Amyotrophic lateral sclerosis

Summary

Amyotrophic lateral sclerosis (MONDO:0004976) is a disease caused by FUS (GenCC Definitive), with 75 cohort genes (169 GWAS associations across 40 studies) and 927 clinical trials. The dominant Reactome pathway is Highly sodium permeable postsynaptic acetylcholine nicotinic receptors (3 cohort genes). Top therapeutic interventions include riluzole, arimoclomol, and edaravone.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: FUS (GenCC Definitive)
• Cohort genes: 75
• GWAS associations: 169
• ClinVar variants: 182
• Phenotypes (HPO): 47
• Clinical trials: 927

Clinical features

Epidemiology

Prevalence records

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

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	2.2	Europe	Validated
Point prevalence	1-9 / 100 000	5.2	Europe	Validated
Annual incidence	1-9 / 100 000	1.06	United Kingdom	Validated
Annual incidence	1-9 / 100 000	2.1	Ireland	Validated
Annual incidence	1-9 / 100 000	2.4	Finland	Validated
Annual incidence	1-9 / 100 000	1.46	United States	Validated
Annual incidence	1-9 / 100 000	1.37	Uruguay	Validated
Annual incidence	1-9 / 100 000	1.4	Denmark	Validated
Annual incidence	1-9 / 100 000	3	Italy	Validated
Annual incidence	1-9 / 100 000	2	France	Validated
Annual incidence	1-9 / 100 000	1.4	Spain	Validated
Annual incidence	1-9 / 100 000	2.2	Norway	Validated
Annual incidence	1-9 / 1 000 000	0.51	Taiwan, Province of China	Validated
Annual incidence	1-9 / 100 000	2.6	Faroe Islands	Validated
Annual incidence	1-9 / 1 000 000	0.42	Iran, Islamic Republic of	Validated
Annual incidence	1-9 / 100 000	2.5	Specific population	Validated
Annual incidence	1-9 / 100 000	1.4	Specific population	Validated
Point prevalence	1-9 / 100 000	4.9	United Kingdom	Validated
Point prevalence	1-9 / 100 000	4.7	Ireland	Validated
Point prevalence	1-9 / 100 000	6.4	Finland	Validated

Signs & symptoms

Clinical features (HPO)

47 HPO clinical features (Orphanet curated; top 47 by frequency):

HPO ID	Term	Frequency
HP:0007354	Amyotrophic lateral sclerosis	Obligate (100%)
HP:0002180	Neurodegeneration	Very frequent (80-99%)
HP:0003324	Generalized muscle weakness	Very frequent (80-99%)
HP:0007373	Motor neuron atrophy	Very frequent (80-99%)
HP:0000217	Xerostomia	Frequent (30-79%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0000712	Emotional lability	Frequent (30-79%)
HP:0000716	Depression	Frequent (30-79%)
HP:0000739	Anxiety	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0001618	Dysphonia	Frequent (30-79%)
HP:0001824	Weight loss	Frequent (30-79%)
HP:0002015	Dysphagia	Frequent (30-79%)
HP:0002094	Dyspnea	Frequent (30-79%)
HP:0002307	Drooling	Frequent (30-79%)
HP:0002380	Fasciculations	Frequent (30-79%)
HP:0002878	Respiratory failure	Frequent (30-79%)
HP:0003202	Skeletal muscle atrophy	Frequent (30-79%)
HP:0003394	Muscle spasm	Frequent (30-79%)
HP:0003470	Paralysis	Frequent (30-79%)
HP:0003484	Upper limb muscle weakness	Frequent (30-79%)
HP:0003487	Babinski sign	Frequent (30-79%)
HP:0003693	Distal amyotrophy	Frequent (30-79%)
HP:0007340	Lower limb muscle weakness	Frequent (30-79%)
HP:0008955	Progressive distal muscular atrophy	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0012473	Tongue atrophy	Frequent (30-79%)
HP:0012531	Pain	Frequent (30-79%)
HP:0030192	Fatigable weakness of bulbar muscles	Frequent (30-79%)
HP:0030195	Fatigable weakness of swallowing muscles	Frequent (30-79%)
HP:0030196	Fatigable weakness of respiratory muscles	Frequent (30-79%)
HP:0030878	Abnormality on pulmonary function testing	Frequent (30-79%)
HP:0031993	Hoffmann sign	Frequent (30-79%)
HP:0100543	Cognitive impairment	Frequent (30-79%)
HP:0001308	Tongue fasciculations	Occasional (5-29%)
HP:0002145	Frontotemporal dementia	Occasional (5-29%)
HP:0002313	Spastic paraparesis	Occasional (5-29%)
HP:0002360	Sleep abnormality	Occasional (5-29%)
HP:0002463	Language impairment	Occasional (5-29%)
HP:0003376	Steppage gait	Occasional (5-29%)
HP:0004326	Cachexia	Occasional (5-29%)
HP:0009027	Foot dorsiflexor weakness	Occasional (5-29%)
HP:0012764	Orthopnea	Occasional (5-29%)
HP:0033683	Jaw hyperreflexia	Occasional (5-29%)
HP:0025425	Laryngospasm	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	amyotrophic lateral sclerosis
Mondo ID	MONDO:0004976
MeSH	D000690
Orphanet	803
DOID	DOID:332
ICD-10-CM	G12.21
ICD-11	1982355687
NCIT	C34373
SNOMED CT	86044005
UMLS	C0002736
MedGen	274
GARD	0005786
MedDRA	10002026
NORD	768
Is cancer (heuristic)	no

Also known as: ALS · amyotrophic lateral sclerosis · Charcot disease · Lou Gehrig disease

Data availability: 182 ClinVar variants · 169 GWAS associations (40 studies) · 48 GenCC gene-disease records · 1 HPO phenotype · 2,122 cell lines.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › spinal cord disorder › anterior horn disorder › amyotrophic lateral sclerosis

Related subtypes (2): spinal muscular atrophy, poliomyelitis

Subtypes (4): familial amyotrophic lateral sclerosis, sporadic amyotrophic lateral sclerosis, amyotrophic lateral sclerosis with polyglucosan bodies, progressive muscular atrophy

Genetics & variants

GWAS landscape

169 GWAS associations across 40 studies. Top hits map to 30 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs2453555	1e-43	C9orf72	A	0.17
rs3849943	4e-30	C9orf72, EMICERI	?	1.19
rs12608932	3e-25	UNC13A	C	0.12
rs80265967	4e-18	SOD1	C	1.08
rs7019351	3e-15	MOB3B	A
rs12973192	4e-15	UNC13A	?	1.12
rs229195	9e-15	G2E3, G2E3-AS1	A	0.09
rs229194	9e-15	G2E3, G2E3-AS1	A	0.09
rs75087725	2e-14	CFAP410	?	1.67
rs12145183	2e-14	TYW3 - LHX8	?	1.55
rs113247976	7e-13	KIF5A	?	1.39
rs8141797	1e-12	SUSD2	?	1.57
rs631312	3e-12	MOBP	G	0.08
rs9275477	4e-12	HLA-DQB1 - MTCO3P1	C	0.14
rs562331457	1e-11	GLG1	G	3.01
rs527757240	2e-11	LINC03062 - MIR4290HG	A	2.69
rs185989172	2e-11	HMGB1	C	4.62
rs181900403	2e-11	TUBAP15 - RNU6-718P	G	2.28
rs141836498	2e-11	CADM1	G	2.55
rs554823684	2e-11	RNU1-98P - NEK4P1	G	3.11
chr9:133154147	2e-11		?	44.7
rs557852210	3e-11	LINC02490	C	3.04
rs3849942	5e-11	EMICERI; C9orf72; C9orf72	G
rs141805452	5e-11	ZC3H14	G	2.17
rs3736947	8e-11	ACSL5	C	1.09
rs17785991	3e-10	SLC9A8	A	0.07
rs10463311	3e-10	TNIP1	C	0.08
rs616147	4e-10	MOBP	?	1.1
rs58854276	7e-10	ACSL5	A	0.06
rs4075094	2e-09	TBK1	A	0.1

