-typ_cation-transptr_C
NTNG2	Other/Unknown	no		EGF, LE_dom, Laminin_N
RANBP17	Other/Unknown	no		Importin-beta_N, ARM-like, ARM-type_fold
SETBP1	Other/Unknown	no		AT_hook_DNA-bd_motif
SEMA6D	Scaffold/PPI	no		Semap_dom, Plexin_repeat, WD40/YVTN_repeat-like_dom_sf
GABRR3	Other/Unknown	no		GABAA/Glycine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
PRMT6	Enzyme (other)	yes	2.1.1.319	Arg_MeTrfase, SAM-dependent_MTases_sf, Methyltransf_25
MDGA1	Antibody/Immunoglobulin	yes		MAM_dom, Ig_sub2, Ig_sub
LGR6	GPCR	yes		GPCR_Rhodpsn, LRRNT, Leu-rich_rpt
ADAM2	Protease	yes		Peptidase_M12B, Disintegrin_dom, Peptidase_M12B_N
DIS3	Other/Unknown	no		RNase_II/R, PIN_dom, NA-bd_OB-fold
CLN6	Other/Unknown	no		CLN6
LRRN1	Antibody/Immunoglobulin	yes		Cys-rich_flank_reg_C, Leu-rich_rpt, Leu-rich_rpt_typical-subtyp
BTBD9	Other/Unknown	no		BTB/POZ_dom, FA58C, Galactose-bd-like_sf
CCDC167	Other/Unknown	no		CC167
SKOR1	Other/Unknown	no		SKI/SNO/DAC, DNA-bd_dom_put_sf, SAND-like_dom_sf
CNTN4	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
STEAP4	Other/Unknown	no		Fe3_Rdtase_TM_dom, P5C_Rdtase_cat_N, NAD(P)-bd_dom_sf
ZNF804B	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, ZNF804A-like/GPATCH8
ASTE1	Other/Unknown	no		XPG_DNA_repair_N, Asteroid, PIN-like_dom_sf
CCDC148	Other/Unknown	no		CCDC148/CCDC112
DACH1	Other/Unknown	no		SKI/SNO/DAC, DNA-bd_dom_put_sf, Ski_DNA-bd_sf
APLF	Other/Unknown	no		SMAD_FHA_dom_sf, APLF_PBZ, APLF
TANC1	Scaffold/PPI	no		Ankyrin_rpt, TPR-like_helical_dom_sf, TPR_rpt
MICALL2	Transcription factor	no		CH_dom, Znf_LIM, bMERB_dom
C1D	Other/Unknown	no		Sas10/Utp3/C1D, Exosome-assoc_fac/DNA_repair
CRBN	Other/Unknown	no		Lon_prtase_N, Yippee/Mis18/Cereblon, PUA-like_sf
DPH6	Other/Unknown	no		Diphthami_syn_dom, Rossmann-like_a/b/a_fold, DPH6/MJ0570
PRAC1	Other/Unknown	no
DCDC2C	Other/Unknown	no		Doublecortin_dom, Doublecortin_dom_sf
UNCX	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
GLO1	Enzyme (other)	yes	4.4.1.5	Glyas_Fos-R_dOase_dom, Glyoxalase_1, Glyoxalase_1_CS
LMO1	Transcription factor	no		Znf_LIM, LMO_RBTN_TF
SMAD3	Other/Unknown	no		SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_dom_sf
MAP2K5	Kinase	yes	2.7.12.2	PB1_dom, Prot_kinase_dom, Ser/Thr_kinase_AS
MEIS1	Transcription factor	no		HD, KN_HD, Homeodomain-like_sf
MEIS2	Transcription factor	no		HD, KN_HD, Homeodomain-like_sf
MYT1	Transcription factor	no		Znf_C2H2C, Myelin_TF, Znf_C2H2C_sf
PKP4	Other/Unknown	no		Armadillo, ARM-like, ARM-type_fold
PMAIP1	Other/Unknown	no		Noxa
PTPRD	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, Tyr_Pase_cat

Expression context

Cohort genes with no expression data: 0.

