Neurodegenerative disease

disease

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Also known as brain degenerationcentral nervous system degenerative disordercentral nervous system neurodegenerative disordercerebral degeneration diseasedegenerative diseasedegenerative disorder of central nervous system

Summary

Neurodegenerative disease (MONDO:0005559) is a disease (an umbrella term covering 22 Mondo subtypes) with 18 cohort genes and 199 clinical trials. Top therapeutic interventions include dextromethorphan, flortaucipir, and donanemab.

At a glance

Umbrella term: 22 Mondo subtypes
Cohort genes: 18
ClinVar variants: 21
Clinical trials: 199

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neurodegenerative disease
Mondo ID	MONDO:0005559
EFO	EFO:0005772
MeSH	D019636
DOID	DOID:1289
NCIT	C4802
SNOMED CT	80690008
UMLS	C0027746
MedGen	17999
Is cancer (heuristic)	no

Also known as: brain degeneration · central nervous system degenerative disorder · central nervous system neurodegenerative disorder · cerebral degeneration disease · degenerative disease · degenerative disorder of central nervous system

Data availability: 21 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 22 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease

Subtypes (22): synucleinopathy, eyelid degenerative disorder, senile degeneration of brain, olivopontocerebellar atrophy, neuroaxonal dystrophy, demyelinating disease, choroidal sclerosis, tauopathy, secondary Parkinson disease, infantile bilateral striatal necrosis, Marchiafava-Bignami disease, superficial siderosis, primary progressive apraxia of speech, human prion disease, primary progressive freezing gait, primary progressive aphasia, motor neuron disorder, brachial amyotrophic diplegia, cerebellar degeneration, inherited neurodegenerative disorder, cerebral degeneration, hypertrophic olivary degeneration

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

21 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 4 likely pathogenic, 4 conflicting classifications of pathogenicity, 4 pathogenic, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
5107	NM_000199.5(SGSH):c.734G>A (p.Arg245His)	CARD14	Pathogenic	criteria provided, multiple submitters, no conflicts
38378	NM_001288705.3(CSF1R):c.2345G>A (p.Arg782His)	CSF1R	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
39500	NM_183075.3(CYP2U1):c.947A>T (p.Asp316Val)	CYP2U1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
183353	NM_194279.4(ISCA2):c.229G>A (p.Gly77Ser)	ISCA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
374126	NM_001386393.1(PANK2):c.564G>A (p.Met188Ile)	PANK2	Pathogenic	criteria provided, single submitter
374127	NM_001386393.1(PANK2):c.739C>T (p.Arg247Trp)	PANK2	Pathogenic	criteria provided, multiple submitters, no conflicts
30459	NM_000199.5(SGSH):c.892T>C (p.Ser298Pro)	SGSH	Pathogenic	criteria provided, multiple submitters, no conflicts
183341	NM_022786.3(ARV1):c.565G>A (p.Gly189Arg)	ARV1	Likely pathogenic	criteria provided, single submitter
1676224	NM_005022.4(PFN1):c.318_319dup (p.Asp107fs)	PFN1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
183337	NM_016955.4(SEPSECS):c.1028_1120+1del	SEPSECS	Likely pathogenic	no assertion criteria provided
812791	NM_001372044.2(SHANK3):c.1797C>A (p.Cys599Ter)	SHANK3	Likely pathogenic	no assertion criteria provided
374008	NM_001098.3(ACO2):c.76C>T (p.Leu26=)	ACO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
183298	NM_031448.6(C19orf12):c.124G>A (p.Gly42Arg)	C19orf12	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
625211	NM_007325.5(GRIA3):c.2327C>T (p.Thr776Met)	GRIA3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
207418	NM_001032221.6(STXBP1):c.569G>A (p.Arg190Gln)	STXBP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
374006	NM_001098.3(ACO2):c.1397A>C (p.Asn466Thr)	ACO2	Uncertain significance	criteria provided, single submitter
374007	NM_001098.3(ACO2):c.1395G>C (p.Lys465Asn)	ACO2	Uncertain significance	criteria provided, single submitter
374009	NM_001098.3(ACO2):c.75C>T (p.Val25=)	ACO2	Uncertain significance	criteria provided, single submitter
37040	NM_005125.2(CCS):c.487C>T (p.Arg163Trp)	CCS	Uncertain significance	no assertion criteria provided
1693901	NM_018834.6(MATR3):c.499C>T (p.Arg167Trp)	MATR3	Uncertain significance	criteria provided, multiple submitters, no conflicts
1027664	NM_018052.5(VAC14):c.2033C>A (p.Thr678Lys)	VAC14	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · Orphanet: 24 · 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
MMS19	Limited	Autosomal recessive	neurodegenerative disease