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90027163	van Rheenen W	2021	27,205	110,881	Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology.
GCST90027164	van Rheenen W	2021	27,205	110,881	Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology.
GCST90013429	Iacoangeli A	2020	22,040	62,644	Genome-wide Meta-analysis Finds the ACSL5-ZDHHC6 Locus Is Associated with ALS and Links Weight Loss to the Disease Genetics.
GCST005647	Nicolas A	2018	20,806	59,804	Genome-wide Analyses Identify KIF5A as a Novel ALS Gene.
GCST90833053	Hop PJ	2026	13,138	69,775	Large-scale exome analyses reveal new rare variant contributions in amyotrophic lateral sclerosis.
GCST005321	Broce I	2018	12,577	23,475	Immune-related genetic enrichment in frontotemporal dementia: An analysis of genome-wide association studies.
GCST004692	van Rheenen W	2016	12,577	23,475	Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis.
GCST004252	McLaughlin RL	2017	10,147	22,094	Genetic correlation between amyotrophic lateral sclerosis and schizophrenia.
GCST90271545	Vasilopoulou C	2023	9,244	12,795	Genome-Wide Gene-Set Analysis Identifies Molecular Mechanisms Associated with ALS.
GCST000820	Shatunov A	2010	4,857	8,987	Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	4
Tier 2: splice/UTR	1
Tier 3: regulatory	0
Tier 4: intronic/intergenic	45

MAF distribution

Bucket	Variants
common (>=0.05)	33
low_freq (0.01-0.05)	2
rare (<0.01)	10
unknown	5

Functional consequences

Consequence	Count
intron_variant	28
intergenic_variant	8
unknown	5
missense_variant	4
non_coding_transcript_exon_variant	3
3_prime_UTR_variant	1
non_coding_transcript_exon_variant; synonymous_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs2453555	9	27563870	G>A	0.248	intron_variant	C9orf72	1e-43	Tier 4: intronic/intergenic
rs3849943	9	27543384	C>A,G,T	0.236	non_coding_transcript_exon_variant	C9orf72, EMICERI	4e-30	Tier 4: intronic/intergenic
rs12608932	19	17641880	A>C,T	0.05	intron_variant	UNC13A	3e-25	Tier 4: intronic/intergenic
rs80265967	21	31667290	A>C,T	0.006	missense_variant	SOD1	4e-18	Tier 1: coding
rs7019351	9	27491264	A>C,T	0.235	intron_variant	MOB3B	3e-15	Tier 4: intronic/intergenic
rs12973192	19	17642430	C>G,T	0.32	intron_variant	UNC13A	4e-15	Tier 4: intronic/intergenic
rs229195	14	30576390	G>A,C	0.337	intron_variant	G2E3, G2E3-AS1	9e-15	Tier 4: intronic/intergenic
rs229194	14	30575975	G>A,C,T	0.337	intron_variant	G2E3, G2E3-AS1	9e-15	Tier 4: intronic/intergenic
rs75087725	21	44333234	C>A	0.008	missense_variant	CFAP410	2e-14	Tier 1: coding
rs12145183	1	74806796	G>A,C	0.05	intergenic_variant	TYW3 - LHX8	2e-14	Tier 4: intronic/intergenic
rs113247976	12	57581917	C>G,T	0.015	missense_variant	KIF5A	7e-13	Tier 1: coding
rs8141797	22	24186073	A>G,T	0.05	missense_variant	SUSD2	1e-12	Tier 1: coding
rs631312	3	39467477	G>A,C,T	0.05	intergenic_variant	MOBP	3e-12	Tier 4: intronic/intergenic
rs9275477	6	32704864	A>C	0.05	intergenic_variant	HLA-DQB1 - MTCO3P1	4e-12	Tier 4: intronic/intergenic
rs562331457	16	74447619	G>T	0.001	3_prime_UTR_variant	GLG1	1e-11	Tier 2: splice/UTR
rs527757240	9	89930664	A>G	0.001	intron_variant	LINC03062 - MIR4290HG	2e-11	Tier 4: intronic/intergenic
rs185989172	13	30491089	C>T	0	intron_variant	HMGB1	2e-11	Tier 4: intronic/intergenic
rs181900403	5	120225296	G>T	0.001	intergenic_variant	TUBAP15 - RNU6-718P	2e-11	Tier 4: intronic/intergenic
rs141836498	11	115358815	G>A	0.001	intron_variant	CADM1	2e-11	Tier 4: intronic/intergenic
rs554823684	21	16940597	G>A	0.001	intergenic_variant	RNU1-98P - NEK4P1	2e-11	Tier 4: intronic/intergenic
chr9:133154147							2e-11	Tier 4: intronic/intergenic
rs557852210	15	53158769	C>G	0.001	intron_variant	LINC02490	3e-11	Tier 4: intronic/intergenic
rs3849942	9;9	27543283	T>A,C,G	0.43	non_coding_transcript_exon_variant; synonymous_variant	EMICERI; C9orf72; C9orf72	5e-11	Tier 4: intronic/intergenic
rs141805452	14	88591970	G>A,C,T	0.001	non_coding_transcript_exon_variant	ZC3H14	5e-11	Tier 4: intronic/intergenic
rs3736947	10	112409432	C>A,G,T	0.05	intron_variant	ACSL5	8e-11	Tier 4: intronic/intergenic
rs17785991	20	49822224	T>A	0.05	intron_variant	SLC9A8	3e-10	Tier 4: intronic/intergenic
rs10463311	5	151031274	C>A,G,T	0.05	intron_variant	TNIP1	3e-10	Tier 4: intronic/intergenic
rs616147	3	39492990	A>G	0.28	intron_variant	MOBP	4e-10	Tier 4: intronic/intergenic
rs58854276	10	112385286	A>G,T	0.05	intron_variant	ACSL5	7e-10	Tier 4: intronic/intergenic
rs4075094	12	64483273	T>A,C	0.05	intron_variant	TBK1	2e-09	Tier 4: intronic/intergenic

ClinVar germline variants

182 retrieved; paginated sample, class counts are floors:

96 uncertain significance, 55 conflicting classifications of pathogenicity, 9 likely pathogenic, 9 pathogenic/likely pathogenic, 7 pathogenic, 2 benign/likely benign, 2 benign, 1 risk factor, 1 likely pathogenic; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
1066545	NM_020919.4(ALS2):c.3624+1G>A	ALS2	Pathogenic	criteria provided, single submitter
961004	NM_020919.4(ALS2):c.2221C>T (p.Arg741Ter)	ALS2	Pathogenic	criteria provided, single submitter
488354	NM_145868.2(ANXA11):c.112G>A (p.Gly38Arg)	ANXA11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1343330	NC_000009.12:g.27573529_27573534GGCCCC[60_?]	C9orf72	Pathogenic	criteria provided, single submitter
447236	NM_004082.5(DCTN1):c.279+1G>C	DCTN1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1721	NM_014845.6(FIG4):c.122T>C (p.Ile41Thr)	FIG4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1723	NM_014845.6(FIG4):c.547C>T (p.Arg183Ter)	FIG4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
245747	NM_014845.6(FIG4):c.1207C>T (p.Gln403Ter)	FIG4	Pathogenic	criteria provided, multiple submitters, no conflicts
448333	NM_015046.7(SETX):c.5308_5311del (p.Glu1770fs)	SETX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14764	NM_000454.5(SOD1):c.140A>G (p.His47Arg)	SOD1	Pathogenic	criteria provided, multiple submitters, no conflicts
574319	NM_000454.5(SOD1):c.301G>A (p.Glu101Lys)	SOD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
695024	NM_000454.5(SOD1):c.317C>T (p.Ser106Leu)	SOD1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
374112	NM_025137.4(SPG11):c.5381T>C (p.Leu1794Pro)	SPG11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
643946	NM_013254.4(TBK1):c.701+1G>A	TBK1	Pathogenic	criteria provided, multiple submitters, no conflicts
807508	NM_013254.4(TBK1):c.1922AAG[2] (p.Glu643del)	TBK1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
807707	NM_013254.4(TBK1):c.992+1G>A	TBK1	Pathogenic	criteria provided, multiple submitters, no conflicts
1699990	NM_020919.4(ALS2):c.142C>G (p.Leu48Val)	ALS2	Likely pathogenic	no assertion criteria provided
976652	NM_001372574.1(ATXN2):c.18GCA[28] (p.Gln14_Gln28dup)	ATXN2	Likely pathogenic; risk factor	criteria provided, multiple submitters, no conflicts
873308	NM_000743.5(CHRNA3):c.725del (p.Leu242fs)	CHRNA3	Likely pathogenic	criteria provided, single submitter
873309	NM_000743.5(CHRNA3):c.708_709insG (p.Ile237fs)	CHRNA3	Likely pathogenic	criteria provided, single submitter
873310	NM_000743.5(CHRNA3):c.247_248insG (p.Thr83fs)	CHRNA3	Likely pathogenic	criteria provided, single submitter
873311	NM_000743.5(CHRNA3):c.1A>G (p.Met1Val)	CHRNA3	Likely pathogenic	criteria provided, single submitter
976655	NM_004082.5(DCTN1):c.1864A>T (p.Ile622Phe)	DCTN1	Likely pathogenic	criteria provided, single submitter
976654	NM_005235.3(ERBB4):c.3814G>A (p.Gly1272Arg)	ERBB4	Likely pathogenic	criteria provided, single submitter
1343332	NM_000454.5(SOD1):c.450T>G (p.Ile150Met)	SOD1	Likely pathogenic	criteria provided, single submitter
997832	NM_006415.4(SPTLC1):c.118_123del (p.Phe40_Ser41del)	SPTLC1	Likely pathogenic	criteria provided, single submitter
976650	NM_144599.5(NIPA1):c.24GGC[21] (p.Ala4_Ala16dup)	LOC130056709	risk factor	criteria provided, single submitter
1810281	NM_019112.4(ABCA7):c.302T>G (p.Leu101Arg)	ABCA7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
333592	NM_020919.4(ALS2):c.3206G>A (p.Gly1069Glu)	ALS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
717612	NM_001145122.2(CAPN14):c.1249C>T (p.Leu417Phe)	CAPN14	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 196 · Orphanet: 115 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 10

