Huntington disease

Summary

Huntington disease (MONDO:0007739) is a disease caused by HTT (GenCC Definitive), with 48 cohort genes (22 GWAS associations across 1 studies) and 273 clinical trials. Top therapeutic interventions include tetrabenazine, atomoxetine, and citalopram.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Causal gene: HTT (GenCC Definitive)
• Cohort genes: 48
• GWAS associations: 22
• ClinVar variants: 24
• Phenotypes (HPO): 53
• Clinical trials: 273

Clinical features

Epidemiology

Prevalence records

32 prevalence record(s), Orphanet, top 20 (validated / broadest geography first):

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 1 000 000	0.38	Worldwide	Validated
Point prevalence	1-9 / 100 000	2.7	Worldwide	Validated
Point prevalence	1-5 / 10 000	12	Europe	Validated
Annual incidence	1-9 / 1 000 000	0.11	Italy	Validated
Annual incidence	1-9 / 1 000 000	0.69	Canada	Validated
Annual incidence	1-9 / 1 000 000	0.3	United States	Validated
Annual incidence	1-9 / 1 000 000	0.65	Australia	Validated
Annual incidence	<1 / 1 000 000	0.046	China	Validated
Annual incidence	<1 / 1 000 000	0.08	Taiwan, Province of China	Validated
Annual incidence	1-9 / 1 000 000	0.14	Iceland	Validated
Annual incidence	1-9 / 1 000 000	0.33	Greece	Validated
Annual incidence	1-9 / 1 000 000	0.12	Cyprus	Validated
Annual incidence	1-9 / 1 000 000	0.35	Spain	Validated
Point prevalence	1-9 / 100 000	4	Greece	Validated
Point prevalence	1-5 / 10 000	10.6	Ireland	Validated
Point prevalence	1-9 / 100 000	1.9	United States	Validated
Point prevalence	1-9 / 1 000 000	0.65	Japan	Validated
Point prevalence	1-9 / 100 000	6.3	Australia	Validated
Point prevalence	1-9 / 1 000 000	0.37	China	Validated
Point prevalence	1-9 / 100 000	5.2	Slovenia	Validated

Signs & symptoms

Clinical features (HPO)

53 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001268	Mental deterioration	Very frequent (80-99%)
HP:0001347	Hyperreflexia	Very frequent (80-99%)
HP:0002072	Chorea	Very frequent (80-99%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0000496	Abnormality of eye movement	Frequent (30-79%)
HP:0000713	Agitation	Frequent (30-79%)
HP:0000716	Depression	Frequent (30-79%)
HP:0000718	Aggressive behavior	Frequent (30-79%)
HP:0000722	Compulsive behaviors	Frequent (30-79%)
HP:0000734	Disinhibition	Frequent (30-79%)
HP:0000737	Irritability	Frequent (30-79%)
HP:0000738	Hallucinations	Frequent (30-79%)
HP:0000739	Anxiety	Frequent (30-79%)
HP:0000741	Apathy	Frequent (30-79%)
HP:0000746	Delusion	Frequent (30-79%)
HP:0001250	Seizure	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0001336	Myoclonus	Frequent (30-79%)
HP:0001824	Weight loss	Frequent (30-79%)
HP:0002067	Bradykinesia	Frequent (30-79%)
HP:0002141	Gait imbalance	Frequent (30-79%)
HP:0002312	Clumsiness	Frequent (30-79%)
HP:0002354	Memory impairment	Frequent (30-79%)
HP:0002375	Hypokinesia	Frequent (30-79%)
HP:0003324	Generalized muscle weakness	Frequent (30-79%)
HP:0004305	Involuntary movements	Frequent (30-79%)
HP:0004408	Abnormality of the sense of smell	Frequent (30-79%)
HP:0007010	Poor fine motor coordination	Frequent (30-79%)
HP:0009088	Speech articulation difficulties	Frequent (30-79%)
HP:0025401	Staring gaze	Frequent (30-79%)
HP:0031473	Hostility	Frequent (30-79%)
HP:0031843	Bradyphrenia	Frequent (30-79%)
HP:0031845	Abnormal libido	Frequent (30-79%)
HP:0001262	Excessive daytime somnolence	Occasional (5-29%)
HP:0002059	Cerebral atrophy	Occasional (5-29%)
HP:0002063	Rigidity	Occasional (5-29%)
HP:0002169	Clonus	Occasional (5-29%)
HP:0002300	Mutism	Occasional (5-29%)
HP:0002340	Caudate atrophy	Occasional (5-29%)
HP:0002500	Abnormal cerebral white matter morphology	Occasional (5-29%)
HP:0002540	Inability to walk	Occasional (5-29%)
HP:0002591	Polyphagia	Occasional (5-29%)
HP:0003107	Abnormality of cholesterol metabolism	Occasional (5-29%)
HP:0003487	Babinski sign	Occasional (5-29%)
HP:0010794	Impaired visuospatial constructive cognition	Occasional (5-29%)
HP:0030842	Choking episodes	Occasional (5-29%)
HP:0030955	Alcoholism	Occasional (5-29%)
HP:0031589	Suicidal ideation	Occasional (5-29%)
HP:0040140	Degeneration of the striatum	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Huntington disease
Mondo ID	MONDO:0007739
MeSH	D006816
OMIM	143100
Orphanet	399
DOID	DOID:12858
ICD-10-CM	G10
ICD-11	2132180242
NCIT	C82342
SNOMED CT	58756001
UMLS	C0020179
MedGen	5654
GARD	0006677
MedDRA	10070668
NORD	1256
Is cancer (heuristic)	no

Also known as: HD · Huntington chorea · Huntington disease · Huntington’s chorea · Huntington’s Disease · Huntington’s disease

Data availability: 24 ClinVar variants · 22 GWAS associations (1 study) · 5 GenCC gene-disease records · 1,666 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › inherited neurodegenerative disorder › Huntington disease and related disorders › Huntington disease

Related subtypes (1): Huntington disease-like syndrome

Subtypes (2): juvenile Huntington disease, Westphal disease

Genetics & variants

GWAS landscape

22 GWAS associations across 1 studies. Top hits map to 17 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs150393409	2e-20	FAN1	A	6.4
rs1232027	1e-10	LINC01337	?
rs12668183	2e-08	CRPPA	C	2.8
rs73786719	9e-07	ADGB	?
rs3889139	2e-06	OR10A2	?	2.79
rs114688092	2e-06	KIF9	?
rs79029191	2e-06	PTPRM	?
rs932428	2e-06	LINC01734 - ATG3P1	?
rs4736525	3e-06	EFR3A	?
rs114643193	3e-06	ADD1	?
rs6882169	3e-06	TENM2-AS1, TENM2	?
rs80260687	3e-06	PTDSS1	?
rs28406206	3e-06	BRF1	?
rs78621558	4e-06	MSH3	?
rs72715653	5e-06	LINC01098, LINC01099	?
rs4720024	5e-06	MINDY4 - AQP1	?
rs117933444	6e-06	RNASET2	?
rs116220136	6e-06	PTPN11P4 - PRDM9	?
rs8031584	8e-06	MTMR10 - TRPM1	?
rs3013648	9e-06	LINC00333 - LINC00375	?
rs11197481	9e-06	ATRNL1 - GFRA1	G	0.19
rs117440785	9e-06	ST8SIA6 - PRPF38AP2	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST004691	Hensman Moss DJ	2017	0	0	Identification of genetic variants associated with Huntington’s disease progression: a genome-wide association study.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	1
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	21