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SGSH	Orphanet:79269	Sanfilippo syndrome type A
STXBP1	Orphanet:495818	9q33.3q34.11 microdeletion syndrome
STXBP1	Orphanet:599373	STXBP1-related encephalopathy
ACO2	Orphanet:313850	Infantile cerebellar-retinal degeneration
ACO2	Orphanet:98676	Autosomal recessive isolated optic atrophy
SHANK3	Orphanet:662169	Phelan-McDermid syndrome due to 22q13.3 deletion
SHANK3	Orphanet:662172	Phelan-McDermid syndrome due to SHANK3 mutation
PANK2	Orphanet:216866	Classic pantothenate kinase-associated neurodegeneration
PANK2	Orphanet:216873	Atypical pantothenate kinase-associated neurodegeneration
CARD14	Orphanet:2897	Pityriasis rubra pilaris
ISCA2	Orphanet:457406	Multiple mitochondrial dysfunctions syndrome type 4
CYP2U1	Orphanet:320411	Autosomal recessive spastic paraplegia type 56
CSF1R	Orphanet:313808	Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia
CSF1R	Orphanet:556985	Early-onset calcifying leukoencephalopathy-skeletal dysplasia
C19orf12	Orphanet:289560	Mitochondrial membrane protein-associated neurodegeneration
C19orf12	Orphanet:320370	Autosomal recessive spastic paraplegia type 43
VAC14	Orphanet:3472	Yunis-Varon syndrome
VAC14	Orphanet:497906	Childhood-onset basal ganglia degeneration syndrome
SEPSECS	Orphanet:247198	Progressive cerebello-cerebral atrophy
SEPSECS	Orphanet:2524	Pontocerebellar hypoplasia type 2
GRIA3	Orphanet:364028	X-linked intellectual disability due to GRIA3 mutations
MATR3	Orphanet:600	Vocal cord and pharyngeal distal myopathy
MATR3	Orphanet:803	Amyotrophic lateral sclerosis
PFN1	Orphanet:803	Amyotrophic lateral sclerosis