Dual-evidence genes (GWAS + Mendelian — highest-confidence targets)

Gene	HGNC	Evidence routes
SOD1	SOD1	GWAS, GenCC, Orphanet
CFAP410	CFAP410	GWAS, GenCC, Orphanet
TBK1	TBK1	GWAS, Orphanet
TNIP1	TNIP1	GWAS, Orphanet
SARM1	SARM1	GWAS
SCFD1	SCFD1	GWAS
UNC13A	UNC13A	GWAS, Orphanet
C9orf72	C9orf72	GWAS, Orphanet
KIF5A	KIF5A	GWAS, Orphanet
MOBP	MOBP	GWAS

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
ANG	Definitive	Autosomal dominant	amyotrophic lateral sclerosis type 9	4
ANXA11	Definitive	Autosomal dominant	amyotrophic lateral sclerosis type 23	7
CHMP2B	Definitive	Autosomal dominant	frontotemporal dementia and/or amyotrophic lateral sclerosis 7	7
FUS	Definitive	Autosomal dominant	amyotrophic lateral sclerosis	7
OPTN	Definitive	Semidominant	amyotrophic lateral sclerosis type 12	9
TARDBP	Definitive	Autosomal dominant	amyotrophic lateral sclerosis type 10	6
UBQLN2	Definitive	X-linked	amyotrophic lateral sclerosis type 15	5
CCNF	Strong	Autosomal dominant	frontotemporal dementia and/or amyotrophic lateral sclerosis 5	4
CHCHD10	Strong	Autosomal dominant	frontotemporal dementia and/or amyotrophic lateral sclerosis 2	10
CYLD	Strong	Autosomal dominant	frontotemporal dementia and/or amyotrophic lateral sclerosis 8	11
ERBB4	Strong	Autosomal dominant	amyotrophic lateral sclerosis type 19	5
FIG4	Strong	Autosomal dominant	amyotrophic lateral sclerosis type 11	15
HNRNPA1	Strong	Autosomal dominant	amyotrophic lateral sclerosis type 20	8
MATR3	Strong	Autosomal dominant	amyotrophic lateral sclerosis type 21	7
PFN1	Strong	Autosomal dominant	amyotrophic lateral sclerosis type 18	5
SOD1	Strong	Autosomal dominant	amyotrophic lateral sclerosis type 1	6
SQSTM1	Strong	Autosomal dominant	frontotemporal dementia and/or amyotrophic lateral sclerosis 3	13
VAPB	Strong	Autosomal dominant	amyotrophic lateral sclerosis type 8	4
VCP	Strong	Autosomal dominant	frontotemporal dementia and/or amyotrophic lateral sclerosis 6	13
AOC1	Moderate	Autosomal dominant	amyotrophic lateral sclerosis	4
ARHGEF28	Moderate	Autosomal dominant	amyotrophic lateral sclerosis	2
DAO	Moderate	Autosomal dominant	amyotrophic lateral sclerosis	4
EWSR1	Moderate	Autosomal dominant	amyotrophic lateral sclerosis	3
HNRNPA2B1	Moderate	Autosomal dominant	amyotrophic lateral sclerosis	6
PRPH	Moderate	Autosomal dominant	amyotrophic lateral sclerosis type 1	4
SS18L1	Moderate	Autosomal dominant	amyotrophic lateral sclerosis	2
CFAP410	Supportive	Autosomal dominant	amyotrophic lateral sclerosis	4
GLE1	Supportive	Autosomal dominant	amyotrophic lateral sclerosis	6
PON1	Supportive	Autosomal dominant	amyotrophic lateral sclerosis
PON2	Supportive	Autosomal dominant	amyotrophic lateral sclerosis

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SOD1	Orphanet:803	Amyotrophic lateral sclerosis
CFAP410	Orphanet:1872	Cone rod dystrophy
CFAP410	Orphanet:653709	Cone rod dystrophy-short stature syndrome
CFAP410	Orphanet:803	Amyotrophic lateral sclerosis
SQSTM1	Orphanet:275864	Behavioral variant of frontotemporal dementia
SQSTM1	Orphanet:275872	Frontotemporal dementia with motor neuron disease
SQSTM1	Orphanet:603	Distal myopathy, Welander type
SQSTM1	Orphanet:803	Amyotrophic lateral sclerosis
TAF15	Orphanet:209916	Extraskeletal myxoid chondrosarcoma
TAF15	Orphanet:803	Amyotrophic lateral sclerosis
TBK1	Orphanet:1930	Herpes simplex virus encephalitis
TBK1	Orphanet:275872	Frontotemporal dementia with motor neuron disease
TBK1	Orphanet:803	Amyotrophic lateral sclerosis
UBQLN2	Orphanet:803	Amyotrophic lateral sclerosis
VCP	Orphanet:100070	Progressive non-fluent aphasia
VCP	Orphanet:275864	Behavioral variant of frontotemporal dementia
VCP	Orphanet:275872	Frontotemporal dementia with motor neuron disease
VCP	Orphanet:329475	Spastic paraplegia-Paget disease of bone syndrome
VCP	Orphanet:329478	Adult-onset distal myopathy due to VCP mutation
VCP	Orphanet:435387	Autosomal dominant Charcot-Marie-Tooth disease type 2Y
VCP	Orphanet:52430	Inclusion body myopathy with Paget disease of bone and frontotemporal dementia
VCP	Orphanet:803	Amyotrophic lateral sclerosis
CHCHD10	Orphanet:275872	Frontotemporal dementia with motor neuron disease
CHCHD10	Orphanet:276435	Lower motor neuron syndrome with late-adult onset
CHCHD10	Orphanet:457050	Autosomal dominant mitochondrial myopathy with exercise intolerance
CHCHD10	Orphanet:803	Amyotrophic lateral sclerosis
CCNF	Orphanet:803	Amyotrophic lateral sclerosis
FIG4	Orphanet:139515	Charcot-Marie-Tooth disease type 4J
FIG4	Orphanet:208441	Bilateral parasagittal parieto-occipital polymicrogyria
FIG4	Orphanet:3472	Yunis-Varon syndrome
FIG4	Orphanet:803	Amyotrophic lateral sclerosis
TNIP1	Orphanet:536	Systemic lupus erythematosus
OPTN	Orphanet:803	Amyotrophic lateral sclerosis
UNC13A	Orphanet:803	Amyotrophic lateral sclerosis
CHMP2B	Orphanet:100069	Semantic dementia
CHMP2B	Orphanet:100070	Progressive non-fluent aphasia
CHMP2B	Orphanet:275864	Behavioral variant of frontotemporal dementia
CHMP2B	Orphanet:803	Amyotrophic lateral sclerosis
DAO	Orphanet:803	Amyotrophic lateral sclerosis
C9orf72	Orphanet:100069	Semantic dementia
C9orf72	Orphanet:100070	Progressive non-fluent aphasia
C9orf72	Orphanet:275864	Behavioral variant of frontotemporal dementia
C9orf72	Orphanet:275872	Frontotemporal dementia with motor neuron disease
C9orf72	Orphanet:401901	Huntington disease-like syndrome due to C9ORF72 expansions
C9orf72	Orphanet:803	Amyotrophic lateral sclerosis
ERBB4	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
ERBB4	Orphanet:803	Amyotrophic lateral sclerosis
EWSR1	Orphanet:209916	Extraskeletal myxoid chondrosarcoma
EWSR1	Orphanet:319	Skeletal Ewing sarcoma
EWSR1	Orphanet:370334	Extraskeletal Ewing sarcoma

Cohort genes → proteins

75 cohort genes, 75 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	19
gwas_and_clinvar	8
multi_evidence	48