MAF distribution

Bucket	Variants
common (>=0.05)	18
low_freq (0.01-0.05)	0
rare (<0.01)	1
unknown	3

Functional consequences

Consequence	Count
intron_variant	16
intergenic_variant	4
missense_variant	1
synonymous_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs150393409	15	30910758	G>A,C	0.001	missense_variant	FAN1	2e-20	Tier 1: coding
rs1232027	5	80619201	G>A	0.05	intron_variant	LINC01337	1e-10	Tier 4: intronic/intergenic
rs12668183	7	16455781	T>C	0.277	intron_variant	CRPPA	2e-08	Tier 4: intronic/intergenic
rs73786719	6	146716848	C>A	0.05	intron_variant	ADGB	9e-07	Tier 4: intronic/intergenic
rs3889139	11	6864198	G>A,C	0.05	intron_variant	OR10A2	2e-06	Tier 4: intronic/intergenic
rs114688092	3	47274048	G>C	0.05	intron_variant	KIF9	2e-06	Tier 4: intronic/intergenic
rs79029191	18	8053865	G>A		intron_variant	PTPRM	2e-06	Tier 4: intronic/intergenic
rs932428	20	39248129	A>C,G	0.05	intron_variant	LINC01734 - ATG3P1	2e-06	Tier 4: intronic/intergenic
rs4736525	8	131971460	G>A,C	0.05	intron_variant	EFR3A	3e-06	Tier 4: intronic/intergenic
rs114643193	4	2868202	C>T	0.05	intron_variant	ADD1	3e-06	Tier 4: intronic/intergenic
rs6882169	5	168241225	A>T	0.05	intron_variant	TENM2-AS1, TENM2	3e-06	Tier 4: intronic/intergenic
rs80260687	8	96292461	T>C	0.05	intron_variant	PTDSS1	3e-06	Tier 4: intronic/intergenic
rs28406206	14	105221745	C>T	0.05	synonymous_variant	BRF1	3e-06	Tier 4: intronic/intergenic
rs78621558	5	80716916	G>A	0.05	intron_variant	MSH3	4e-06	Tier 4: intronic/intergenic
rs72715653	4	177805806	C>A,T		intron_variant	LINC01098, LINC01099	5e-06	Tier 4: intronic/intergenic
rs4720024	7	30901640	G>T	0.05	intron_variant	MINDY4 - AQP1	5e-06	Tier 4: intronic/intergenic
rs117933444	6	166949385	C>T	0.05	intron_variant	RNASET2	6e-06	Tier 4: intronic/intergenic
rs116220136	5	23353146	T>C	0.05	intergenic_variant	PTPN11P4 - PRDM9	6e-06	Tier 4: intronic/intergenic
rs8031584	15	30995140	A>G,T	0.05	intron_variant	MTMR10 - TRPM1	8e-06	Tier 4: intronic/intergenic
rs3013648	13	84755019	A>C,T	0.05	intergenic_variant	LINC00333 - LINC00375	9e-06	Tier 4: intronic/intergenic
rs11197481	10	115949292	G>A	0.176	intergenic_variant	ATRNL1 - GFRA1	9e-06	Tier 4: intronic/intergenic
rs117440785	10	17483962	A>G		intergenic_variant	ST8SIA6 - PRPF38AP2	9e-06	Tier 4: intronic/intergenic

ClinVar germline variants

24 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 5 likely pathogenic, 2 conflicting classifications of pathogenicity, 2 benign/likely benign, 2 likely benign, 2 benign, 2 not provided, 2 other, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
409	NC_000004.11:g.3076606GCA[40_?]	HTT	Pathogenic	practice guideline
1687507	NM_001388492.1(HTT):c.54GCA[40] (p.Gln18_Gln38dup)	HTT	Likely pathogenic	criteria provided, single submitter
3779748	NM_001388492.1(HTT):c.99_102del (p.Gln33fs)	HTT	Likely pathogenic	criteria provided, single submitter
3779749	NM_001388492.1(HTT):c.99del (p.Gln33fs)	HTT	Likely pathogenic	criteria provided, single submitter
3897713	NM_001388492.1:c.52CAG[55_59]	HTT	Likely pathogenic	criteria provided, single submitter
3779747	NM_001388492.1(HTT):c.107del (p.Gln36fs)	LOC129929027	Likely pathogenic	criteria provided, single submitter
1301634	NM_001388492.1(HTT):c.54GCA[22] (p.Gln36_Gln38dup)	HTT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3779750	NM_001388492.1(HTT):c.54GCA[29] (p.Gln38_Pro39insGlnGlnGlnGlnGlnGlnGlnGlnGlnGln)	HTT	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1298952	NM_001388492.1(HTT):c.2758G>A (p.Asp920Asn)	HTT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1355049	NM_001388492.1(HTT):c.7498G>A (p.Val2500Ile)	HTT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1405485	NM_001388492.1(HTT):c.6250G>A (p.Gly2084Arg)	HTT	Uncertain significance	criteria provided, multiple submitters, no conflicts
417742	NM_001388492.1(HTT):c.2108C>T (p.Pro703Leu)	HTT	Uncertain significance	criteria provided, multiple submitters, no conflicts
4278357	NM_001388492.1(HTT):c.7849G>A (p.Val2617Met)	HTT	Uncertain significance	criteria provided, single submitter
812582	NC_000004.11:g.3076606GCA[36_39]	HTT	other	practice guideline
812592	NC_000004.11:g.3076606GCA[27_35]	HTT	other	practice guideline
982633	NM_001388492.1(HTT):c.8903G>A (p.Gly2968Asp)	HTT	Uncertain significance	criteria provided, multiple submitters, no conflicts
1599166	NM_001388492.1(HTT):c.7765+10G>A	HTT	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1671702	NM_001388492.1(HTT):c.4638C>G (p.Val1546=)	HTT	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
1809691	NM_001388492.1(HTT):c.99_100del (p.Gln34fs)	HTT	Likely benign	criteria provided, single submitter
21303	NM_002111.8(HTT):c.52CAG[?_25]	HTT	Benign	no assertion criteria provided
812591	NC_000004.11:g.3076606GCA[(?_26)]	HTT	Benign	practice guideline
982628	NM_001388492.1(HTT):c.54GCA[13] (p.Gln33_Gln38del)	HTT	Likely benign	criteria provided, single submitter
31915	NM_002111.8(HTT):c.52CAG[27_35] (p.Gln18_Gln38delinsGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGlnGln)	HTT	not provided	no classification provided
31916	NM_002111.8(HTT):c.52CAG[36_39]	HTT	not provided	no classification provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 16 · 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
HTT	Definitive	Autosomal dominant	Huntington disease	7
SLC6A4	Definitive	Autosomal dominant	Huntington disease	9
SLC2A3	Supportive	Autosomal dominant	Huntington disease