Cohort genes → proteins

18 cohort genes, 18 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	18

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MMS19	HGNC:13824	ENSG00000155229	Q96T76	MMS19 nucleotide excision repair protein homolog	gencc
SGSH	HGNC:10818	ENSG00000181523	P51688	N-sulphoglucosamine sulphohydrolase	clinvar
STXBP1	HGNC:11444	ENSG00000136854	P61764	Syntaxin-binding protein 1	clinvar
ACO2	HGNC:118	ENSG00000100412	Q99798	Aconitate hydratase, mitochondrial	clinvar
SHANK3	HGNC:14294	ENSG00000251322	Q9BYB0	SH3 and multiple ankyrin repeat domains protein 3	clinvar
PANK2	HGNC:15894	ENSG00000125779	Q9BZ23	Pantothenate kinase 2, mitochondrial	clinvar
CCS	HGNC:1613	ENSG00000173992	O14618	Copper chaperone for superoxide dismutase	clinvar
CARD14	HGNC:16446	ENSG00000141527	Q9BXL6	Caspase recruitment domain-containing protein 14	clinvar
ISCA2	HGNC:19857	ENSG00000165898	Q86U28	Iron-sulfur cluster assembly 2 homolog, mitochondrial	clinvar
CYP2U1	HGNC:20582	ENSG00000155016	Q7Z449	Cytochrome P450 2U1	clinvar
CSF1R	HGNC:2433	ENSG00000182578	P07333	Macrophage colony-stimulating factor 1 receptor	clinvar
C19orf12	HGNC:25443	ENSG00000131943	Q9NSK7	Protein C19orf12	clinvar
VAC14	HGNC:25507	ENSG00000103043	Q08AM6	Protein VAC14 homolog	clinvar
ARV1	HGNC:29561	ENSG00000173409	Q9H2C2	Protein ARV1	clinvar
SEPSECS	HGNC:30605	ENSG00000109618	Q9HD40	O-phosphoseryl-tRNA(Sec) selenium transferase	clinvar
GRIA3	HGNC:4573	ENSG00000125675	P42263	Glutamate receptor 3	clinvar
MATR3	HGNC:6912	ENSG00000015479	P43243	Matrin-3	clinvar
PFN1	HGNC:8881	ENSG00000108518	P07737	Profilin-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MMS19	MMS19 nucleotide excision repair protein homolog	Key component of the cytosolic iron-sulfur protein assembly (CIA) complex, a multiprotein complex that mediates the incorporation of iron-sulfur cluster into apoproteins specifically involved in DNA metabolism and genomic integrity.
SGSH	N-sulphoglucosamine sulphohydrolase	Catalyzes a step in lysosomal heparan sulfate degradation.
STXBP1	Syntaxin-binding protein 1	Participates in the regulation of synaptic vesicle docking and fusion through interaction with GTP-binding proteins.
ACO2	Aconitate hydratase, mitochondrial	Catalyzes the isomerization of citrate to isocitrate via cis-aconitate.
SHANK3	SH3 and multiple ankyrin repeat domains protein 3	Major scaffold postsynaptic density protein which interacts with multiple proteins and complexes to orchestrate the dendritic spine and synapse formation, maturation and maintenance.
PANK2	Pantothenate kinase 2, mitochondrial	Mitochondrial isoform that catalyzes the phosphorylation of pantothenate to generate 4’-phosphopantothenate in the first and rate-determining step of coenzyme A (CoA) synthesis.
CCS	Copper chaperone for superoxide dismutase	Delivers copper to copper zinc superoxide dismutase (SOD1).
CARD14	Caspase recruitment domain-containing protein 14	Acts as a scaffolding protein that can activate the inflammatory transcription factor NF-kappa-B and p38/JNK MAP kinase signaling pathways.
ISCA2	Iron-sulfur cluster assembly 2 homolog, mitochondrial	Involved in the maturation of mitochondrial 4Fe-4S proteins functioning late in the iron-sulfur cluster assembly pathway.
CYP2U1	Cytochrome P450 2U1	A cytochrome P450 monooxygenase involved in the metabolism of arachidonic acid and its conjugates.
CSF1R	Macrophage colony-stimulating factor 1 receptor	Tyrosine-protein kinase that acts as a cell-surface receptor for CSF1 and IL34 and plays an essential role in the regulation of survival, proliferation and differentiation of hematopoietic precursor cells, especially mononuclear phagocytes…
VAC14	Protein VAC14 homolog	Scaffold protein component of the PI(3,5)P2 regulatory complex which regulates both the synthesis and turnover of phosphatidylinositol 3,5-bisphosphate (PtdIns(3,5)P2).
ARV1	Protein ARV1	Plays a role as a mediator in the endoplasmic reticulum (ER) cholesterol and bile acid homeostasis.
SEPSECS	O-phosphoseryl-tRNA(Sec) selenium transferase	Converts O-phosphoseryl-tRNA(Sec) to selenocysteinyl-tRNA(Sec) required for selenoprotein biosynthesis.
GRIA3	Glutamate receptor 3	Ionotropic glutamate receptor that functions as a ligand-gated cation channel, gated by L-glutamate and glutamatergic agonists such as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), quisqualic acid, and kainic acid.
MATR3	Matrin-3	May play a role in transcription or may interact with other nuclear matrix proteins to form the internal fibrogranular network.
PFN1	Profilin-1	Binds to actin and affects the structure of the cytoskeleton.

Protein-family classification

Druggable: 5 · Difficult: 3 · Unknown: 10 · Druggable fraction: 0.28

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	1	4.7×	0.559
Enzyme (other)	3	2.0×	0.559
Scaffold/PPI	2	1.9×	0.559
Kinase	1	1.5×	0.726
Other/Unknown	10	1.0×	0.726
Transcription factor	1	0.5×	0.902

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MMS19	Other/Unknown	no		ARM-like, ARM-type_fold, MMS19_C
SGSH	Phosphatase	yes	3.10.1.1	Sulfatase_N, Alkaline_phosphatase_core_sf, Sulfatase_CS
STXBP1	Other/Unknown	no		Sec1-like, Sec1-like_dom2, Sec1-like_sf
ACO2	Enzyme (other)	yes	4.2.1.3	AconitaseA/IPMdHydase_ssu_swvl, Acoase/IPM_deHydtase_lsu_aba, Aconitase_mito-like
SHANK3	Scaffold/PPI	no		SH3_domain, PDZ, SAM
PANK2	Enzyme (other)	yes	2.7.1.33	Type_II_PanK, ATPase_NBD
CCS	Other/Unknown	no		SOD_Cu_Zn_dom, HMA_dom, SOD_Cu/Zn_BS
CARD14	Scaffold/PPI	no		CARD, PDZ, Guanylate_kin-like_dom
ISCA2	Other/Unknown	no		ATAP_core_dom, ATAP, FeS_cluster_insertion_CS
CYP2U1	Other/Unknown	no		Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_E_grp-I_CYP2D-like
CSF1R	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Tyr_kinase_rcpt_3_CS
C19orf12	Other/Unknown	no		C19orf12
VAC14	Other/Unknown	no		ARM-like, ARM-type_fold, VAC14_Fig4p-bd
ARV1	Other/Unknown	no		Arv1
SEPSECS	Enzyme (other)	yes	2.9.1.2	SepSecS/SepCysS, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase
GRIA3	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt
MATR3	Transcription factor	no		RRM_dom, Matrin/U1-C_Znf_C2H2, Matrin/U1-like-C_Znf_C2H2
PFN1	Other/Unknown	no		Profilin1/2/3_vertebrate, PFN_euk, Profilin_CS