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SOD1	HGNC:11179	ENSG00000142168	P00441	Superoxide dismutase [Cu-Zn]	gwas,gencc,clinvar
CFAP410	HGNC:1260	ENSG00000160226	O43822	Cilia- and flagella-associated protein 410	gwas,gencc,clinvar
SQSTM1	HGNC:11280	ENSG00000161011	Q13501	Sequestosome-1	gencc,clinvar
TAF15	HGNC:11547	ENSG00000270647	Q92804	TATA-binding protein-associated factor 2N	gencc,clinvar
TBK1	HGNC:11584	ENSG00000183735	Q9UHD2	Serine/threonine-protein kinase TBK1	gwas,clinvar
DNAJC7	HGNC:12392	ENSG00000168259	Q99615	DnaJ homolog subfamily C member 7	gencc,clinvar
UBQLN2	HGNC:12509	ENSG00000188021	Q9UHD9	Ubiquilin-2	gencc,clinvar
VCP	HGNC:12666	ENSG00000165280	P55072	Transitional endoplasmic reticulum ATPase	gencc,clinvar
CHCHD10	HGNC:15559	ENSG00000250479	Q8WYQ3	Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial	gencc,clinvar
SS18L1	HGNC:15592	ENSG00000184402	O75177	Calcium-responsive transactivator	gencc,clinvar
CCNF	HGNC:1591	ENSG00000162063	P41002	Cyclin-F	gencc,clinvar
FIG4	HGNC:16873	ENSG00000112367	Q92562	Polyphosphoinositide phosphatase	gencc,clinvar
TNIP1	HGNC:16903	ENSG00000145901	Q15025	TNFAIP3-interacting protein 1	gwas,clinvar
SARM1	HGNC:17074	ENSG00000004139	Q6SZW1	NAD(+) hydrolase SARM1	gwas,clinvar
OPTN	HGNC:17142	ENSG00000123240	Q96CV9	Optineurin	gencc,clinvar
SCFD1	HGNC:20726	ENSG00000092108	Q8WVM8	Sec1 family domain-containing protein 1	gwas,clinvar
UNC13A	HGNC:23150	ENSG00000130477	Q9UPW8	Protein unc-13 homolog A	gwas,clinvar
CHMP2B	HGNC:24537	ENSG00000083937	Q9UQN3	Charged multivesicular body protein 2b	gencc,clinvar
DAO	HGNC:2671	ENSG00000110887	P14920	D-amino-acid oxidase	gencc,clinvar
C9orf72	HGNC:28337	ENSG00000147894	Q96LT7	Guanine nucleotide exchange factor C9orf72	gwas,clinvar
ERBB4	HGNC:3432	ENSG00000178568	Q15303	Receptor tyrosine-protein kinase erbB-4	gencc,clinvar
EWSR1	HGNC:3508	ENSG00000182944	Q01844	RNA-binding protein EWS	gencc,clinvar
FUS	HGNC:4010	ENSG00000089280	P35637	RNA-binding protein FUS	gencc,clinvar
GLE1	HGNC:4315	ENSG00000119392	Q53GS7	mRNA export factor GLE1	gencc,clinvar
ANG	HGNC:483	ENSG00000214274	P03950	Angiogenin	gencc,clinvar
ANXA11	HGNC:535	ENSG00000122359	P50995	Annexin A11	gencc,clinvar
KIF5A	HGNC:6323	ENSG00000155980	Q12840	Kinesin heavy chain isoform 5A	gwas,clinvar
MATR3	HGNC:6912	ENSG00000015479	P43243	Matrin-3	gencc,clinvar
MOBP	HGNC:7189	ENSG00000168314	Q13875	Myelin-associated oligodendrocyte basic protein	gwas,clinvar
NEFH	HGNC:7737	ENSG00000100285	P12036	Neurofilament heavy polypeptide	gencc,clinvar
AOC1	HGNC:80	ENSG00000002726	P19801	Diamine oxidase [copper-containing]	gencc,clinvar
PFN1	HGNC:8881	ENSG00000108518	P07737	Profilin-1	gencc,clinvar
PON1	HGNC:9204	ENSG00000005421	P27169	Serum paraoxonase/arylesterase 1	gencc,clinvar
PON3	HGNC:9206	ENSG00000105852	Q15166	Serum paraoxonase/lactonase 3	gencc,clinvar
PRPH	HGNC:9461	ENSG00000135406	P41219	Peripherin	gencc,clinvar
TARDBP	HGNC:11571	ENSG00000120948	Q13148	TAR DNA-binding protein 43	gencc
VAPB	HGNC:12649	ENSG00000124164	O95292	Vesicle-associated membrane protein-associated protein B/C	gencc
CLEC4C	HGNC:13258	ENSG00000198178	Q8WTT0	C-type lectin domain family 4 member C	gencc
RAPGEF2	HGNC:16854	ENSG00000109756	Q9Y4G8	Rap guanine nucleotide exchange factor 2	gencc
CYLD	HGNC:2584	ENSG00000083799	Q9NQC7	Ubiquitin carboxyl-terminal hydrolase CYLD	gencc
ARHGEF28	HGNC:30322	ENSG00000214944	Q8N1W1	Rho guanine nucleotide exchange factor 28	gencc
HNRNPA1	HGNC:5031	ENSG00000135486	P09651	Heterogeneous nuclear ribonucleoprotein A1	gencc
HNRNPA2B1	HGNC:5033	ENSG00000122566	P22626	Heterogeneous nuclear ribonucleoproteins A2/B1	gencc
APEX1	HGNC:587	ENSG00000100823	P27695	DNA repair nuclease/redox regulator APEX1	gencc
PCDHA9	HGNC:8675	ENSG00000204961	Q9Y5H5	Protocadherin alpha-9	gencc
PON2	HGNC:9205	ENSG00000105854	Q15165	Serum paraoxonase/arylesterase 2	gencc
PPIA	HGNC:9253	ENSG00000196262	P62937	Peptidyl-prolyl cis-trans isomerase A	gencc
ATXN1	HGNC:10548	ENSG00000124788	P54253	Ataxin-1	gwas
ATXN2	HGNC:10555	ENSG00000204842	Q99700	Ataxin-2	clinvar
SCN7A	HGNC:10594	ENSG00000136546	Q01118	Sodium channel protein type 7 subunit alpha	gwas