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HTT	Orphanet:248111	Juvenile Huntington disease
HTT	Orphanet:399	Huntington disease
HTT	Orphanet:528084	Non-specific syndromic intellectual disability
SLC2A3	Orphanet:399	Huntington disease
SH3BP2	Orphanet:184	Cherubism
BRF1	Orphanet:444072	Cerebellar-facial-dental syndrome
UQCRB	Orphanet:1460	Isolated complex III deficiency
SETD2	Orphanet:597738	Luscan-Lumish syndrome
SETD2	Orphanet:597743	SETD2-related microcephaly-severe intellectual disability-multiple congenital anomalies syndrome
RNASET2	Orphanet:85136	Cystic leukoencephalopathy without megalencephaly
DHFR	Orphanet:319651	Constitutional megaloblastic anemia with severe neurologic disease
FAN1	Orphanet:401996	Karyomegalic interstitial nephritis
NBEAL2	Orphanet:721	Gray platelet syndrome
TRPM1	Orphanet:714079	Complete congenital stationary night blindness, Schubert-Bornschein type
MSH3	Orphanet:480536	MSH3-related polyposis
PTDSS1	Orphanet:2658	Lenz-Majewski hyperostotic dysplasia

Cohort genes → proteins

48 cohort genes, 40 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	45
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC6A4	HGNC:11050	ENSG00000108576	P31645	Sodium-dependent serotonin transporter	gencc,clinvar
HTT	HGNC:4851	ENSG00000197386	P42858	Huntingtin	gencc,clinvar
SLC2A3	HGNC:11007	ENSG00000059804	P11169	Solute carrier family 2, facilitated glucose transporter member 3	gencc
SH3BP2	HGNC:10825	ENSG00000087266	P78314	SH3 domain-binding protein 2	gwas
BRF1	HGNC:11551	ENSG00000185024	Q92994	Transcription factor IIIB 90 kDa subunit	gwas
UQCRB	HGNC:12582	ENSG00000156467	P14927	Cytochrome b-c1 complex subunit 7	gwas
OR10A4	HGNC:15130	ENSG00000170782	Q9H209	Olfactory receptor 10A4	gwas
OR10A5	HGNC:15131	ENSG00000166363	Q9H207	Olfactory receptor 10A5	gwas
PPP1R16B	HGNC:15850	ENSG00000101445	Q96T49	Protein phosphatase 1 regulatory inhibitor subunit 16B	gwas
DHX35	HGNC:15861	ENSG00000101452	Q9H5Z1	Probable ATP-dependent RNA helicase DHX35	gwas
SACK1D	HGNC:16122	ENSG00000101447	Q9H4H8	Protein FAM83D	gwas
KIF9	HGNC:16666	ENSG00000088727	Q9HAQ2	Kinesin-like protein KIF9	gwas
NOP14	HGNC:16821	ENSG00000087269	P78316	Nucleolar protein 14	gwas
SLC75A1	HGNC:16894	ENSG00000109736	Q14728	Solute carrier family 75 member 1	gwas
CEP43	HGNC:17012	ENSG00000213066	O95684	Centrosomal protein 43	gwas
SETD2	HGNC:18420	ENSG00000181555	Q9BYW2	Histone-lysine N-methyltransferase SETD2	gwas
NRADDP	HGNC:19337	ENSG00000236409		neurotrophin receptor associated death domain, pseudogene	gwas
NOP14-AS1	HGNC:20205	ENSG00000249673		NOP14 antisense RNA 1	gwas
ADGB	HGNC:21212	ENSG00000118492	Q8N7X0	Androglobin	gwas
RNASET2	HGNC:21686	ENSG00000026297	O00584	Ribonuclease T2	gwas
MINDY4	HGNC:21916	ENSG00000106125	Q4G0A6	Probable ubiquitin carboxyl-terminal hydrolase MINDY-4	gwas
ST8SIA6	HGNC:23317	ENSG00000148488	P61647	Alpha-2,8-sialyltransferase 8F	gwas
MTERF3	HGNC:24258	ENSG00000156469	Q96E29	Transcription termination factor 3, mitochondrial	gwas
ADD1	HGNC:243	ENSG00000087274	P35611	Alpha-adducin	gwas
MTMR10	HGNC:25999	ENSG00000166912	Q9NXD2	Myotubularin-related protein 10	gwas
KIF9-AS1	HGNC:26822	ENSG00000227398		KIF9 antisense RNA 1	gwas
LINC01098	HGNC:27731	ENSG00000231171		long intergenic non-protein coding RNA 1098	gwas
CCDC12	HGNC:28332	ENSG00000160799	Q8WUD4	Coiled-coil domain-containing protein 12	gwas
DHFR	HGNC:2861	ENSG00000228716	P00374	Dihydrofolate reductase	gwas
EFR3A	HGNC:28970	ENSG00000132294	Q14156	Protein EFR3 homolog A	gwas
ATRNL1	HGNC:29063	ENSG00000107518	Q5VV63	Attractin-like protein 1	gwas
KLHL18	HGNC:29120	ENSG00000114648	O94889	Kelch-like protein 18	gwas
FAN1	HGNC:29170	ENSG00000198690	Q9Y2M0	Fanconi-associated nuclease 1	gwas
TENM2	HGNC:29943	ENSG00000145934	Q9NT68	Teneurin-2	gwas
NBEAL2	HGNC:31928	ENSG00000160796	Q6ZNJ1	Neurobeachin-like protein 2	gwas
MTRNR2L2	HGNC:37156		P0CJ69	Humanin-like 2	gwas
MIR3939	HGNC:38931	ENSG00000265828		microRNA 3939	gwas
INMT-MINDY4	HGNC:41995	ENSG00000254959		INMT-MINDY4 readthrough (NMD candidate)	gwas
ST8SIA6-AS1	HGNC:44880	ENSG00000204832		ST8SIA6 antisense RNA 1	gwas
LINC01099	HGNC:49222	ENSG00000251504		long intergenic non-protein coding RNA 1099	gwas
AQP1	HGNC:633	ENSG00000240583	P29972	Aquaporin-1	gwas
TRPM1	HGNC:7146	ENSG00000134160	Q7Z4N2	Transient receptor potential cation channel subfamily M member 1	gwas
MSH3	HGNC:7326	ENSG00000113318	P20585	DNA mismatch repair protein Msh3	gwas
OC90	HGNC:8100	ENSG00000253117	Q02509	Otoconin-90	gwas
OR10A2	HGNC:8161	ENSG00000170790	Q9H208	Olfactory receptor 10A2	gwas
OR2D2	HGNC:8244	ENSG00000166368	Q9H210	Olfactory receptor 2D2	gwas
PTDSS1	HGNC:9587	ENSG00000156471	P48651	Phosphatidylserine synthase 1	gwas
PTPRM	HGNC:9675	ENSG00000173482	P28827	Receptor-type tyrosine-protein phosphatase mu	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC6A4	Sodium-dependent serotonin transporter	Serotonin transporter that cotransports serotonin with one Na(+) ion in exchange for one K(+) ion and possibly one proton in an overall electroneutral transport cycle.