37 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)	1
broad (>20)	44
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	7
ganglionic eminence	6
calcaneal tendon	6
ventricular zone	6
pancreatic ductal cell	5
cerebellar hemisphere	4
cortical plate	4
buccal mucosa cell	4
cerebellar cortex	4
sural nerve	3
leukocyte	3
monocyte	3
primordial germ cell in gonad	3
left testis	3
sperm	3
cerebellum	3
colonic mucosa	2
mucosa of sigmoid colon	2
jejunal mucosa	2
islet of Langerhans	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RNF8	284	ubiquitous	marker	cortical plate, ganglionic eminence, cerebellar hemisphere
SLC40A1	260	ubiquitous	marker	pancreatic ductal cell, epithelial cell of pancreas, oviduct epithelium
TOX3	220	broad	marker	mucosa of sigmoid colon, pancreatic ductal cell, colonic mucosa
UTRN	272	ubiquitous	marker	calcaneal tendon, tendon, sural nerve
ATP2C1	289	ubiquitous	marker	cortical plate, secondary oocyte, ventricular zone
NTNG2	173	broad	marker	pancreatic ductal cell, monocyte, leukocyte
RANBP17	197	ubiquitous	marker	calcaneal tendon, male germ line stem cell (sensu Vertebrata) in testis, adrenal tissue
SETBP1	280	ubiquitous	marker	ventricular zone, buccal mucosa cell, caput epididymis
SEMA6D	251	broad	marker	jejunal mucosa, substantia nigra pars reticulata, substantia nigra pars compacta
GABRR3	9	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, pancreatic ductal cell, tibialis anterior
PRMT6	232	ubiquitous	yes	primordial germ cell in gonad, islet of Langerhans, palpebral conjunctiva
MDGA1	223	broad	yes	cerebellar hemisphere, cardiac muscle of right atrium, cerebellar cortex
LGR6	201	broad	marker	right coronary artery, descending thoracic aorta, thoracic aorta
ADAM2	34	tissue_specific	yes	testis, left testis, right testis
DIS3	274	ubiquitous	marker	sperm, calcaneal tendon, male germ cell
CLN6	139	ubiquitous	marker	monocyte, leukocyte, bone marrow
LRRN1	209	broad	marker	ventricular zone, ganglionic eminence, dorsal root ganglion
BTBD9	206	ubiquitous	marker	endothelial cell, mucosa of paranasal sinus, bone marrow cell
CCDC167	234	ubiquitous	marker	ganglionic eminence, ventricular zone, cortical plate
SKOR1	119	tissue_specific	yes	right hemisphere of cerebellum, cerebellum, cerebellar cortex
CNTN4	214	broad	marker	sperm, buccal mucosa cell, lateral nuclear group of thalamus
STEAP4	239	broad	marker	pericardium, palpebral conjunctiva, synovial joint
ZNF804B	24	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, left lobe of thyroid gland, thyroid gland
ASTE1	233	ubiquitous	yes	sperm, male germ cell, male germ line stem cell (sensu Vertebrata) in testis
CCDC148	172		marker	bronchial epithelial cell, bronchus, male germ line stem cell (sensu Vertebrata) in testis
DACH1	235	broad	marker	ventricular zone, endothelial cell, ganglionic eminence
APLF	168	ubiquitous	yes	calcaneal tendon, male germ line stem cell (sensu Vertebrata) in testis, buccal mucosa cell
TANC1	257	ubiquitous	marker	upper arm skin, cardiac muscle of right atrium, left ventricle myocardium
MICALL2	218	ubiquitous	marker	tibial nerve, sural nerve, right adrenal gland cortex
C1D	133	ubiquitous	marker	islet of Langerhans, monocyte, leukocyte