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SOD1	Superoxide dismutase [Cu-Zn]	Destroys radicals which are normally produced within the cells and which are toxic to biological systems.
CFAP410	Cilia- and flagella-associated protein 410	Plays a role in cilia formation and/or maintenance.
SQSTM1	Sequestosome-1	Molecular adapter required for selective macroautophagy (aggrephagy) by acting as a bridge between polyubiquitinated proteins and autophagosomes.
TAF15	TATA-binding protein-associated factor 2N	RNA and ssDNA-binding protein that may play specific roles during transcription initiation at distinct promoters.
TBK1	Serine/threonine-protein kinase TBK1	Serine/threonine kinase that plays an essential role in regulating inflammatory responses to foreign agents.
DNAJC7	DnaJ homolog subfamily C member 7	Acts as a co-chaperone regulating the molecular chaperones HSP70 and HSP90 in folding of steroid receptors, such as the glucocorticoid receptor and the progesterone receptor.
UBQLN2	Ubiquilin-2	Plays an important role in the regulation of different protein degradation mechanisms and pathways including ubiquitin-proteasome system (UPS), autophagy and the endoplasmic reticulum-associated protein degradation (ERAD) pathway.
VCP	Transitional endoplasmic reticulum ATPase	Necessary for the fragmentation of Golgi stacks during mitosis and for their reassembly after mitosis.
CHCHD10	Coiled-coil-helix-coiled-coil-helix domain-containing protein 10, mitochondrial	May be involved in the maintenance of mitochondrial organization and mitochondrial cristae structure.
SS18L1	Calcium-responsive transactivator	Transcriptional activator which is required for calcium-dependent dendritic growth and branching in cortical neurons.
CCNF	Cyclin-F	Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins.
FIG4	Polyphosphoinositide phosphatase	Dual specificity phosphatase 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).
TNIP1	TNFAIP3-interacting protein 1	Inhibits NF-kappa-B activation and TNF-induced NF-kappa-B-dependent gene expression by regulating TAX1BP1 and A20/TNFAIP3-mediated deubiquitination of IKBKG; proposed to link A20/TNFAIP3 to ubiquitinated IKBKG.
SARM1	NAD(+) hydrolase SARM1	NAD(+) hydrolase, which plays a key role in axonal degeneration following injury by regulating NAD(+) metabolism.
OPTN	Optineurin	Plays an important role in the maintenance of the Golgi complex, in membrane trafficking, in exocytosis, through its interaction with myosin VI and Rab8.
SCFD1	Sec1 family domain-containing protein 1	Plays a role in SNARE-pin assembly and Golgi-to-ER retrograde transport via its interaction with COG4.
UNC13A	Protein unc-13 homolog A	Plays a role in vesicle maturation during exocytosis as a target of the diacylglycerol second messenger pathway.
CHMP2B	Charged multivesicular body protein 2b	Probable core component of the endosomal sorting required for transport complex III (ESCRT-III) which is involved in multivesicular bodies (MVBs) formation and sorting of endosomal cargo proteins into MVBs.
DAO	D-amino-acid oxidase	Catalyzes the oxidative deamination of D-amino acids with broad substrate specificity.
C9orf72	Guanine nucleotide exchange factor C9orf72	Acts as a guanine-nucleotide releasing factor (GEF) for Rab GTPases by promoting the conversion of inactive RAB-GDP to the active form RAB-GTP.
ERBB4	Receptor tyrosine-protein kinase erbB-4	Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins and EGF family members and regulates development of the heart, the central nervous system and the mammary gland, gene transcription, cell prolife…
EWSR1	RNA-binding protein EWS	Binds to ssRNA containing the consensus sequence 5’-AGGUAA-3'.
FUS	RNA-binding protein FUS	DNA/RNA-binding protein that plays a role in various cellular processes such as transcription regulation, RNA splicing, RNA transport, DNA repair and damage response.
GLE1	mRNA export factor GLE1	Required for the export of mRNAs containing poly(A) tails from the nucleus into the cytoplasm.
ANG	Angiogenin	Secreted ribonuclease that can either promote or restrict cell proliferation of target cells, depending on the context.
ANXA11	Annexin A11	Binds specifically to calcyclin in a calcium-dependent manner.
KIF5A	Kinesin heavy chain isoform 5A	Microtubule-dependent motor required for slow axonal transport of neurofilament proteins (NFH, NFM and NFL).
MATR3	Matrin-3	May play a role in transcription or may interact with other nuclear matrix proteins to form the internal fibrogranular network.
MOBP	Myelin-associated oligodendrocyte basic protein	May play a role in compacting or stabilizing the myelin sheath, possibly by binding the negatively charged acidic phospholipids of the cytoplasmic membrane.
NEFH	Neurofilament heavy polypeptide	Neurofilaments usually contain three intermediate filament proteins: NEFL, NEFM, and NEFH which are involved in the maintenance of neuronal caliber.
AOC1	Diamine oxidase [copper-containing]	Catalyzes the oxidative deamination of primary amines to the corresponding aldehydes with the concomitant production of hydrogen peroxide and ammonia.
PFN1	Profilin-1	Binds to actin and affects the structure of the cytoskeleton.
PON1	Serum paraoxonase/arylesterase 1	Hydrolyzes the toxic metabolites of a variety of organophosphorus insecticides.
PON3	Serum paraoxonase/lactonase 3	Has low activity towards the organophosphate paraxon and aromatic carboxylic acid esters.
PRPH	Peripherin	Class-III neuronal intermediate filament protein.
TARDBP	TAR DNA-binding protein 43	RNA-binding protein that is involved in various steps of RNA biogenesis and processing.
VAPB	Vesicle-associated membrane protein-associated protein B/C	Endoplasmic reticulum (ER)-anchored protein that mediates the formation of contact sites between the ER and endosomes via interaction with FFAT motif-containing proteins such as STARD3 or WDR44.
CLEC4C	C-type lectin domain family 4 member C	Lectin-type cell surface receptor which may play a role in antigen capturing by dendritic cells.
RAPGEF2	Rap guanine nucleotide exchange factor 2	Functions as a guanine nucleotide exchange factor (GEF), which activates Rap and Ras family of small GTPases by exchanging bound GDP for free GTP in a cAMP-dependent manner.
CYLD	Ubiquitin carboxyl-terminal hydrolase CYLD	Deubiquitinase that specifically cleaves ‘Lys-63’- and linear ‘Met-1’-linked polyubiquitin chains and is involved in NF-kappa-B activation and TNF-induced necroptosis.
ARHGEF28	Rho guanine nucleotide exchange factor 28	Functions as a RHOA-specific guanine nucleotide exchange factor regulating signaling pathways downstream of integrins and growth factor receptors.
HNRNPA1	Heterogeneous nuclear ribonucleoprotein A1	Involved in the packaging of pre-mRNA into hnRNP particles, transport of poly(A) mRNA from the nucleus to the cytoplasm and modulation of splice site selection.
HNRNPA2B1	Heterogeneous nuclear ribonucleoproteins A2/B1	Heterogeneous nuclear ribonucleoprotein (hnRNP) that associates with nascent pre-mRNAs, packaging them into hnRNP particles.
APEX1	DNA repair nuclease/redox regulator APEX1	Multifunctional protein that plays a central role in the cellular response to oxidative stress.
PCDHA9	Protocadherin alpha-9	Potential calcium-dependent cell-adhesion protein.
PON2	Serum paraoxonase/arylesterase 2	Capable of hydrolyzing lactones and a number of aromatic carboxylic acid esters.
PPIA	Peptidyl-prolyl cis-trans isomerase A	Catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.
ATXN1	Ataxin-1	Chromatin-binding factor that repress Notch signaling in the absence of Notch intracellular domain by acting as a CBF1 corepressor.
ATXN2	Ataxin-2	Involved in EGFR trafficking, acting as negative regulator of endocytic EGFR internalization at the plasma membrane.
SCN7A	Sodium channel protein type 7 subunit alpha	Sodium leak channel functioning as an osmosensor regulating sodium ion levels in various tissues and organs.

Protein-family classification

Druggable: 24 · Difficult: 13 · Unknown: 38 · Druggable fraction: 0.32

Family distribution

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

Family	Genes	Fold	FDR
Enzyme (other)	12	1.9×	0.229
Complement	1	3.6×	0.786
Ion channel	2	3.0×	0.786
Kinase	4	1.5×	0.786
Scaffold/PPI	5	1.1×	0.960
Phosphatase	1	1.1×	0.960
Protease	2	1.0×	0.960
Other/Unknown	38	0.9×	0.960
Transcription factor	8	0.9×	0.960
Antibody/Immunoglobulin	1	0.4×	0.960
GPCR	1	0.3×	0.960