HTT	Huntingtin	May play a role in microtubule-mediated transport or vesicle function.
SLC2A3	Solute carrier family 2, facilitated glucose transporter member 3	Facilitative glucose transporter.
SH3BP2	SH3 domain-binding protein 2	Binds differentially to the SH3 domains of certain proteins of signal transduction pathways.
BRF1	Transcription factor IIIB 90 kDa subunit	General activator of RNA polymerase which utilizes different TFIIIB complexes at structurally distinct promoters.
UQCRB	Cytochrome b-c1 complex subunit 7	Component of the ubiquinol-cytochrome c oxidoreductase, a multisubunit transmembrane complex that is part of the mitochondrial electron transport chain which drives oxidative phosphorylation.
OR10A4	Olfactory receptor 10A4	Odorant receptor (Potential).
OR10A5	Olfactory receptor 10A5	Odorant receptor (Potential).
PPP1R16B	Protein phosphatase 1 regulatory inhibitor subunit 16B	Regulator of protein phosphatase 1 (PP1) that acts as a positive regulator of pulmonary endothelial cell (EC) barrier function.
DHX35	Probable ATP-dependent RNA helicase DHX35	May be involved in pre-mRNA splicing.
SACK1D	Protein FAM83D	Through the degradation of FBXW7, may act indirectly on the expression and downstream signaling of MTOR, JUN and MYC.
KIF9	Kinesin-like protein KIF9	Essential for normal male fertility and for progressive motility of spermatozoa.
NOP14	Nucleolar protein 14	Involved in nucleolar processing of pre-18S ribosomal RNA.
SLC75A1	Solute carrier family 75 member 1	Probable organic anion transporter which may serve as a transporter for some non-steroidal anti-inflammatory drugs (NSAIDs) as well as other organic anions across the luminal membranes of renal proximal tubules at the final excretion step…
CEP43	Centrosomal protein 43	Required for anchoring microtubules to the centrosomes.
SETD2	Histone-lysine N-methyltransferase SETD2	Histone methyltransferase that specifically trimethylates ‘Lys-36’ of histone H3 (H3K36me3) using dimethylated ‘Lys-36’ (H3K36me2) as substrate.
ADGB	Androglobin	Probable chimeric globin with a bis-histidyl six-coordinate heme-iron atom through which it could bind dioxygen, carbon monoxide and nitric oxide.
RNASET2	Ribonuclease T2	Ribonuclease that plays an essential role in innate immune response by recognizing and degrading RNAs from microbial pathogens that are subsequently sensed by TLR8.
MINDY4	Probable ubiquitin carboxyl-terminal hydrolase MINDY-4	Probable hydrolase that can remove ‘Lys-48’-linked conjugated ubiquitin from proteins.
ST8SIA6	Alpha-2,8-sialyltransferase 8F	Alpha-2,8-sialyltransferase that prefers O-glycans to N-glycans or glycolipids as acceptor substrates.
MTERF3	Transcription termination factor 3, mitochondrial	Binds promoter DNA and regulates initiation of transcription.
ADD1	Alpha-adducin	Membrane-cytoskeleton-associated protein that promotes the assembly of the spectrin-actin network.
DHFR	Dihydrofolate reductase	Catalyzes the reduction of 7,8-dihydrofolate (DHF) to 5,6,7,8-tetrahydrofolate in a NADPH-dependent manner.
EFR3A	Protein EFR3 homolog A	Component of a complex required to localize phosphatidylinositol 4-kinase (PI4K) to the plasma membrane.
ATRNL1	Attractin-like protein 1	May play a role in melanocortin signaling pathways that regulate energy homeostasis.
KLHL18	Kelch-like protein 18	Substrate-specific adapter of a BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complex required for mitotic progression and cytokinesis.
FAN1	Fanconi-associated nuclease 1	Nuclease required for the repair of DNA interstrand cross-links (ICL) recruited at sites of DNA damage by monoubiquitinated FANCD2.
TENM2	Teneurin-2	Involved in neural development, regulating the establishment of proper connectivity within the nervous system.
NBEAL2	Neurobeachin-like protein 2	Probably involved in thrombopoiesis.
MTRNR2L2	Humanin-like 2	Plays a role as a neuroprotective and antiapoptotic factor.
AQP1	Aquaporin-1	Forms a water channel that facilitates the transport of water across cell membranes, playing a crucial role in water homeostasis in various tissues.
TRPM1	Transient receptor potential cation channel subfamily M member 1	Constitutively open nonselective divalent cation-conducting channels which mediate the influx of Ca(2+), Mg(2+), Mn(2+), Ba(2+), and Ni(2+) into the cytoplasm, leading to membrane depolarization.
MSH3	DNA mismatch repair protein Msh3	Component of the post-replicative DNA mismatch repair system (MMR).
OC90	Otoconin-90	Major protein of the otoconia, a calcium carbonate structure in the saccule and utricle of the ear.
OR10A2	Olfactory receptor 10A2	Odorant receptor.
OR2D2	Olfactory receptor 2D2	Odorant receptor.
PTDSS1	Phosphatidylserine synthase 1	Catalyzes a base-exchange reaction in which the polar head group of phosphatidylethanolamine (PE) or phosphatidylcholine (PC) is replaced by L-serine.
PTPRM	Receptor-type tyrosine-protein phosphatase mu	Receptor protein-tyrosine phosphatase that mediates homotypic cell-cell interactions and plays a role in adipogenic differentiation via modulation of p120 catenin/CTNND1 phosphorylation.