Protein interactions among cohort

Intra-cohort edges: 14.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMAD3	6,440
DIS3	3,833
RNF8	3,568
PTPRD	3,052
PRMT6	2,825
MAP2K5	2,820
ATP2C1	2,410
MEIS1	2,354
CRBN	2,201
SETBP1	2,077

Intra-cohort edges

A	B	Sources
BTBD9	MAP2K5	string_interaction
BTBD9	MEIS1	string_interaction
BTBD9	PTPRD	string_interaction
BTBD9	TOX3	string_interaction
C1D	DIS3	biogrid_interaction, intact, string_interaction
CRBN	LRRN1	string_interaction
CRBN	MEIS2	string_interaction
DACH1	SMAD3	intact
LMO1	RANBP17	string_interaction
LRRN1	PTPRD	biogrid_interaction, intact
MAP2K5	MEIS1	string_interaction
MAP2K5	PTPRD	string_interaction
MDGA1	NTNG2	string_interaction
MEIS1	MEIS2	biogrid_interaction

Structural data

PDB: 20 · AlphaFold-only: 25 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CRBN	Q96SW2	90
GLO1	Q04760	16
APLF	Q8IW19	14
PRMT6	Q96LA8	13
SMAD3	P84022	12
ATP2C1	P98194	11
SLC40A1	Q9NP59	8
PTPRD	P23468	8
RNF8	O76064	5
MEIS2	O14770	4
UTRN	P46939	3
NTNG2	Q96CW9	3
MDGA1	Q8NFP4	3
DIS3	Q9Y2L1	3
MAP2K5	Q13163	3
STEAP4	Q687X5	2
MEIS1	O00470	2
DACH1	Q9UI36	1
MYT1	Q01538	1
PMAIP1	Q13794	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DPH6	Q7L8W6	89.85
BTBD9	Q96Q07	88.71
C1D	Q13901	88.37
LMO1	P25800	88.15
CCDC167	Q9P0B6	87.71
CNTN4	Q8IWV2	86.72
CLN6	Q9NWW5	85.86
RANBP17	Q9H2T7	85.42
ASTE1	Q2TB18	85.40
LRRN1	Q6UXK5	82.05
ADAM2	Q99965	81.05
CCDC148	Q8NFR7	79.14
LGR6	Q9HBX8	77.94
GABRR3	A8MPY1	76.27
DCDC2C	A8MYV0	70.53
SEMA6D	Q8NFY4	67.95
TANC1	Q9C0D5	62.14
TOX3	O15405	60.22
PRAC1	Q96KF2	59.63
UNCX	A6NJT0	59.38
PKP4	Q99569	57.96
MICALL2	Q8IY33	56.94
SKOR1	P84550	55.96
SETBP1	Q9Y6X0	43.30
ZNF804B	A4D1E1	43.04