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SOD1	Enzyme (other)	yes	1.15.1.1	SOD_Cu_Zn_dom, SOD_Cu/Zn_BS, SOD_Cu/Zn_/chaperone
CFAP410	Other/Unknown	no		Leu-rich_rpt, U2A’_phosphoprotein32A_C, LRR_dom_sf
SQSTM1	Transcription factor	no		PB1_dom, Znf_ZZ, UBA-like_sf
TAF15	Transcription factor	no		RRM_dom, Znf_RanBP2, Nucleotide-bd_a/b_plait_sf
TBK1	Kinase	yes		Prot_kinase_dom, Kinase-like_dom_sf, Protein_kinase_ATP_BS
DNAJC7	Other/Unknown	no		DnaJ_domain, TPR-like_helical_dom_sf, TPR_rpt
UBQLN2	Other/Unknown	no		Ubiquitin-like_dom, STI1_HS-bd, UBA-like_sf
VCP	Enzyme (other)	yes	3.6.4.6	CDC4_N-term_subdom, AAA+_ATPase, ATPase_AAA_core
CHCHD10	Other/Unknown	no		CHCH, CHCHD2/10-like
SS18L1	Other/Unknown	no		SS18_N
CCNF	Other/Unknown	no		F-box_dom, Cyclin_C-dom, Cyclin_N
FIG4	Other/Unknown	no		SAC_dom, Fig4-like
TNIP1	Other/Unknown	no
SARM1	Other/Unknown	no		TIR_dom, SAM, ARM-like
OPTN	Other/Unknown	no		NEMO_N, CC2-LZ_dom, NEMO_ZF
SCFD1	Other/Unknown	no		Sec1-like, Sec1-like_dom2, Sec1-like_sf
UNC13A	Other/Unknown	no		C2_dom, PKC_DAG/PE, MUN_dom
CHMP2B	Other/Unknown	no		Snf7_fam
DAO	Enzyme (other)	yes	1.4.3.3	FAD-dep_OxRdtase, D-amino_acid_oxidase_CS, DAO
C9orf72	Other/Unknown	no		C9orf72
ERBB4	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
EWSR1	Transcription factor	no		RRM_dom, Znf_RanBP2, Nucleotide-bd_a/b_plait_sf
FUS	Transcription factor	no		RRM_dom, Znf_RanBP2, Nucleotide-bd_a/b_plait_sf
GLE1	Other/Unknown	no		GLE1, GLE1-like_sf
ANG	Other/Unknown	no		RNaseA, RNaseA_AS, RNaseA_domain
ANXA11	Other/Unknown	no		Annexin, ANX11, Annexin_repeat_CS
KIF5A	Other/Unknown	no		Kinesin_motor_dom, Kinesin_motor_CS, P-loop_NTPase
MATR3	Transcription factor	no		RRM_dom, Matrin/U1-C_Znf_C2H2, Matrin/U1-like-C_Znf_C2H2
MOBP	Other/Unknown	no		FYVE_2, Intracell_Transport_Effector
NEFH	Other/Unknown	no		DUF1388, IF_conserved, IF_rod_dom
AOC1	Enzyme (other)	yes	1.4.3.22	Cu_amine_oxidase, Cu_amine_oxidase_C, Cu_amine_oxidase_N2
PFN1	Other/Unknown	no		Profilin1/2/3_vertebrate, PFN_euk, Profilin_CS
PON1	Enzyme (other)	yes	3.1.1.2	Arylesterase, Paraoxonase1, 6-blade_b-propeller_TolB-like
PON3	Enzyme (other)	yes	3.1.1.2	Arylesterase, Paraoxonase2, 6-blade_b-propeller_TolB-like
PRPH	Other/Unknown	no		Keratin_I, Intermed_filament_DNA-bd, IF_conserved
TARDBP	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, RBD_domain_sf
VAPB	Antibody/Immunoglobulin	yes		MSP_dom, PapD-like_sf, Ig-like_fold
CLEC4C	Other/Unknown	no		C-type_lectin-like, C-type_lectin-like/link_sf, CTDL_fold
RAPGEF2	Scaffold/PPI	no		RA_dom, cNMP-bd_dom, Ras-like_Gua-exchang_fac_N
CYLD	Protease	yes		CAP-Gly_domain, Peptidase_C19_UCH, USP_CS
ARHGEF28	Scaffold/PPI	no		DH_dom, PH_domain, PKC_DAG/PE
HNRNPA1	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, HnRNPA1/A2_C
HNRNPA2B1	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, HnRNPA1/A2_C
APEX1	Phosphatase	yes	4.2.99.18	AP_endonuc_1, Endo/exonuclease/phosphatase, AP_endonuclease_F1_BS
PCDHA9	Other/Unknown	no		Cadherin-like_dom, Cadherin_N, Cadherin-like_sf
PON2	Enzyme (other)	yes	3.1.1.2	Arylesterase, Paraoxonase2, 6-blade_b-propeller_TolB-like
PPIA	Enzyme (other)	yes	5.2.1.8	Cyclophilin-type_PPIase_dom, Cyclophilin-type_PPIase_CS, Cyclophilin-type_PPIase
ATXN1	Other/Unknown	no		Ataxin_AXH_dom, Ataxin-1_N, Ataxin_AXH_dom_sf
ATXN2	Other/Unknown	no		LsmAD_domain, PAM2_motif, LSM_dom_sf
SCN7A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_trans_assoc_dom

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	1
broad (>20)	74
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ventricular zone	9
ganglionic eminence	6
cortical plate	6
endothelial cell	6
secondary oocyte	6
lateral nuclear group of thalamus	5
right hemisphere of cerebellum	5
liver	5
right lobe of liver	5
pons	4
right frontal lobe	4
right testis	4
calcaneal tendon	4
lower esophagus mucosa	4
buccal mucosa cell	4
mucosa of transverse colon	4
ileal mucosa	4
dorsal root ganglion	3
adenohypophysis	3
right adrenal gland cortex	3

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SOD1	304	ubiquitous	marker	pons, dorsal root ganglion, substantia nigra pars compacta
CFAP410	190	ubiquitous	marker	right uterine tube, adenohypophysis, right frontal lobe
SQSTM1	241	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left adrenal gland
TAF15	134	ubiquitous	yes	endometrium, ganglionic eminence, right testis
TBK1	284	ubiquitous	marker	colonic epithelium, calcaneal tendon, lateral nuclear group of thalamus
DNAJC7	288	ubiquitous	marker	nucleus accumbens, lower esophagus mucosa, caudate nucleus
UBQLN2	295	ubiquitous	marker	cerebellar vermis, pons, postcentral gyrus
VCP	294	ubiquitous	marker	stromal cell of endometrium, adrenal tissue, islet of Langerhans
CHCHD10	133	ubiquitous	marker	apex of heart, heart left ventricle, hindlimb stylopod muscle
SS18L1	288	ubiquitous	yes	lateral nuclear group of thalamus, cortical plate, cerebellar vermis
CCNF	213	ubiquitous	marker	type B pancreatic cell, olfactory bulb, hair follicle
FIG4	295	ubiquitous	marker	middle temporal gyrus, endothelial cell, lateral nuclear group of thalamus
TNIP1	298	ubiquitous	marker	lower esophagus mucosa, blood, hindlimb stylopod muscle
SARM1	206	ubiquitous	marker	body of pancreas, cortical plate, islet of Langerhans
OPTN	302	ubiquitous	marker	amniotic fluid, gastrocnemius, muscle of leg
SCFD1	301	ubiquitous	marker	calcaneal tendon, body of pancreas, adenohypophysis
UNC13A	193	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
CHMP2B	300	ubiquitous	marker	medial globus pallidus, amniotic fluid, mucosa of sigmoid colon
DAO	131	tissue_specific	marker	right lobe of liver, liver, right hemisphere of cerebellum
C9orf72	250	ubiquitous	marker	monocyte, leukocyte, mucosa of paranasal sinus
ERBB4	226	broad	marker	endothelial cell, secondary oocyte, cranial nerve II
EWSR1	294	ubiquitous	marker	right uterine tube, left testis, right testis
FUS	304	ubiquitous	marker	right testis, ventricular zone, right hemisphere of cerebellum
GLE1	267	ubiquitous	marker	buccal mucosa cell, tendon of biceps brachii, right testis
ANG	238	ubiquitous	marker	right lobe of liver, liver, left ovary
ANXA11	300	ubiquitous	marker	lower esophagus mucosa, palpebral conjunctiva, mucosa of transverse colon
KIF5A	198	broad	marker	right frontal lobe, right hemisphere of cerebellum, cerebellar hemisphere
MATR3	135	ubiquitous	marker	cortical plate, corpus callosum, ganglionic eminence
MOBP	201	tissue_specific	marker	C1 segment of cervical spinal cord, cranial nerve II, pons
NEFH	222	broad	marker	dorsal root ganglion, pons, lateral nuclear group of thalamus

Protein interactions among cohort

Intra-cohort edges: 83.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VCP	10,015
SQSTM1	7,269
TARDBP	7,245
UBQLN2	6,872
SOD1	6,807
CAV1	6,673
CCNF	6,626
HNRNPA1	6,616
HNRNPA2B1	5,996
TBK1	5,476

Intra-cohort edges

A	B	Sources
ACSL5	CHCHD10	intact
ARHGEF28	SOD1	string_interaction
ARHGEF28	TARDBP	biogrid_interaction
ATXN1	ATXN2	string_interaction
ATXN1	UBQLN2	intact
ATXN2	C9orf72	string_interaction
ATXN2	CCNF	biogrid_interaction
ATXN2	CHCHD10	string_interaction
ATXN2	FUS	string_interaction
ATXN2	TARDBP	biogrid_interaction, string_interaction
C9orf72	CHCHD10	string_interaction
C9orf72	CHMP2B	string_interaction
C9orf72	FUS	string_interaction
C9orf72	SOD1	string_interaction
C9orf72	SQSTM1	string_interaction
C9orf72	TAF15	string_interaction
C9orf72	TARDBP	string_interaction
C9orf72	TBK1	intact, string_interaction
C9orf72	UBQLN2	string_interaction
C9orf72	VCP	string_interaction
CHCHD10	FUS	string_interaction
CHCHD10	MATR3	string_interaction
CHCHD10	OPTN	string_interaction
CHCHD10	TARDBP	string_interaction
CHCHD10	UBQLN2	string_interaction
CHCHD10	VCP	string_interaction
CHMP2B	FIG4	string_interaction
CHMP2B	FUS	string_interaction
CHMP2B	TARDBP	string_interaction
CHMP2B	VCP	string_interaction
CYLD	TNIP1	string_interaction
ERBB4	VAPB	intact
EWSR1	TAF15	intact
FIG4	NEFH	string_interaction
FIG4	SOD1	string_interaction
FIG4	SQSTM1	string_interaction
FIG4	TARDBP	string_interaction
FIG4	VAPB	string_interaction
FUS	HNRNPA1	intact, string_interaction
FUS	HNRNPA2B1	string_interaction
FUS	MATR3	intact, string_interaction
FUS	NEFH	string_interaction
FUS	OPTN	string_interaction
FUS	PFN1	biogrid_interaction
FUS	SOD1	string_interaction
FUS	TAF15	intact
FUS	TARDBP	intact, string_interaction
FUS	UBQLN2	string_interaction
FUS	VAPB	string_interaction
FUS	VCP	biogrid_interaction