Protein-family classification

Druggable: 15 · Difficult: 5 · Unknown: 28 · Druggable fraction: 0.31

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
Phosphatase	2	3.5×	0.419
Transporter	2	3.2×	0.419
GPCR	4	2.0×	0.419
Ion channel	1	2.3×	0.541
Scaffold/PPI	4	1.4×	0.541
Enzyme (other)	5	1.2×	0.541
Other/Unknown	28	1.1×	0.541
Protease	1	0.8×	0.828
Transcription factor	1	0.2×	0.998

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC6A4	Other/Unknown	no		Na/ntran_symport, Na/ntran_symport_serotonin_N, SNS_sf
HTT	Other/Unknown	no		Huntingtin, ARM-like, ARM-type_fold
SLC2A3	Transporter	yes		Glc_transpt_3, Sugar/inositol_transpt, MFS_sugar_transport-like
SH3BP2	Scaffold/PPI	no		SH2, PH_domain, PH-like_dom_sf
BRF1	Transcription factor	no		TFIIB, BRF1_TBP-bd_dom, Znf_TFIIB
UQCRB	Enzyme (other)	yes	7.1.1.8	QCR7, QCR7_sf
OR10A4	GPCR	yes		GPCR_Rhodpsn, Olfact_rcpt, GPCR_Rhodpsn_7TM
OR10A5	GPCR	yes		GPCR_Rhodpsn, Olfact_rcpt, GPCR_Rhodpsn_7TM
PPP1R16B	Scaffold/PPI	no		Ankyrin_rpt, Pase-1_reg_su_16AB, Ankyrin_rpt-contain_sf
DHX35	Other/Unknown	no		Helicase_C-like, DNA/RNA_helicase_DEAH_CS, Helicase-assoc_dom
SACK1D	Other/Unknown	no		SACK1, FAM83
KIF9	Other/Unknown	no		Kinesin_motor_dom, Kinesin_motor_CS, P-loop_NTPase
NOP14	Other/Unknown	no		Nop14
SLC75A1	Transporter	yes		MFS, MFS_dom, MFS_trans_sf
CEP43	Other/Unknown	no		LisH, FOP_dimerisation-dom_N
SETD2	Scaffold/PPI	no	2.1.1.359	WW_dom, SET_dom, Post-SET_dom
NRADDP	Other/Unknown	no
NOP14-AS1	Other/Unknown	no
ADGB	Protease	yes		Peptidase_C2_calpain_cat, Globin/Proto, Papain-like_cys_pep_sf
RNASET2	Enzyme (other)	yes	4.6.1.19	RNase_T2-like, RNase_T2_His_AS_1, RNase_T2_His_AS_2
MINDY4	Other/Unknown	no		MINDY-3/4_CD, MINY3/4, MINDY4_N
ST8SIA6	Enzyme (other)	yes	2.4.99.8	Glyco_trans_29, Sialyl_trans, GT29-like_sf
MTERF3	Other/Unknown	no		MTERF, MTERF_sf
ADD1	Other/Unknown	no		Aldolase_II/adducin_N, Aldolase_II/adducin_N_sf, Aldolase-II_Adducin_sf
MTMR10	Phosphatase	yes		Myotubularin-like_Pase_dom, PH-like_dom_sf, MTMR12-like_C
KIF9-AS1	Other/Unknown	no
LINC01098	Other/Unknown	no
CCDC12	Other/Unknown	no		mRNA_splic_Cwf18-like
DHFR	Enzyme (other)	yes	1.5.1.3	DHFR_dom, DHFR, DHFR_CS
EFR3A	Other/Unknown	no		ARM-type_fold, EFR3-like_ARM, EFR3_Homologs
ATRNL1	Other/Unknown	no		EGF, CUB_dom, C-type_lectin-like
KLHL18	Other/Unknown	no		BTB/POZ_dom, Kelch_1, SKP1/BTB/POZ_sf
FAN1	Other/Unknown	no		Rad18_UBZ4, tRNA_endonuc-like_dom_sf, VRR_NUC
TENM2	Other/Unknown	no		EGF, EGF-like_Ca-bd_dom, YD
NBEAL2	Scaffold/PPI	no		BEACH_dom, WD40_rpt, ARM-like
MTRNR2L2	Other/Unknown	no		Humanin
MIR3939	Other/Unknown	no
INMT-MINDY4	Other/Unknown	no
ST8SIA6-AS1	Other/Unknown	no
LINC01099	Other/Unknown	no
AQP1	Other/Unknown	no		MIP, MIP_CS, Aquaporin-like
TRPM1	Ion channel	yes		Ion_trans_dom, TRPM_tetra, TRPM_tetra_sf
MSH3	Other/Unknown	no		DNA_mismatch_repair_MutS_C, DNA_mismatch_repair_MutS-lik_N, DNA_mismatch_repair_MutS_core
OC90	Other/Unknown	no		PLA2, PLA2-like_dom, PLA2_Asp_AS
OR10A2	GPCR	yes		GPCR_Rhodpsn, Olfact_rcpt, GPCR_Rhodpsn_7TM
OR2D2	GPCR	yes		GPCR_Rhodpsn, Olfact_rcpt, GPCR_Rhodpsn_7TM
PTDSS1	Enzyme (other)	yes	2.7.8.29	PSS
PTPRM	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, MAM_dom

Expression context

Cohort genes with no expression data: 1.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	3
moderate (6-20)	2
broad (>20)	42
unknown	1

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	12
sural nerve	7
colonic epithelium	6
primordial germ cell in gonad	6
right uterine tube	5
granulocyte	4
right hemisphere of cerebellum	4
bone marrow cell	4
cortical plate	4
endothelial cell	3
heart right ventricle	3
bronchial epithelial cell	3
gastrocnemius	3
secondary oocyte	3
right lung	2
vena cava	2
monocyte	2
orbitofrontal cortex	2
mucosa of stomach	2
sperm	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC6A4	162	tissue_specific	marker	right lung, jejunal mucosa, ileal mucosa
HTT	208	ubiquitous	marker	sural nerve, body of pancreas, colonic epithelium
SLC2A3	284	ubiquitous	marker	endothelial cell, vena cava, pericardium
SH3BP2	213	ubiquitous	marker	granulocyte, sural nerve, monocyte
BRF1	198	ubiquitous	marker	sural nerve, right uterine tube, right hemisphere of cerebellum
UQCRB	304	ubiquitous	marker	heart right ventricle, vena cava, renal medulla
OR10A4	5		yes	male germ line stem cell (sensu Vertebrata) in testis, bone marrow cell, colonic epithelium
OR10A5	4		yes	male germ line stem cell (sensu Vertebrata) in testis, bone marrow cell, colonic epithelium
PPP1R16B	257	broad	marker	CA1 field of hippocampus, lateral globus pallidus, orbitofrontal cortex
DHX35	216	ubiquitous	marker	lower esophagus muscularis layer, lower esophagus, esophagogastric junction muscularis propria
SACK1D	199	ubiquitous	marker	esophagus squamous epithelium, pharyngeal mucosa, mucosa of stomach
KIF9	255	ubiquitous	marker	bronchial epithelial cell, bronchus, sperm
NOP14	257	ubiquitous	marker	sural nerve, pancreatic ductal cell, gastrocnemius
SLC75A1	270	ubiquitous	marker	right uterine tube, oocyte, right hemisphere of cerebellum
CEP43	278	ubiquitous	marker	sperm, secondary oocyte, tendon of biceps brachii
SETD2	291	ubiquitous	marker	tendon of biceps brachii, endothelial cell, colonic epithelium
NRADDP	130		yes	male germ line stem cell (sensu Vertebrata) in testis, lower esophagus mucosa, esophagus mucosa
NOP14-AS1	183	ubiquitous	marker	cortical plate, granulocyte, mucosa of stomach
ADGB	124	tissue_specific	marker	right uterine tube, bronchial epithelial cell, epithelium of bronchus
RNASET2	291	ubiquitous	marker	right uterine tube, granulocyte, blood
MINDY4	133	ubiquitous	marker	right uterine tube, male germ line stem cell (sensu Vertebrata) in testis, right coronary artery
ST8SIA6	130	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, substantia nigra
MTERF3	286	ubiquitous	marker	oocyte, secondary oocyte, heart right ventricle
ADD1	304	ubiquitous	marker	right hemisphere of cerebellum, nerve, tibial nerve
MTMR10	256	ubiquitous	yes	corpus callosum, inferior vagus X ganglion, spinal cord
KIF9-AS1	163	ubiquitous	yes	sural nerve, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
LINC01098	86		marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, cortical plate
CCDC12	255	ubiquitous	marker	sural nerve, monocyte, leukocyte
DHFR	290	ubiquitous	marker	buccal mucosa cell, ventricular zone, ganglionic eminence
EFR3A	299	ubiquitous	marker	choroid plexus epithelium, endothelial cell, pons

Protein interactions among cohort

Intra-cohort edges: 11.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HTT	13,156
SETD2	4,668
AQP1	4,259
DHFR	4,152
DHX35	2,955
SLC2A3	2,671
NOP14	2,559
UQCRB	2,538
SLC6A4	2,328
MSH3	2,276