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	18
unknown	0

Top tissues across cohort

Tissue	Cohort genes
left ventricle myocardium	3
cerebellar cortex	2
cerebellar hemisphere	2
right hemisphere of cerebellum	2
Brodmann (1909) area 23	2
middle temporal gyrus	2
endothelial cell	2
monocyte	2
stromal cell of endometrium	2
right lobe of liver	2
cardiac muscle of right atrium	2
epithelial cell of pancreas	2
granulocyte	2
ileal mucosa	2
adrenal cortex	1
left adrenal gland	1
left adrenal gland cortex	1
lateral nuclear group of thalamus	1
apex of heart	1
heart right ventricle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MMS19	286	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
SGSH	272	ubiquitous	marker	left adrenal gland, left adrenal gland cortex, adrenal cortex
STXBP1	287	ubiquitous	marker	middle temporal gyrus, lateral nuclear group of thalamus, Brodmann (1909) area 23
ACO2	291	ubiquitous	marker	heart right ventricle, apex of heart, left ventricle myocardium
SHANK3	246	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
PANK2	282	ubiquitous	marker	endothelial cell, stromal cell of endometrium, monocyte
CCS	278	ubiquitous	marker	right lobe of liver, right ovary, left ovary
CARD14	179	tissue_specific	yes	lower esophagus mucosa, skin of leg, skin of abdomen
ISCA2	257	ubiquitous	marker	left ventricle myocardium, deltoid, cardiac muscle of right atrium
CYP2U1	241	ubiquitous	marker	thymus, germinal epithelium of ovary, epithelial cell of pancreas
CSF1R	245	broad	marker	granulocyte, monocyte, leukocyte
C19orf12	253	ubiquitous	marker	endothelial cell, kidney epithelium, epithelial cell of pancreas
VAC14	233	ubiquitous	marker	stromal cell of endometrium, primordial germ cell in gonad, hindlimb stylopod muscle
ARV1	258	ubiquitous	marker	cardiac muscle of right atrium, myocardium, left ventricle myocardium
SEPSECS	219	ubiquitous	yes	ileal mucosa, male germ line stem cell (sensu Vertebrata) in testis, right lobe of liver
GRIA3	205	broad	marker	Brodmann (1909) area 23, middle temporal gyrus, primary visual cortex
MATR3	135	ubiquitous	marker	cortical plate, corpus callosum, ganglionic eminence
PFN1	289	ubiquitous	marker	granulocyte, mucosa of transverse colon, ileal mucosa

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACO2	4,776
CSF1R	4,392
PFN1	3,926
MATR3	3,804
SHANK3	3,702
STXBP1	3,003
GRIA3	2,380
MMS19	2,359
VAC14	2,357
CARD14	1,902

Intra-cohort edges

A	B	Sources
ACO2	ISCA2	string_interaction
C19orf12	PANK2	string_interaction
GRIA3	STXBP1	string_interaction

Structural data

PDB: 9 · AlphaFold-only: 9 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CSF1R	P07333	26
PFN1	P07737	22
CCS	O14618	7
SEPSECS	Q9HD40	7
SHANK3	Q9BYB0	3
SGSH	P51688	2
STXBP1	P61764	1
PANK2	Q9BZ23	1
VAC14	Q08AM6	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACO2	Q99798	95.44
MMS19	Q96T76	91.00
CYP2U1	Q7Z449	88.45
GRIA3	P42263	83.98
ARV1	Q9H2C2	82.17
ISCA2	Q86U28	77.98
CARD14	Q9BXL6	75.89
C19orf12	Q9NSK7	59.50
MATR3	P43243	57.64