Structural data

PDB: 52 · AlphaFold-only: 23 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PPIA	P62937	202
SOD1	P00441	156
VCP	P55072	144
HNRNPA1	P09651	73
APEX1	P27695	67
ANG	P03950	56
SARM1	Q6SZW1	55
TARDBP	Q13148	44
SQSTM1	Q13501	26
VRK1	Q99986	26
TBK1	Q9UHD2	25
FUS	P35637	23
DAO	P14920	22
PFN1	P07737	22
HDAC4	P56524	19
SPTLC1	O15269	17
TAF15	Q92804	15
OPTN	Q96CV9	14
ERBB4	Q15303	14
HNRNPA2B1	P22626	13
TNIP1	Q15025	8
ATXN1	P54253	7
CYLD	Q9NQC7	6
CHCHD10	Q8WYQ3	5
AOC1	P19801	5
CLEC4C	Q8WTT0	5
UBQLN2	Q9UHD9	4
C9orf72	Q96LT7	4
KIF5A	Q12840	4
CACNA1A	O00555	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PON2	Q15165	96.94
PON3	Q15166	96.36
TUBA4A	P68366	92.02
ST3GAL3	Q11203	90.87
DNAJC7	Q99615	90.83
ACSL5	Q9ULC5	90.55
OR52K1	Q8NGK4	88.29
TSPEAR	Q8WU66	87.47
CAPN14	A8MX76	86.02
SCFD1	Q8WVM8	85.70
LRRC3	Q9BY71	83.43
ASB1	Q9Y576	80.61
PRPH	P41219	79.24
SLC39A11	Q8N1S5	76.64
PCDHA9	Q9Y5H5	73.68
UNC13A	Q9UPW8	73.58
PNPLA6	Q8IY17	69.75
ZNF142	P52746	61.51
CREB5	Q02930	57.95
MATR3	P43243	57.64
MOBP	Q13875	55.69
NEFH	P12036	54.28
SS18L1	O75177	51.33

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 505. Enrichment computed across 137 evidence-associated genes (97 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 97 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Highly sodium permeable postsynaptic acetylcholine nicotinic receptors	3	50.5×	0.008	CHRNA3, CHRNA4, CHRNB4
Synthesis of 5-eicosatetraenoic acids	3	39.2×	0.008	PON1, PON3, PON2
Highly calcium permeable nicotinic acetylcholine receptors	3	39.2×	0.008	CHRNA3, CHRNA4, CHRNB4
Highly calcium permeable postsynaptic nicotinic acetylcholine receptors	3	32.1×	0.012	CHRNA3, CHRNA4, CHRNB4
Presynaptic nicotinic acetylcholine receptors	3	29.4×	0.012	CHRNA3, CHRNA4, CHRNB4
Acetylcholine binding and downstream events	3	25.2×	0.013	CHRNA3, CHRNA4, CHRNB4
Postsynaptic nicotinic acetylcholine receptors	3	25.2×	0.013	CHRNA3, CHRNA4, CHRNB4
RHO GTPase cycle	8	5.0×	0.013	VCP, SCFD1, CAV1, ARAP2, ARHGEF28, ALS2, KALRN, ARHGEF2
RHOA GTPase cycle	7	5.4×	0.018	SCFD1, VAPB, CAV1, ARAP2, ARHGEF28, KALRN, ARHGEF2
Selective autophagy	4	11.5×	0.020	SQSTM1, TBK1, VCP, TUBA4A
Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)	3	18.6×	0.022	TBK1, SARM1, OPTN
Signaling by Rho GTPases	10	3.5×	0.022	VCP, SCFD1, KIF5A, TUBA4A, CAV1, ARAP2, ARHGEF28, ALS2 (+2 more)
SARS-CoV-1 Infection	5	7.4×	0.022	TBK1, VCP, ST3GAL3, CAV1, HNRNPA1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	10	3.5×	0.022	VCP, SCFD1, KIF5A, TUBA4A, CAV1, ARAP2, ARHGEF28, ALS2 (+2 more)
COPI-independent Golgi-to-ER retrograde traffic	4	8.6×	0.040	TUBA4A, BICD2, DCTN1, DYNC1H1
TNFR1-induced proapoptotic signaling	3	13.6×	0.042	TBK1, OPTN, CYLD
Macroautophagy	5	6.0×	0.045	SQSTM1, TBK1, VCP, CHMP2B, TUBA4A
Atorvastatin ADME	2	29.4×	0.054	PON1, PON3
PINK1-PRKN Mediated Mitophagy	3	11.0×	0.065	SQSTM1, TBK1, OPTN
Signal Transduction	19	2.0×	0.065	SQSTM1, TBK1, VCP, SCFD1, KIF5A, ST3GAL3, TUBA4A, CAV1 (+11 more)
Mitophagy	2	21.4×	0.087	SQSTM1, TBK1
Josephin domain DUBs	2	19.6×	0.087	VCP, ATXN3
Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation	2	19.6×	0.087	TBK1, OPTN
Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation	3	9.3×	0.087	SOD1, HNRNPA2B1, PPIA
Autophagy	4	6.1×	0.087	SQSTM1, TBK1, VCP, TUBA4A
MHC class II antigen presentation	5	4.6×	0.087	KIF5A, TUBA4A, KIFAP3, DCTN1, DYNC1H1
Membrane Trafficking	8	3.1×	0.087	SCFD1, KIF5A, TBC1D1, TUBA4A, KIFAP3, BICD2, SEC16B, ALS2
Death Receptor Signaling	4	5.7×	0.093	SQSTM1, TBK1, KALRN, ARHGEF2
Asparagine N-linked glycosylation	6	3.7×	0.096	VCP, SCFD1, ST3GAL3, TUBA4A, SEC16B, B4GALT6
TICAM1-dependent activation of IRF3/IRF7	2	16.8×	0.099	TBK1, OPTN

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 131 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
lactone catabolic process	3	128.6×	5e-04	PON1, PON3, PON2
nervous system development	13	4.6×	0.003	SARM1, ERBB4, MOBP, SEMA6A, HDAC4, CHRNA3, CNTN4, DCTN1 (+5 more)
behavioral response to nicotine	3	42.9×	0.013	CHRNA3, CHRNA4, CHRNB4
neurofilament cytoskeleton organization	3	38.6×	0.013	SOD1, NEFH, ARHGEF28
stress granule assembly	4	18.4×	0.013	C9orf72, ANG, ATXN2, DYNC1H1
cellular response to misfolded protein	3	32.2×	0.017	VCP, CAV1, ATXN3
membrane depolarization	4	15.6×	0.018	CAV1, CHRNA3, CHRNA4, CHRNB4
regulation of smooth muscle contraction	3	27.6×	0.021	CAV1, CHRNA3, CHRNB4
carboxylic acid catabolic process	2	85.8×	0.021	PON1, PON3
positive regulation of neuron migration	3	22.7×	0.030	SEMA6A, RAPGEF2, ARHGEF2
synaptic transmission involved in micturition	2	64.3×	0.030	CHRNA3, CHRNB4
viral release from host cell	3	21.4×	0.030	CHMP2B, VAPB, PPIA
positive regulation of ERAD pathway	3	20.3×	0.030	UBQLN2, CAV1, ATXN3
endosome organization	4	11.4×	0.030	SQSTM1, CHMP2B, WASHC5, ALS2
synaptic transmission, cholinergic	3	18.4×	0.039	CHRNA3, CHRNA4, CHRNB4
locomotory behavior	5	6.8×	0.054	SOD1, FIG4, CHRNA3, CHRNB4, ALS2
anterograde dendritic transport of neurotransmitter receptor complex	2	36.8×	0.067	KIF5A, KIFAP3
positive regulation of cholesterol efflux	3	14.3×	0.067	PON1, CAV1, ABCA7
acetylcholine receptor signaling pathway	3	14.3×	0.067	CHRNA3, CHRNA4, CHRNB4
signal transduction	18	2.2×	0.067	SARM1, OPTN, ERBB4, ANG, TSPEAR, VRK1, CAMK1G, ARAP2 (+10 more)
negative regulation of protein phosphorylation	3	13.3×	0.072	C9orf72, TARDBP, PPIA
positive regulation of xenophagy	2	32.2×	0.078	TBK1, OPTN
mitotic nuclear membrane disassembly	2	28.6×	0.081	VRK1, DCTN1
central nervous system neuron axonogenesis	2	28.6×	0.081	ARHGEF28, B4GALT6
myelin assembly	2	28.6×	0.081	FIG4, PMP22
neuromuscular junction development	3	12.1×	0.081	SPG11, DCTN1, ALS2
regulation of Rho protein signal transduction	3	11.7×	0.081	KANK1, ARHGEF28, ARHGEF2
macroautophagy	4	7.3×	0.081	SQSTM1, TBK1, VCP, CHMP2B
retrograde axonal transport	2	23.4×	0.090	SOD1, DYNC1H1
RNA transport	2	23.4×	0.090	ATXN2, HNRNPA2B1