Intra-cohort edges

A	B	Sources
CCDC12	KIF9	string_interaction
CCDC12	KLHL18	string_interaction
CCDC12	NBEAL2	string_interaction
CEP43	RNASET2	string_interaction
DHX35	PPP1R16B	string_interaction
FAN1	MTMR10	string_interaction
FAN1	TRPM1	string_interaction
HTT	SETD2	string_interaction
KIF9	KLHL18	string_interaction
MTMR10	TRPM1	string_interaction
PPP1R16B	SACK1D	string_interaction

Structural data

PDB: 22 · AlphaFold-only: 18 · No structure: 8

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DHFR	P00374	89
SETD2	Q9BYW2	43
HTT	P42858	31
SLC6A4	P31645	30
MSH3	P20585	24
FAN1	Q9Y2M0	18
AQP1	P29972	10
SLC2A3	P11169	7
PTDSS1	P48651	6
UQCRB	P14927	5
PTPRM	P28827	5
NOP14	P78316	3
SH3BP2	P78314	2
SACK1D	Q9H4H8	2
CCDC12	Q8WUD4	2
TENM2	Q9NT68	2
KIF9	Q9HAQ2	1
SLC75A1	Q14728	1
CEP43	O95684	1
RNASET2	O00584	1
MTERF3	Q96E29	1
EFR3A	Q14156	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KLHL18	O94889	93.41
OR10A5	Q9H207	89.20
OR10A4	Q9H209	88.56
OR2D2	Q9H210	87.31
DHX35	Q9H5Z1	86.94
OR10A2	Q9H208	86.46
ST8SIA6	P61647	86.04
ATRNL1	Q5VV63	80.91
MTMR10	Q9NXD2	79.94
PPP1R16B	Q96T49	70.73
BRF1	Q92994	70.22
MINDY4	Q4G0A6	68.40
ADGB	Q8N7X0	67.79
TRPM1	Q7Z4N2	66.74
OC90	Q02509	66.43
ADD1	P35611	65.73
MTRNR2L2	P0CJ69	65.49
NBEAL2	Q6ZNJ1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 115. Enrichment computed across 48 evidence-associated genes (28 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 28 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Synthesis of PS	1	203.9×	0.187	PTDSS1
Defective Mismatch Repair Associated With MSH3	1	203.9×	0.187	MSH3
Defective Mismatch Repair Associated With MSH2	1	135.9×	0.187	MSH3
Serotonin clearance from the synaptic cleft	1	102.0×	0.187	SLC6A4
Mismatch Repair	1	102.0×	0.187	MSH3
Diseases of Mismatch Repair (MMR)	1	102.0×	0.187	MSH3
Vitamin C (ascorbate) metabolism	1	51.0×	0.190	SLC2A3
Neurotransmitter clearance	1	45.3×	0.190	SLC6A4
Erythrocytes take up oxygen and release carbon dioxide	1	45.3×	0.190	AQP1
O2/CO2 exchange in erythrocytes	1	45.3×	0.190	AQP1
Tetrahydrobiopterin (BH4) synthesis, recycling, salvage and regulation	1	40.8×	0.190	DHFR
FGFR1 mutant receptor activation	1	40.8×	0.190	CEP43
Mitophagy	1	37.1×	0.190	MTERF3
Mitochondrial mRNA modification	1	37.1×	0.190	MTERF3
Caspase-mediated cleavage of cytoskeletal proteins	1	34.0×	0.190	ADD1
Erythrocytes take up carbon dioxide and release oxygen	1	31.4×	0.190	AQP1
Passive transport by Aquaporins	1	31.4×	0.190	AQP1
rRNA modification in the mitochondrion	1	31.4×	0.190	MTERF3
Expression and translocation of olfactory receptors	4	4.0×	0.190	OR10A4, OR10A5, OR10A2, OR2D2
Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)	1	29.1×	0.193	MSH3
N-Glycan antennae elongation	1	27.2×	0.193	ST8SIA6
Synthesis of PIPs at the early endosome membrane	1	25.5×	0.193	MTMR10
Signaling by cytosolic FGFR1 fusion mutants	1	22.7×	0.193	CEP43
Metabolism of folate and pterines	1	22.7×	0.193	DHFR
Regulation of MITF-M-dependent genes involved in apoptosis	1	22.7×	0.193	TRPM1
MECP2 regulates neuronal receptors and channels	1	21.5×	0.193	SLC2A3
Diseases of DNA repair	1	20.4×	0.193	MSH3
N-glycan antennae elongation in the medial/trans-Golgi	1	20.4×	0.193	ST8SIA6
Cellular hexose transport	1	19.4×	0.193	SLC2A3
IRE1alpha activates chaperones	1	18.5×	0.193	ADD1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 38 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to methotrexate	1	443.5×	0.060	DHFR
metanephric descending thin limb development	1	443.5×	0.060	AQP1
metanephric proximal straight tubule development	1	443.5×	0.060	AQP1
metanephric proximal convoluted tubule segment 2 development	1	443.5×	0.060	AQP1
tRNA transcription	1	221.7×	0.060	BRF1
positive regulation of serotonin secretion	1	221.7×	0.060	SLC6A4
obsolete positive regulation of inositol 1,4,5-trisphosphate-sensitive calcium-release channel activity	1	221.7×	0.060	HTT
carbon dioxide transmembrane transport	1	221.7×	0.060	AQP1
corticotropin secretion	1	221.7×	0.060	AQP1
regulation of podosome assembly	1	221.7×	0.060	KIF9
metanephric glomerulus vasculature development	1	221.7×	0.060	AQP1
regulation of thalamus size	1	221.7×	0.060	SLC6A4
protein localization to mitotic spindle	1	221.7×	0.060	SACK1D
positive regulation of adherens junction organization	1	221.7×	0.060	ADD1
renal water transport	1	147.8×	0.060	AQP1
phosphatidylserine biosynthetic process	1	147.8×	0.060	PTDSS1
negative regulation of cerebellar granule cell precursor proliferation	1	147.8×	0.060	SLC6A4
negative regulation of synaptic transmission, dopaminergic	1	147.8×	0.060	SLC6A4
otolith mineralization	1	147.8×	0.060	OC90
dihydrofolate metabolic process	1	147.8×	0.060	DHFR
positive regulation of saliva secretion	1	147.8×	0.060	AQP1
transcription preinitiation complex assembly	1	147.8×	0.060	BRF1
cellular response to mercury ion	1	147.8×	0.060	AQP1
retrograde trans-synaptic signaling by trans-synaptic protein complex	1	147.8×	0.060	TENM2
positive regulation of mitotic cell cycle phase transition	1	147.8×	0.060	KLHL18
positive regulation of CAMKK-AMPK signaling cascade	1	147.8×	0.060	HTT
regulation of protein localization to chromatin	1	147.8×	0.060	SETD2
mismatch repair	2	34.1×	0.060	SETD2, MSH3
detection of chemical stimulus involved in sensory perception of smell	4	13.0×	0.060	OR10A4, OR10A5, OR10A2, OR2D2
somatic recombination of immunoglobulin gene segments	1	110.9×	0.062	MSH3

Therapeutics

Drugs indicated for this disease

1 approved, 11 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Tetrabenazine	Approved (phase 4)
Creatine	Phase 3 (in late-stage trials)
Dalzanemdor	Phase 3 (in late-stage trials)
Latrepirdine	Phase 3 (in late-stage trials)
Metformin	Phase 3 (in late-stage trials)
Olanzapine	Phase 3 (in late-stage trials)
Pridopidine	Phase 3 (in late-stage trials)
Resveratrol	Phase 3 (in late-stage trials)
Riluzole	Phase 3 (in late-stage trials)
Tominersen	Phase 3 (in late-stage trials)
Ubidecarenone	Phase 3 (in late-stage trials)
Valbenazine	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): ANX-005, Acetylcysteine, Biotin, Bupropion, Cannabidiol, Cannabinol, Epigalocatechin Gallate, Fenofibrate, Laquinimod, Lithium Carbonate, Memantine, Minocycline, Triheptanoin.