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 142. Enrichment computed across 45 evidence-associated genes (26 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 26 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Post-translational modification: synthesis of GPI-anchored proteins	3	19.4×	0.068	NTNG2, MDGA1, CNTN4
Signalling to ERK5	1	219.6×	0.092	MAP2K5
Defective SLC40A1 causes hemochromatosis 4 (HFE4) (macrophages)	1	219.6×	0.092	SLC40A1
Defective CP causes aceruloplasminemia (ACERULOP)	1	219.6×	0.092	SLC40A1
Defective SLC40A1 causes hemochromatosis 4 (HFE4) (duodenum)	1	219.6×	0.092	SLC40A1
Iron uptake and transport	2	26.6×	0.092	SLC40A1, STEAP4
Nuclear RNA decay	2	23.7×	0.092	DIS3, C1D
Loss of Function of SMAD4 in Cancer	1	146.4×	0.097	SMAD3
SMAD4 MH2 Domain Mutants in Cancer	1	146.4×	0.097	SMAD3
SMAD2/3 MH2 Domain Mutants in Cancer	1	146.4×	0.097	SMAD3
Loss of Function of TGFBR1 in Cancer	1	87.8×	0.102	SMAD3
RUNX3 regulates BCL2L11 (BIM) transcription	1	87.8×	0.102	SMAD3
Activation of NOXA and translocation to mitochondria	1	73.2×	0.102	PMAIP1
Loss of Function of SMAD2/3 in Cancer	1	73.2×	0.102	SMAD3
Signaling by TGF-beta Receptor Complex in Cancer	1	73.2×	0.102	SMAD3
SMAD2/3 Phosphorylation Motif Mutants in Cancer	1	73.2×	0.102	SMAD3
TGFBR1 KD Mutants in Cancer	1	73.2×	0.102	SMAD3
rRNA processing in the nucleus and cytosol	2	12.4×	0.102	DIS3, C1D
rRNA processing	2	11.3×	0.102	DIS3, C1D
RUNX3 regulates CDKN1A transcription	1	62.8×	0.112	SMAD3
Synthesis of diphthamide-EEF2	1	54.9×	0.122	DPH6
BH3-only proteins associate with and inactivate anti-apoptotic BCL-2 members	1	48.8×	0.131	PMAIP1
Interaction With Cumulus Cells And The Zona Pellucida	1	39.9×	0.148	ADAM2
Fertilization	1	36.6×	0.148	ADAM2
Deadenylation-dependent mRNA decay	1	33.8×	0.148	DIS3
PERK regulates gene expression	1	31.4×	0.148	DIS3
Formation of axial mesoderm	1	31.4×	0.148	SMAD3
Signaling by Activin	1	29.3×	0.148	SMAD3
Regulation of mRNA stability by proteins that bind AU-rich elements	1	29.3×	0.148	DIS3
mRNA decay by 3’ to 5’ exoribonuclease	1	27.4×	0.148	DIS3

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 41 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
embryonic pattern specification	3	39.8×	0.020	SMAD3, MEIS1, MEIS2
double-strand break repair via nonhomologous end joining	3	30.8×	0.022	RNF8, ASTE1, APLF
serotonin metabolic process	2	82.2×	0.028	MDGA1, BTBD9
visual learning	3	22.4×	0.028	ADAM2, TANC1, MEIS2
presynapse assembly	2	58.7×	0.036	MDGA1, PTPRD
circadian sleep/wake cycle, non-REM sleep	1	411.0×	0.047	BTBD9
spleen trabecula formation	1	411.0×	0.047	SLC40A1
negative regulation of lung blood pressure	1	411.0×	0.047	SMAD3
ERK5 cascade	1	411.0×	0.047	MAP2K5
regulation of miRNA transcription	1	411.0×	0.047	SMAD3
iron ion export across plasma membrane	1	411.0×	0.047	SLC40A1
negative regulation of myeloid cell differentiation	2	45.7×	0.047	MEIS1, MEIS2
release of cytochrome c from mitochondria	2	34.2×	0.047	SMAD3, PMAIP1
DNA repair-dependent chromatin remodeling	2	32.9×	0.047	RNF8, APLF
multicellular organismal-level iron ion homeostasis	2	28.4×	0.047	SLC40A1, BTBD9
synaptic membrane adhesion	2	28.4×	0.047	NTNG2, PTPRD
regulation of presynapse assembly	2	26.5×	0.047	NTNG2, MDGA1
modulation of chemical synaptic transmission	3	13.4×	0.047	NTNG2, BTBD9, PTPRD
brain development	4	7.8×	0.047	MDGA1, CNTN4, MEIS1, MEIS2
regulation of immune response	2	24.2×	0.054	SMAD3, PTPRD
methylglyoxal metabolic process	1	205.5×	0.066	GLO1
Golgi calcium ion homeostasis	1	205.5×	0.066	ATP2C1
Golgi calcium ion transport	1	205.5×	0.066	ATP2C1
positive regulation of transforming growth factor beta3 production	1	205.5×	0.066	SMAD3
nuclear mRNA surveillance of mRNA 3’-end processing	1	205.5×	0.066	DIS3
trans-Golgi network membrane organization	1	205.5×	0.066	ATP2C1
positive regulation of Wnt signaling pathway	2	18.7×	0.067	LGR6, CRBN
iron import into cell	1	137.0×	0.069	STEAP4
negative regulation of monoatomic ion transmembrane transport	1	137.0×	0.069	CRBN
response to dsRNA	1	137.0×	0.069	PMAIP1