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 59. Enrichment computed across 18 evidence-associated genes (14 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 14 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Metabolism	7	5.8×	0.004	SGSH, STXBP1, ACO2, MMS19, ISCA2, ARV1, SEPSECS
Maturation of TCA enzymes and regulation of TCA cycle	2	81.6×	0.008	ACO2, ISCA2
Citric acid cycle (TCA cycle)	2	60.4×	0.009	ACO2, ISCA2
MPS IIIA - Sanfilippo syndrome A	1	815.7×	0.014	SGSH
Defective CYP2U1 causes SPG56	1	815.7×	0.014	CYP2U1
Activation of AMPA receptors	1	203.9×	0.048	GRIA3
Mucopolysaccharidoses	1	135.9×	0.056	SGSH
Coenzyme A biosynthesis	1	102.0×	0.056	PANK2
Synthesis of (16-20)-hydroxyeicosatetraenoic acids (HETE)	1	90.6×	0.056	CYP2U1
Cholesterol biosynthesis	1	81.6×	0.056	ARV1
Synthesis of PIPs at the late endosome membrane	1	68.0×	0.056	VAC14
Miscellaneous substrates	1	68.0×	0.056	CYP2U1
Mitochondrial iron-sulfur cluster biogenesis	1	58.3×	0.056	ISCA2
Diseases of carbohydrate metabolism	1	58.3×	0.056	SGSH
Cytosolic iron-sulfur cluster assembly	1	54.4×	0.056	MMS19
Synthesis of PIPs at the early endosome membrane	1	51.0×	0.056	VAC14
Acetylcholine Neurotransmitter Release Cycle	1	48.0×	0.056	STXBP1
Trafficking of GluR2-containing AMPA receptors	1	48.0×	0.056	GRIA3
Synthesis of PIPs at the Golgi membrane	1	45.3×	0.056	VAC14
Serotonin Neurotransmitter Release Cycle	1	45.3×	0.056	STXBP1
Norepinephrine Neurotransmitter Release Cycle	1	45.3×	0.056	STXBP1
GABA synthesis, release, reuptake and degradation	1	45.3×	0.056	STXBP1
Heparan sulfate/heparin (HS-GAG) metabolism	1	38.8×	0.056	SGSH
Trafficking of AMPA receptors	1	38.8×	0.056	GRIA3
Unblocking of NMDA receptors, glutamate binding and activation	1	38.8×	0.056	GRIA3
Synaptic adhesion-like molecules	1	38.8×	0.056	GRIA3
Aerobic respiration and respiratory electron transport	2	12.7×	0.056	ACO2, ISCA2
HS-GAG degradation	1	35.5×	0.057	SGSH
Dopamine Neurotransmitter Release Cycle	1	35.5×	0.057	STXBP1
Other interleukin signaling	1	34.0×	0.057	CSF1R

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 18 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of actin filament bundle assembly	2	312.1×	0.003	SHANK3, PFN1
protein maturation	3	27.3×	0.015	MMS19, CCS, ISCA2
regulation of plasma membrane sterol distribution	1	936.2×	0.030	ARV1
obsolete positive regulation of vesicle docking	1	936.2×	0.030	STXBP1
regulation of acrosomal vesicle exocytosis	1	936.2×	0.030	STXBP1
conversion of seryl-tRNAsec to selenocys-tRNAsec	1	468.1×	0.030	SEPSECS
guanylate kinase-associated protein clustering	1	468.1×	0.030	SHANK3
positive regulation of glutamate secretion, neurotransmission	1	468.1×	0.030	STXBP1
axon target recognition	1	312.1×	0.030	STXBP1
forebrain neuron differentiation	1	312.1×	0.030	CSF1R
macrophage colony-stimulating factor signaling pathway	1	312.1×	0.030	CSF1R
positive regulation of synapse structural plasticity	1	312.1×	0.030	SHANK3
obsolete regulation of bile acid metabolic process	1	312.1×	0.030	PANK2
citrate metabolic process	1	234.1×	0.030	ACO2
striatal medium spiny neuron differentiation	1	234.1×	0.030	SHANK3
negative regulation of synaptic transmission, GABAergic	1	234.1×	0.030	STXBP1
regulation of intracellular cholesterol transport	1	234.1×	0.030	ARV1
presynaptic dense core vesicle exocytosis	1	234.1×	0.030	STXBP1
regulation of macrophage migration	1	234.1×	0.030	CSF1R
platelet degranulation	1	187.2×	0.030	STXBP1
developmental process involved in reproduction	1	187.2×	0.030	STXBP1
intracellular sterol transport	1	187.2×	0.030	ARV1
cellular response to macrophage colony-stimulating factor stimulus	1	187.2×	0.030	CSF1R
negative regulation of cell volume	1	187.2×	0.030	SHANK3
AMPA glutamate receptor clustering	1	187.2×	0.030	SHANK3
NMDA glutamate receptor clustering	1	187.2×	0.030	SHANK3
positive regulation of macrophage proliferation	1	187.2×	0.030	CSF1R
regulation of long-term synaptic depression	1	187.2×	0.030	SHANK3
cytochrome metabolic process	1	187.2×	0.030	CYP2U1
positive regulation of protein phosphorylation	2	30.7×	0.030	CARD14, CSF1R