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 5 · Undrugged: 43

Druggability breadth: 14 of 48 evidence-associated genes (29%) 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
SLC6A4	CETIRIZINE
HTT	BEPRIDIL
DHFR	TRIMETREXATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC6A4	422	4
HTT	165	4
DHFR	23	4
SETD2	3	2
DHX35	1	2
SLC2A3	0	0
SH3BP2	0	0
BRF1	0	0
UQCRB	0	0
OR10A4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CETIRIZINE	4	SLC6A4
BEPRIDIL	4	HTT, SLC6A4
CLOTRIMAZOLE	4	HTT, SLC6A4
ACETOPHENAZINE	4	SLC6A4
NIRAPARIB	4	SLC6A4
INDACATEROL	4	SLC6A4
IMIPRAMINE	4	SLC6A4
EPINASTINE	4	SLC6A4
ARIPIPRAZOLE	4	SLC6A4
AMOXAPINE	4	SLC6A4
IDARUBICIN	4	HTT, SLC6A4
DESVENLAFAXINE	4	SLC6A4
NORETHINDRONE	4	SLC6A4
PONATINIB	4	SLC6A4
DESLORATADINE	4	SLC6A4
DULOXETINE	4	HTT, SLC6A4
CELECOXIB	4	SLC6A4
UMECLIDINIUM	4	SLC6A4
PALONOSETRON	4	SLC6A4
PHENIRAMINE	4	SLC6A4
VILANTEROL	4	SLC6A4
ESCITALOPRAM OXALATE	4	SLC6A4
TIOCONAZOLE	4	SLC6A4
NEFAZODONE HYDROCHLORIDE	4	SLC6A4
ETHYLESTRENOL	4	SLC6A4
CALCIPOTRIENE	4	SLC6A4
CINACALCET HYDROCHLORIDE	4	SLC6A4
CITALOPRAM HYDROBROMIDE	4	SLC6A4
NORGESTIMATE	4	SLC6A4
VENLAFAXINE HYDROCHLORIDE	4	SLC6A4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 7.

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

Symbol	Assays	Type breakdown
SLC6A4	1,055	Binding:1021, Functional:18, ADMET:9, Toxicity:6, Unclassified:1
DHFR	457	Binding:426, ADMET:16, Functional:12, Toxicity:3
HTT	77	Binding:72, Functional:5
SETD2	64	Binding:64
PTPRM	15	Binding:14, ADMET:1
SLC2A3	11	Binding:10, Functional:1
UQCRB	9	Binding:9
DHX35	8	Binding:8
AQP1	8	Binding:8
KIF9	3	Binding:3
CEP43	2	Binding:2
PTDSS1	2	Binding:2
BRF1	1	Binding:1
SLC75A1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
UQCRB	7.1.1.8	quinol-cytochrome-c reductase
SETD2	2.1.1.359	[histone H3]-lysine36 N-trimethyltransferase
RNASET2	4.6.1.19	ribonuclease T2
ST8SIA6	2.4.99.8	alpha-N-acetylneuraminate alpha-2,8-sialyltransferase
DHFR	1.5.1.3	dihydrofolate reductase
PTDSS1	2.7.8.29	L-serine-phosphatidylethanolamine phosphatidyltransferase
PTPRM	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
SLC6A4	1,055
DHFR	457

Pharmacogenomics

Cohort genes with a PharmGKB record: 41; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
SLC6A4	1

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)
CETIRIZINE	4	SLC6A4
BEPRIDIL	4	HTT, SLC6A4
CLOTRIMAZOLE	4	HTT, SLC6A4
ACETOPHENAZINE	4	SLC6A4
NIRAPARIB	4	SLC6A4
INDACATEROL	4	SLC6A4
IMIPRAMINE	4	SLC6A4
EPINASTINE	4	SLC6A4
ARIPIPRAZOLE	4	SLC6A4
AMOXAPINE	4	SLC6A4
IDARUBICIN	4	HTT, SLC6A4
DESVENLAFAXINE	4	SLC6A4
NORETHINDRONE	4	SLC6A4
PONATINIB	4	SLC6A4
DESLORATADINE	4	SLC6A4
DULOXETINE	4	HTT, SLC6A4
CELECOXIB	4	SLC6A4
UMECLIDINIUM	4	SLC6A4
PALONOSETRON	4	SLC6A4
PHENIRAMINE	4	SLC6A4
VILANTEROL	4	SLC6A4
ESCITALOPRAM OXALATE	4	SLC6A4
TIOCONAZOLE	4	SLC6A4
NEFAZODONE HYDROCHLORIDE	4	SLC6A4
ETHYLESTRENOL	4	SLC6A4
CALCIPOTRIENE	4	SLC6A4
CINACALCET HYDROCHLORIDE	4	SLC6A4
CITALOPRAM HYDROBROMIDE	4	SLC6A4
NORGESTIMATE	4	SLC6A4
VENLAFAXINE HYDROCHLORIDE	4	SLC6A4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	SLC6A4, HTT, DHFR
B	Phased (≥1) drug, not yet approved	2	DHX35, SETD2
C	Druggable family + PDB, no drug	6	SLC2A3, UQCRB, SLC75A1, RNASET2, PTDSS1, PTPRM
D	Druggable family + AlphaFold only, no drug	8	OR10A4, OR10A5, ADGB, ST8SIA6, MTMR10, TRPM1, OR10A2, OR2D2
E	Difficult family or no structure, no drug	29	SH3BP2, BRF1, PPP1R16B, SACK1D, KIF9, NOP14, CEP43, NRADDP, NOP14-AS1, MINDY4 (+19 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SLC2A3	11	—
SH3BP2	0	—
BRF1	1	—
UQCRB	9	—
OR10A4	0	—
OR10A5	0	—
PPP1R16B	0	—
SACK1D	0	—
KIF9	3	—
NOP14	0	—
SLC75A1	1	—
CEP43	2	—
NRADDP	0	—
NOP14-AS1	0	—
ADGB	0	—
RNASET2	0	—
MINDY4	0	—
ST8SIA6	0	—
MTERF3	0	—
ADD1	0	—
MTMR10	0	—
KIF9-AS1	0	—
LINC01098	0	—
CCDC12	0	—
EFR3A	0	—
ATRNL1	0	—
KLHL18	0	—
FAN1	0	—
TENM2	0	—
NBEAL2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 273.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	133
PHASE2	50
PHASE1	38
PHASE1/PHASE2	18
PHASE3	17
PHASE2/PHASE3	7
EARLY_PHASE1	6
PHASE4	4