Therapeutics

Drugs indicated for this disease

3 approved, 10 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Gabapentin	Approved (phase 4)
Gabapentin Enacarbil	Approved (phase 4)
Rotigotine	Approved (phase 4)
Benserazide	Phase 3 (in late-stage trials)
Cabergoline	Phase 3 (in late-stage trials)
Ferric Carboxymaltose	Phase 3 (in late-stage trials)
Levodopa	Phase 3 (in late-stage trials)
Lisuride	Phase 3 (in late-stage trials)
Naloxone	Phase 3 (in late-stage trials)
Oxycodone	Phase 3 (in late-stage trials)
Pramipexole	Phase 3 (in late-stage trials)
Pregabalin	Phase 3 (in late-stage trials)
Ropinirole	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Bupropion, Diphenhydramine, Ergocalciferol, IRON ISOMALTOSIDE 1000, Levetiracetam, Methadone, Rasagiline, Sodium Chloride, Suvorexant.

Drug target analysis

Approved (phase 4): 6 · Phase ≥3: 6 · Phased (≥1): 10 · Undrugged: 35

Druggability breadth: 18 of 45 evidence-associated genes (40%) 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
PRMT6	SULFATHIAZOLE
CRBN	DASABUVIR
GLO1	TOLMETIN
SMAD3	FLUORESCEIN
MAP2K5	PONATINIB
MYT1	DASATINIB ANHYDROUS

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MAP2K5	69	4
CRBN	18	4
GLO1	11	4
MYT1	4	4
PRMT6	2	4
SMAD3	2	4
SLC40A1	1	1
UTRN	1	2
GABRR3	1	1
DACH1	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SULFATHIAZOLE	4	PRMT6
DASABUVIR	4	CRBN
POMALIDOMIDE	4	CRBN
THALIDOMIDE	4	CRBN
LENALIDOMIDE	4	CRBN
PONATINIB	4	CRBN, MAP2K5
ASCIMINIB	4	CRBN
BRIGATINIB	4	CRBN
CRIZOTINIB	4	CRBN
TOLMETIN	4	GLO1
SULINDAC	4	GLO1
ACEMETACIN	4	GLO1
INDOMETHACIN	4	GLO1
FLUORESCEIN	4	SMAD3
AFATINIB	4	MAP2K5
VEMURAFENIB	4	MAP2K5
FEDRATINIB	4	MAP2K5
LENVATINIB	4	MAP2K5
AXITINIB	4	MAP2K5
SORAFENIB	4	MAP2K5
NERATINIB	4	MAP2K5
IBRUTINIB	4	MAP2K5
DABRAFENIB	4	MAP2K5
CABOZANTINIB	4	MAP2K5
VANDETANIB	4	MAP2K5
NILOTINIB	4	MAP2K5
BOSUTINIB	4	MAP2K5
GILTERITINIB	4	MAP2K5
PAZOPANIB	4	MAP2K5
NINTEDANIB	4	MAP2K5

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 6.