Therapeutics

Drugs indicated for this disease

0 approved, 2 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Latozinemab	Phase 3 (in late-stage trials)
Pimavanserin	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Dextromethorphan, Niacinamide.

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 4 · Undrugged: 14

Druggability breadth: 9 of 18 evidence-associated genes (50%) 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
CYP2U1	PAZOPANIB
CSF1R	PONATINIB
GRIA3	PERAMPANEL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CSF1R	79	4
GRIA3	7	4
CYP2U1	1	4
MATR3	1	2
MMS19	0	0
SGSH	0	0
STXBP1	0	0
ACO2	0	0
SHANK3	0	0
PANK2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PAZOPANIB	4	CSF1R, CYP2U1
PONATINIB	4	CSF1R
FEDRATINIB	4	CSF1R
AXITINIB	4	CSF1R
SORAFENIB	4	CSF1R
DASATINIB ANHYDROUS	4	CSF1R
SUNITINIB MALATE	4	CSF1R
NERATINIB	4	CSF1R
IBRUTINIB	4	CSF1R
ENTRECTINIB	4	CSF1R
PACRITINIB	4	CSF1R
VANDETANIB	4	CSF1R
NILOTINIB	4	CSF1R
BOSUTINIB	4	CSF1R
FILGOTINIB	4	CSF1R
BRIGATINIB	4	CSF1R
PEXIDARTINIB	4	CSF1R
NINTEDANIB	4	CSF1R
SUNITINIB	4	CSF1R
DASATINIB	4	CSF1R
QUIZARTINIB	4	CSF1R
CRIZOTINIB	4	CSF1R
MIDOSTAURIN	4	CSF1R
IMATINIB	4	CSF1R
PERAMPANEL	4	GRIA3
CYCLOTHIAZIDE	4	GRIA3
VATALANIB	3	CSF1R
DACTOLISIB	3	CSF1R
MASITINIB	3	CSF1R
LINIFANIB	3	CSF1R

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 5.

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

Symbol	Assays	Type breakdown
CSF1R	897	Binding:879, Functional:17, ADMET:1
CYP2U1	183	ADMET:181, Binding:2
GRIA3	126	Binding:113, Functional:13
MATR3	7	Binding:7
MMS19	1	Binding:1
STXBP1	1	Binding:1
PANK2	1	Binding:1
VAC14	1	Binding:1
PFN1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SGSH	3.10.1.1	N-sulfoglucosamine sulfohydrolase
ACO2	4.2.1.3	aconitate hydratase
PANK2	2.7.1.33	pantothenate kinase
CSF1R	2.7.10.1	receptor protein-tyrosine kinase
SEPSECS	2.9.1.2	O-phospho-L-seryl-tRNASec:L-selenocysteinyl-tRNA synthase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CYP2U1	183
CSF1R	897
GRIA3	126

Pharmacogenomics

Cohort genes with a PharmGKB record: 18; 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)
PAZOPANIB	4	CSF1R, CYP2U1
PONATINIB	4	CSF1R
FEDRATINIB	4	CSF1R
AXITINIB	4	CSF1R
SORAFENIB	4	CSF1R
DASATINIB ANHYDROUS	4	CSF1R
SUNITINIB MALATE	4	CSF1R
NERATINIB	4	CSF1R
IBRUTINIB	4	CSF1R
ENTRECTINIB	4	CSF1R
PACRITINIB	4	CSF1R
VANDETANIB	4	CSF1R
NILOTINIB	4	CSF1R
BOSUTINIB	4	CSF1R
FILGOTINIB	4	CSF1R
BRIGATINIB	4	CSF1R
PEXIDARTINIB	4	CSF1R
NINTEDANIB	4	CSF1R
SUNITINIB	4	CSF1R
DASATINIB	4	CSF1R
QUIZARTINIB	4	CSF1R
CRIZOTINIB	4	CSF1R
MIDOSTAURIN	4	CSF1R
IMATINIB	4	CSF1R
PERAMPANEL	4	GRIA3
CYCLOTHIAZIDE	4	GRIA3
VATALANIB	3	CSF1R
DACTOLISIB	3	CSF1R
MASITINIB	3	CSF1R
LINIFANIB	3	CSF1R