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00652457	PHASE4	COMPLETED	Study of Memantine to Treat Huntington’s Disease
NCT01834911	PHASE4	COMPLETED	Effect of Tetrabenazine on Stroop Interference in HD
NCT02509793	PHASE4	UNKNOWN	A Pilot Study Assessing Impulsivity in Patients With Huntington’s Disease on Xenazine (Tetrabenazine)
NCT07601516	PHASE4	COMPLETED	Real World Effectiveness and Safety of Deutetrabenazine in Adult Chinese Patients With Huntington’s Disease (HD) Chorea in China
NCT04713982	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Impact of Deutetrabenazine on Functional Speech and Gait Dynamics in Huntington Disease
NCT06873334	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Study of SKY-0515 for Safety, Efficacy, and Pharmacodynamics in Participants With Huntington’s Disease
NCT07326709	PHASE3	RECRUITING	A Study to Investigate the Efficacy, Safety and Tolerability of Votoplam in Participants With Huntington’s Disease
NCT07378644	PHASE2/PHASE3	RECRUITING	Study to Evaluate the Pharmacodynamics, Safety and Efficacy of SKY-0515 in Participants With Huntington’s Disease
NCT07537075	PHASE2/PHASE3	ENROLLING_BY_INVITATION	An Extension of SKY-0515 in Participants With Huntington’s Disease
NCT07609108	PHASE3	NOT_YET_RECRUITING	PRidopidine Phase 3 Study to Establish Clinical Impact and Safety in Huntington’s Disease
NCT00146211	PHASE3	COMPLETED	TREND-HD - A Trial of Ethyl-EPA (Miraxion™) in Treating Mild to Moderate Huntington’s Disease
NCT00219804	PHASE3	COMPLETED	Efficacy and Safety of Tetrabenazine in Chorea
NCT00277355	PHASE2/PHASE3	COMPLETED	Pilot Study of Minocycline in Huntington’s Disease
NCT00277602	PHASE3	COMPLETED	Riluzole in Huntington’s Disease
NCT00608881	PHASE3	TERMINATED	Coenzyme Q10 in Huntington’s Disease (HD)
NCT00632645	PHASE3	COMPLETED	Neuroleptic and Huntington Disease Comparison of : Olanzapine, la Tetrabenazine and Tiapride
NCT00665223	PHASE3	COMPLETED	A Study of Treatment With Pridopidine (ACR16) in Participants With Huntington’s Disease
NCT00712426	PHASE3	TERMINATED	Creatine Safety, Tolerability, & Efficacy in Huntington’s Disease (CREST-E)
NCT00920946	PHASE3	COMPLETED	A Safety and Efficacy Study of Dimebon in Patients With Huntington Disease
NCT01085266	PHASE3	TERMINATED	An Extension of the HORIZON Protocol Evaluating the Safety of Dimebon (Latrepirdine) in Subjects With Huntington Disease
NCT02101957	PHASE2/PHASE3	UNKNOWN	Multicentric Trial of the Treatment of Huntington’s Disease by Cysteamine (RP103)
NCT03842969	PHASE3	COMPLETED	An Open-Label Extension Study to Evaluate Long-Term Safety and Tolerability of RO7234292 (RG6042) in Huntington’s Disease Participants Who Participated in Prior Roche and Genentech Sponsored Studies
NCT03854019	PHASE3	COMPLETED	Evaluating the Efficacy of Dextromethorphan/Quinidine in Treating Irritability in Huntington’s Disease
NCT04219241	PHASE2/PHASE3	UNKNOWN	Clinical Extension Study for Safety and Efficacy Evaluation of Cellavita-HD Administration in Huntington’s Patients.
NCT04556656	PHASE3	COMPLETED	PRidopidine’s Outcome On Function in Huntington Disease, PROOF- HD
NCT04826692	PHASE3	COMPLETED	TEsting METformin Against Cognitive Decline in HD
NCT05655520	PHASE3	TERMINATED	A Study to Evaluate the Safety and Tolerability of SAGE-718 in Participants With Huntington’s Disease
NCT06097780	PHASE3	UNKNOWN	Efficacy and Safety of NestaCell® in Huntington’s Disease
NCT04120493	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Safety and Proof-of-Concept (POC) Study With AMT-130 in Adults With Early Manifest Huntington’s Disease
NCT04478734	PHASE2	RECRUITING	Trial of the Combined Use of Thiamine and Biotin in Patients With Huntington’s Disease
NCT05243017	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Safety and Efficacy of AMT-130 in European Adults With Early Manifest Huntington’s Disease
NCT05509153	PHASE2	RECRUITING	A Randomised Controlled Trial, Of N-Acetyl Cysteine (NAC), for Premanifest Huntingtin Gene Expansion Carriers
NCT05541627	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study to Evaluate AB-1001 Striatal Administration in Adults With Early Manifest Huntington’s Disease
NCT05686551	PHASE2	ACTIVE_NOT_RECRUITING	GENERATION HD2. A Study to Evaluate the Safety, Biomarkers, and Efficacy of Tominersen Compared With Placebo in Participants With Prodromal and Early Manifest Huntington’s Disease
NCT05822908	PHASE1/PHASE2	RECRUITING	A Safety and Pharmacokinetics Trial of VO659 in SCA1, SCA3 and HD
NCT06254482	PHASE2	ACTIVE_NOT_RECRUITING	An Extension Study to Evaluate the Long-Term Safety and Efficacy of Votoplam in Participants With Huntington’s Disease (HD)
NCT06826612	PHASE1/PHASE2	RECRUITING	A Randomized Study of SPK-10001 Gene Therapy in Participants With Huntington’s Disease
NCT06853743	PHASE2	RECRUITING	The NAD-HD Study: A Study to Investigate Efficacy and Safety of Nicotinamide Riboside Compared With Placebo in Huntington’s Disease
NCT07339514	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Phase I Clinical Study of ER2001 Injection for the Treatment of Early Manifest Huntington’s Disease.
NCT07451613	PHASE1/PHASE2	RECRUITING	Safety and Tolerability Study of Human Neural Stem Cells for Huntington’s Disease

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TETRABENAZINE	4	5
ATOMOXETINE	4	3
CITALOPRAM	4	3
DEXTROMETHORPHAN	4	3
MEMANTINE	4	2
MINOCYCLINE	4	2
PHENYLBUTANOIC ACID	4	2
ALPRAZOLAM	4	1
AMANTADINE	4	1
CANNABIDIOL	4	1
DIGOXIN	4	1
DIVALPROEX SODIUM	4	1
FENOFIBRATE	4	1
IDEBENONE	4	1
KETOCONAZOLE	4	1
LEVOKETOCONAZOLE	4	1
OMEPRAZOLE	4	1
RAMELTEON	4	1
RILUZOLE	4	1
TRIHEPTANOIN	4	1
URSODIOL	4	1
LATREPIRDINE	3	13
CREATINE	3	7
PRIDOPIDINE	3	7
DALZANEMDOR	3	4
TOMINERSEN	3	3
UBIDECARENONE	3	3
ANX-005	3	1
LAQUINIMOD	3	1
LITHIUM	3	1