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

Symbol	Assays	Type breakdown
CRBN	5,948	Binding:5779, Functional:154, ADMET:15
MAP2K5	207	Binding:205, Functional:1, ADMET:1
PRMT6	194	Binding:179, Functional:15
GLO1	72	Binding:70, ADMET:1, Functional:1
SMAD3	24	Binding:18, Functional:6
SLC40A1	14	Binding:14
MYT1	9	Binding:9
GABRR3	7	Functional:7
DACH1	7	Binding:7
UTRN	5	Binding:3, ADMET:2
MEIS1	5	Binding:5
ATP2C1	1	Binding:1
LGR6	1	Binding:1
DIS3	1	Binding:1
CLN6	1	Binding:1
PKP4	1	Binding:1
PMAIP1	1	Binding:1
PTPRD	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RNF8	2.3.2.27	RING-type E3 ubiquitin transferase
ATP2C1	7.2.2.10	P-type Ca2+ transporter
PRMT6	2.1.1.319	type I protein arginine methyltransferase
GLO1	4.4.1.5	lactoylglutathione lyase
MAP2K5	2.7.12.2	mitogen-activated protein kinase kinase
PTPRD	3.1.3.48	protein-tyrosine-phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
PRMT6	194
CRBN	5,948
MAP2K5	207

Pharmacogenomics

Cohort genes with a PharmGKB record: 45; 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)
SULFATHIAZOLE	4	PRMT6
DASABUVIR	4	CRBN
POMALIDOMIDE	4	CRBN
THALIDOMIDE	4	CRBN
LENALIDOMIDE	4	CRBN
PONATINIB	4	CRBN, MAP2K5
ASCIMINIB	4	CRBN
BRIGATINIB	4	CRBN
CRIZOTINIB	4	CRBN
TOLMETIN	4	GLO1
SULINDAC	4	GLO1
ACEMETACIN	4	GLO1
INDOMETHACIN	4	GLO1
FLUORESCEIN	4	SMAD3
AFATINIB	4	MAP2K5
VEMURAFENIB	4	MAP2K5
FEDRATINIB	4	MAP2K5
LENVATINIB	4	MAP2K5
AXITINIB	4	MAP2K5
SORAFENIB	4	MAP2K5
NERATINIB	4	MAP2K5
IBRUTINIB	4	MAP2K5
DABRAFENIB	4	MAP2K5
CABOZANTINIB	4	MAP2K5
VANDETANIB	4	MAP2K5
NILOTINIB	4	MAP2K5
BOSUTINIB	4	MAP2K5
GILTERITINIB	4	MAP2K5
PAZOPANIB	4	MAP2K5
NINTEDANIB	4	MAP2K5

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	6	PRMT6, CRBN, GLO1, SMAD3, MAP2K5, MYT1
B	Phased (≥1) drug, not yet approved	4	SLC40A1, UTRN, GABRR3, DACH1
C	Druggable family + PDB, no drug	2	MDGA1, PTPRD
D	Druggable family + AlphaFold only, no drug	4	LGR6, ADAM2, LRRN1, CNTN4
E	Difficult family or no structure, no drug	29	RNF8, TOX3, ATP2C1, NTNG2, RANBP17, SETBP1, SEMA6D, DIS3, CLN6, BTBD9 (+19 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
LRRN1	0	CRBN
BTBD9	0	MAP2K5
MEIS2	0	CRBN
RNF8	0	—
TOX3	0	—
ATP2C1	1	—
NTNG2	0	—
RANBP17	0	—
SETBP1	0	—
SEMA6D	0	—
MDGA1	0	—
LGR6	1	—
ADAM2	0	—
DIS3	1	—
CLN6	1	—
CCDC167	0	—
SKOR1	0	—
CNTN4	0	—
STEAP4	0	—
ZNF804B	0	—
ASTE1	0	—
CCDC148	0	—
APLF	0	—
TANC1	0	—
MICALL2	0	—
C1D	0	—
DPH6	0	—
PRAC1	0	—
DCDC2C	0	—
UNCX	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 233.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	111
PHASE3	40
PHASE2	35
PHASE4	29
PHASE1	8
PHASE2/PHASE3	5
PHASE1/PHASE2	5