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	CYP2U1, CSF1R, GRIA3
B	Phased (≥1) drug, not yet approved	1	MATR3
C	Druggable family + PDB, no drug	3	SGSH, PANK2, SEPSECS
D	Druggable family + AlphaFold only, no drug	1	ACO2
E	Difficult family or no structure, no drug	10	MMS19, STXBP1, SHANK3, CCS, CARD14, ISCA2, C19orf12, VAC14, ARV1, PFN1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MMS19	1	—
SGSH	0	—
STXBP1	1	—
ACO2	0	—
SHANK3	0	—
PANK2	1	—
CCS	0	—
CARD14	0	—
ISCA2	0	—
C19orf12	0	—
VAC14	1	—
ARV1	0	—
SEPSECS	0	—
PFN1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 199.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	158
PHASE2	14
PHASE1	10
PHASE3	4
PHASE1/PHASE2	4
EARLY_PHASE1	4
PHASE4	3
PHASE2/PHASE3	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05357612	PHASE4	RECRUITING	Characterization of the Serotonin 2A Receptor Selective PET Tracer [18F]MH.MZ in Patients With Neurodegenerative Diseases
NCT01662414	PHASE4	COMPLETED	Effect of Undenatured Cysteine-Rich Whey Protein Isolate (HMS 90®) in Patients With Parkinson’s Disease
NCT04871464	PHASE4	UNKNOWN	Role and Mechanism of Probiotics in Improving Motor Symptoms in Mild to Moderate Parkinson’s Disease
NCT03143374	PHASE2/PHASE3	RECRUITING	PET Tau - Neurodegenerative Disease Imaging
NCT05508789	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Donanemab (LY3002813) in Participants With Early Symptomatic Alzheimer’s Disease (TRAILBLAZER-ALZ 5)
NCT05738486	PHASE3	ACTIVE_NOT_RECRUITING	A Study of Different Donanemab (LY3002813) Dosing Regimens in Adults With Early Alzheimer’s Disease (TRAILBLAZER-ALZ 6)
NCT06672237	PHASE3	RECRUITING	A Phase 3 Study of NTLA-2001 in ATTRv-PN
NCT06111014	PHASE3	TERMINATED	Continuation Study for Latozinemab
NCT06122662	PHASE2/PHASE3	COMPLETED	AMX0035 and Progressive Supranuclear Palsy
NCT04838301	PHASE2	RECRUITING	Allopregnanolone Regenerative Therapeutic for Mild Alzheimer’s Disease
NCT06934720	PHASE1/PHASE2	NOT_YET_RECRUITING	VR-based Physical Activity and Reminiscence Therapy
NCT00001365	PHASE2	COMPLETED	Dextromethorphan for the Treatment of Parkinson’s Disease and Similar Conditions of the Nervous System
NCT00406029	PHASE2	COMPLETED	Dyskinesia in Parkinson’s Disease (Study P04501)
NCT00537017	PHASE2	COMPLETED	Follow Up Safety Study of SCH 420814 in Subjects With Parkinson’s Disease (P05175)
NCT00907283	PHASE2	UNKNOWN	Ferrochelating Treatment in Patients Affected by Neurodegeneration With Brain Iron Accumulation (NBIA)
NCT01518374	PHASE2	COMPLETED	Clinical Evaluation of Florbetapir F 18 (18F-AV-45)
NCT02656498	PHASE2	COMPLETED	[18F]THK-5351 Positron Emission Computed Tomography Study of Normal, Mild Cognitive Impairment, Alzheimer’s Disease and Other Neurodegenerative Disease
NCT03127514	PHASE2	COMPLETED	AMX0035 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT03295786	PHASE1/PHASE2	COMPLETED	Clinical Study to Test the Safety of CDNF by Brain Infusion in Patients With Parkinson’s Disease
NCT03538522	PHASE2	COMPLETED	A Double-Blind, Placebo-Controlled Safety and Efficacy Study of NA-831
NCT04937452	PHASE2	COMPLETED	Dopaminergic Therapy for Frontotemporal Dementia Patients
NCT05318976	PHASE2	COMPLETED	A Study of XPro1595 in Patients With Early Alzheimer’s Disease With Biomarkers of Inflammation
NCT05321498	PHASE2	WITHDRAWN	Study to Assess the Efficacy of XPro1595 in Patients With Mild Cognitive Impairment With Biomarkers of Inflammation
NCT05479981	PHASE2	COMPLETED	Extension of AOC 1001-CS1 (MARINA) Study in Adult Myotonic Dystrophy Type 1 (DM1) Patients
NCT05522387	PHASE2	TERMINATED	An Open-Label Extension of XPro1595 in Patients With Alzheimer’s Disease
NCT05853471	PHASE1/PHASE2	UNKNOWN	[18F]MC225-PET in Neurodegenerative Disease
NCT06447194	PHASE1/PHASE2	WITHDRAWN	Effect of RECK in Posterior Spinal Fusion
NCT07232147	PHASE1	NOT_YET_RECRUITING	Clinical Research on Stem Cell Therapy for Parkinson’s Disease
NCT00316797	PHASE1	COMPLETED	Biodistribution and Safety of a Radiopharmaceutical in Healthy Subjects
NCT01758510	PHASE1	COMPLETED	Safety Study of HLA-haplo Matched Allogenic Bone Marrow Derived Stem Cell Treatment in Amyotrophic Lateral Sclerosis
NCT02267434	PHASE1	COMPLETED	Study Assessing Tolerability and Safety of AFFITOPE® PD03A in Patients With Early Parkinson’s Disease
NCT02270489	PHASE1	COMPLETED	Study Assessing Safety and Therapeutic Activity of AFFITOPE® PD01A and PD03A in Patients With Early MSA
NCT03065192	PHASE1	COMPLETED	Safety and Efficacy Study of VY-AADC01 for Advanced Parkinson’s Disease
NCT04578028	PHASE1	COMPLETED	A First in Human Study to Assess the Safety, Tolerability and Pharmacokinetics of ONO-2808-01 in Healthy Participants
NCT05143463	PHASE1	COMPLETED	A FIH Study to Assess the Safety and Tolerability of NS Intravenous NS101 Infusion
NCT05490576	PHASE1	UNKNOWN	Tau And Connectomics In TES Study
NCT05792163	PHASE1	COMPLETED	A First Time in Human Study of SNP318 as a Treatment for Neurodegenerative Diseases Including Alzheimer’s Disease
NCT06181513	EARLY_PHASE1	RECRUITING	Probiotics in Mild Alzheimer’s Disease
NCT07470710	EARLY_PHASE1	NOT_YET_RECRUITING	Study on the Application of ¹⁸F-FCOB04, a MAO-B Targeted PET Imaging Agent, in Neurodegenerative Diseases
NCT02452216	EARLY_PHASE1	COMPLETED	Using Ferumoxytol-Enhanced MRI to Measure Inflammation in Patients With Brain Tumors or Other Conditions of the CNS