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02670161	PHASE4	ENROLLING_BY_INVITATION	Quality Improvement and Practice Based Research in Neurology Using the EMR
NCT05003648	PHASE4	ACTIVE_NOT_RECRUITING	Treating Leg Symptoms in Women With X-linked Adrenoleukodystrophy
NCT00200941	PHASE4	COMPLETED	Efficacy and Safety Study of Topiramate to Treat Restless Legs Syndrome
NCT00329602	PHASE4	COMPLETED	Long-term Study Of Ropinirole In Restless Legs Syndrome
NCT00344994	PHASE4	COMPLETED	SWITCH:Restless Legs Patients Switched to Ropinirole From Pramipexole
NCT00349531	PHASE4	COMPLETED	A Phase IV Trial With Pramipexole to Investigate the Effects on RLS Symptoms and Sleep Disturbance in Patients With RLS
NCT00356096	PHASE4	COMPLETED	Phase IV Trial With Pramipexole to Evaluate Safety and Efficacy in Patients With RLS Associated With Mood Disturbances
NCT00373542	PHASE4	COMPLETED	12-week Polysomnography Study of Ropinirole Controlled Release for Restless Legs Syndrome
NCT00375284	PHASE4	COMPLETED	A 6 Week Trial to Study the Efficacy and Safety of a Starting Dose 0.25 mg Pramipexole (Mirapex) in Patients With RLS
NCT00472199	PHASE4	COMPLETED	Long-term Efficacy, Safety and Tolerability of Pramipexole in Patients With Idiopathic Moderate to Severe Restless Legs Syndrome (RLS)
NCT00584246	PHASE4	WITHDRAWN	Pregabalin (Lyrica) for the Treatment of Restless Legs Syndrome
NCT01245777	PHASE4	COMPLETED	Restless Legs Syndrome With Iron Deficiency or Anaemia in the 3rd Trimester of Pregnancy
NCT01455012	PHASE4	COMPLETED	Effects of Neupro on Cardiovascular Observations in Patients With Restless Legs Syndrome
NCT01668667	PHASE4	COMPLETED	Gabapentin Enacarbil (GSK1838262) Adult Restless Leg Syndrome (RLS) Post Marketing Commitment Study
NCT01823770	PHASE4	COMPLETED	Effect of Rotigotine Patch Treatment on Cardiovascular Markers in Idiopathic Restless Legs Syndrome
NCT01976871	PHASE4	COMPLETED	Switching From Oral Dopamine Agonists to Rotigotine
NCT01981941	PHASE4	COMPLETED	Post-marketing Study of Gabapentin Enacarbil to Evaluate the Effect in Restless Leg Syndrome (RLS) Patients With Moderate Renal Impairment
NCT02025608	PHASE4	COMPLETED	Autonomic Function and Cardiovascular Risk in Restless Legs Syndrome
NCT02117076	PHASE4	TERMINATED	Blinded, Randomized Study of Gabapentin (Neurontin®) and Gabapentin Enacarbil (Horizant™) in Restless Leg Syndrome
NCT02138357	PHASE4	WITHDRAWN	Butrans for Treatment of Restless Legs Syndrome
NCT02424695	PHASE4	UNKNOWN	Effects of Gabapentin Enacarbil on Arousals, Heart Rate, Blood Pressure and PLMs in Restless Legs Syndrome
NCT02560766	PHASE4	UNKNOWN	An Efficacy and Safety Evaluation of HORIZANT in Adolescents With Moderate-to-Severe Primary RLS
NCT02633683	PHASE4	UNKNOWN	An Extension Study to Evaluate the Efficacy and Safety of HORIZANT in Adolescents With Moderate-to-Severe Primary RLS
NCT03053427	PHASE4	COMPLETED	A Study of Oral Dosing of Gabapentin Enacarbil in Japanese Restless Legs Syndrome Patients
NCT03817554	PHASE4	TERMINATED	Pramipexole for Restless Leg Syndrome in Peritoneal Dialysis Patients
NCT04610827	PHASE4	TERMINATED	Oral Iron Frequency for Childhood Restless Leg Syndrome/Periodic Limb Movement Disorder
NCT04706091	PHASE4	COMPLETED	Efficacy of Suvorexant in Patients With Effectively Treated Restless Legs Syndrome and Persistent Chronic Insomnia
NCT05529095	PHASE4	UNKNOWN	Sublingual Apomorphine in Refractory Restless Legs Syndrome
NCT05581576	PHASE4	UNKNOWN	Pitolisant in Refractory Restless Legs Syndrome
NCT00133198	PHASE3	COMPLETED	Efficacy and Safety of Pramipexole Compared to Placebo in the Treatment of Restless Legs Syndrome (RLS)
NCT00135993	PHASE3	COMPLETED	Four Different Transdermal Doses of Rotigotine in Subjects With Idiopathic Restless Legs Syndrome
NCT00136045	PHASE3	COMPLETED	Three Different Transdermal Doses of Rotigotine in Subjects With Idiopathic Restless Leg Syndrome
NCT00144209	PHASE3	COMPLETED	Assess Efficacy and Safety of the Dopamine Agonist Pramipexole Versus Levodopa / Benserazide (Madopar® DR) in Patients With Restless Legs Syndrome
NCT00152958	PHASE3	COMPLETED	A Study in Patients Suffering From Idiopathic Restless Legs Syndrome Who Responded to a Preceding, 6-month Treatment With Open-label Pramipexole Including Titration (0.125, 0.25, 0.5, 0.75 mg Orally q.n.)
NCT00197080	PHASE3	COMPLETED	Ropinirole XR (Extended Release) In Patients With Restless Legs Syndrome
NCT00225862	PHASE3	COMPLETED	A Clinical Research Study Evaluating Ropinirole Treatment For Restless Legs Syndrome (RLS)
NCT00256854	PHASE3	COMPLETED	Converting From Ropinirole Immediate Release (IR) To Ropinirole Controlled-Release for RLS (Restless Legs Syndrome)
NCT00263068	PHASE3	COMPLETED	An Extension Trial to Investigate Long-Term Treatment With Transdermal Rotigotine in Idiopathic Restless Legs Syndrome
NCT00275236	PHASE3	COMPLETED	A Sleep Lab Trial to Investigate the Efficacy and Safety of Transdermal Rotigotine in Subjects With Idiopathic Restless Legs Syndrome
NCT00275457	PHASE3	COMPLETED	Efficacy and Safety of Pramipexole (PPX) in Moderate to Severe Idiopathic Restless Legs Syndrome (RLS) Patients

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ROPINIROLE	4	32
PRAMIPEXOLE	4	19
ROTIGOTINE	4	18
GABAPENTIN ENACARBIL	4	14
BUPROPION	4	3
PITOLISANT	4	3
CABERGOLINE	4	2
FERRIC CARBOXYMALTOSE	4	2
FERROUS SULFATE	4	2
SUVOREXANT	4	2
ASCORBIC ACID	4	1
BIOTIN	4	1
DIPHENHYDRAMINE	4	1
FERUMOXYTOL	4	1
INCOBOTULINUMTOXINA	4	1
ISTRADEFYLLINE	4	1
LEVODOPA	4	1
MAGNESIUM CITRATE	4	1
METHYLPREDNISOLONE ACETATE	4	1
PREGABALIN	4	1
RASAGILINE	4	1
TOPIRAMATE	4	1
TYROSINE	4	1
VITAMIN E	4	1
DEXPRAMIPEXOLE	3	18
CRISUGABALIN	3	1
ECOPIPAM	3	1
ESMETHADONE	3	1
IRON ISOMALTOSIDE 1000	3	1
LISURIDE	3	1