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DEXTROMETHORPHAN	4	3
FLORTAUCIPIR	4	3
DONANEMAB	4	2
FLORBETAPIR F 18	4	2
LEVODOPA	4	2
BREXANOLONE	4	1
DEFERIPRONE	4	1
DEXAMETHASONE	4	1
FERUMOXYTOL	4	1
FLORBETABEN F18	4	1
IOFLUPANE I 123	4	1
PIMAVANSERIN	4	1
ROTIGOTINE	4	1
CITICOLINE	3	2
PRELADENANT	3	2
CHAMOMILE	3	1
CROCIN	3	1
LATOZINEMAB	3	1
LEUCINE	3	1
NICOTINAMIDE RIBOSIDE	3	1
PEGIPANERMIN	2	3
ELTANOLONE	2	1
INTERLEUKIN-10	2	1
ISOXAFLUTOLE	2	1
NEXIGURAN	2	1
ZICLUMERAN	2	1
CHEMBL38856	0	1
CHEMBL104383	0	1
APIGENIN	0	1
TNF-ALPHA	0	1

Cohort genes: MMS19, SGSH, STXBP1, ACO2, SHANK3, PANK2, CCS, CARD14, ISCA2, CYP2U1, CSF1R, C19orf12, VAC14, ARV1, SEPSECS, GRIA3, MATR3, PFN1
Drugs: Dextromethorphan, Flortaucipir, Donanemab, FLORBETAPIR F 18, Levodopa, Brexanolone, Deferiprone, Dexamethasone, Ferumoxytol, FLORBETABEN F18, IOFLUPANE I 123, Pimavanserin, Rotigotine, Citicoline, Preladenant, Chamomile, Crocin, Latozinemab, Nicotinamide Riboside
Associated genes: IRF2BPL