Therapeutics

Drugs indicated for this disease

3 approved, 19 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Edaravone	Approved (phase 4)
Riluzole	Approved (phase 4)
Tofersen	Approved (phase 4)
Arimoclomol	Phase 3 (in late-stage trials)
Cannabidiol	Phase 3 (in late-stage trials)
Ceftriaxone	Phase 3 (in late-stage trials)
Creatine	Phase 3 (in late-stage trials)
Cyanocobalamin	Phase 3 (in late-stage trials)
Dexpramipexole	Phase 3 (in late-stage trials)
Dextromethorphan	Phase 3 (in late-stage trials)
Levosimendan	Phase 3 (in late-stage trials)
Lithium Carbonate	Phase 3 (in late-stage trials)
Masitinib	Phase 3 (in late-stage trials)
Mecasermin	Phase 3 (in late-stage trials)
Minocycline	Phase 3 (in late-stage trials)
Olesoxime	Phase 3 (in late-stage trials)
Quinidine	Phase 3 (in late-stage trials)
Ravulizumab	Phase 3 (in late-stage trials)
Sodium Chloride	Phase 3 (in late-stage trials)
Taurolithocholic Acid	Phase 3 (in late-stage trials)
Tirasemtiv	Phase 3 (in late-stage trials)
Vitamin E	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): ANX-005, Acetylcarnitine, Albumin Human, Aldesleukin, Ambroxol, Anakinra, Atropine, Basiliximab, Biotin, Cannabinol, Celecoxib, Ciprofloxacin, Colchicine, Corticotropin, Creatinine, Cromolyn, Darifenacin, Deferiprone, Dexmedetomidine, Dextrose, Dronabinol, Dutasteride, Ezogabine, Fasudil, Filgrastim, Glatiramer Acetate, Ibudilast, Inosine, Latozinemab, Mecobalamin, Memantine, Methylprednisolone, Mycophenolate Mofetil, Nitrofurazone, Olanzapine, Pegcetacoplan, Perampanel, Pimozide, Pioglitazone, Prednisone, Pridopidine, Ranolazine, Rasagiline, Reldesemtiv, Scopolamine, Serine, Sirolimus, Somatropin, Tacrolimus Anhydrous, Tamoxifen, Thalidomide, Tocilizumab, Trehalose, Ubidecarenone, Verdiperstat, Withanolide D, Zilucoplan.

Drug target analysis

Approved (phase 4): 16 · Phase ≥3: 16 · Phased (≥1): 20 · Undrugged: 55

Druggability breadth: 75 of 137 evidence-associated genes (55%) 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
TBK1	MOMELOTINIB
VCP	CLOTRIMAZOLE
SARM1	NIACINAMIDE
DAO	CEFTRIAXONE
ERBB4	MOBOCERTINIB
AOC1	PENTAMIDINE
TARDBP	MITOXANTRONE
APEX1	CEFOTAXIME SODIUM
PPIA	CYCLOSPORINE
SCN7A	IMIPRAMINE
SQLE	AMIODARONE
TUBA4A	COLCHICINE
CACNA1A	NIMODIPINE
HDAC4	CELECOXIB
CAMK1G	FEDRATINIB
ACSL5	GILTERITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
APEX1	53	4
ERBB4	47	4
TBK1	38	4
HDAC4	31	4
TUBA4A	22	4
SCN7A	20	4
CAMK1G	14	4
SARM1	7	4
PPIA	6	4
VCP	4	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOMELOTINIB	4	TBK1
AMLEXANOX	4	TBK1
FEDRATINIB	4	CAMK1G, ERBB4, TBK1
RUXOLITINIB	4	CAMK1G, TBK1
ENTRECTINIB	4	TBK1
PACRITINIB	4	TBK1
BOSUTINIB	4	ERBB4, TBK1
FILGOTINIB	4	TBK1
NINTEDANIB	4	CAMK1G, TBK1
SUNITINIB	4	CAMK1G, TBK1
ERLOTINIB	4	ERBB4, TBK1
CRIZOTINIB	4	TBK1
MIDOSTAURIN	4	CAMK1G, ERBB4, TBK1
CLOTRIMAZOLE	4	VCP
GANCICLOVIR	4	VCP
HEXACHLOROPHENE	4	VCP
NIACINAMIDE	4	SARM1
PHENAZOPYRIDINE HYDROCHLORIDE	4	SARM1
DEXLANSOPRAZOLE	4	SARM1
RABEPRAZOLE	4	SARM1
NITROFURAZONE	4	SARM1
CEFTRIAXONE	4	DAO
MOBOCERTINIB	4	ERBB4
AFATINIB	4	ERBB4
NERATINIB	4	ERBB4
IBRUTINIB	4	ERBB4
AFATINIB DIMALEATE	4	ERBB4
DACOMITINIB	4	ERBB4
DACOMITINIB ANHYDROUS	4	ERBB4
VANDETANIB	4	ERBB4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 15.

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

Symbol	Assays	Type breakdown
HDAC4	1,941	Binding:1919, ADMET:13, Functional:6, Toxicity:3
TUBA4A	1,695	Binding:1654, Functional:35, ADMET:6
ERBB4	591	Binding:579, ADMET:8, Functional:4
TBK1	475	Binding:473, Functional:2
PPIA	155	Binding:154, Functional:1
CAMK1G	137	Binding:136, Functional:1
VCP	120	Binding:120
DAO	85	Binding:85
VRK1	74	Binding:74
APEX1	49	Binding:45, Functional:4
SCN7A	48	Binding:32, Functional:16
SOD1	38	Binding:32, Functional:5, ADMET:1
SARM1	25	Binding:25
SQLE	23	Binding:21, Functional:2
SQSTM1	20	Binding:20
CACNA1A	19	Binding:18, Functional:1
SELL	16	Binding:16
EWSR1	14	Binding:14
AOC1	12	Binding:11, Functional:1
HNRNPA2B1	12	Binding:12
PON1	11	Binding:11
KIF5A	8	Binding:8
TARDBP	8	Binding:7, Functional:1
DNAJC7	7	Binding:7
FUS	7	Binding:7
ANXA11	7	Binding:7
MATR3	7	Binding:7
HNRNPA1	7	Binding:7
ATXN2	5	Binding:3, Functional:2
CAV1	5	Binding:5
SPTLC1	4	Binding:4
CLEC4C	3	Binding:3
CYLD	3	Binding:3
ANG	2	Binding:2
ST3GAL3	2	Binding:2
ACSL5	2	Binding:2
CFAP410	1	Binding:1
TAF15	1	Binding:1
UBQLN2	1	Binding:1
SCFD1	1	Binding:1
PFN1	1	Binding:1
PON3	1	Binding:1
PRPH	1	Binding:1
VAPB	1	Binding:1
PON2	1	Binding:1
SPG11	1	Binding:1
SLC39A11	1	Binding:1
PNPLA6	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
SOD1	1.15.1.1	superoxide dismutase
VCP	3.6.4.6	vesicle-fusing ATPase
DAO	1.4.3.3	D-amino-acid oxidase
ERBB4	2.7.10.1	receptor protein-tyrosine kinase
AOC1	1.4.3.22	diamine oxidase
PON1	3.1.1.2, 3.1.1.25, 3.1.1.81, 3.1.8.1, 3.1.8.2	arylesterase, 1,4-lactonase, quorum-quenching N-acyl-homoserine lactonase, aryldialkylphosphatase, diisopropyl-fluorophosphatase
PON3	3.1.1.2, 3.1.1.25, 3.1.8.1	arylesterase, 1,4-lactonase, aryldialkylphosphatase
APEX1	4.2.99.18	DNA-(apurinic or apyrimidinic site) lyase
PON2	3.1.1.2, 3.1.1.25	arylesterase, 1,4-lactonase
PPIA	5.2.1.8	peptidylprolyl isomerase
ST3GAL3	2.4.99.2, 2.4.99.6	beta-D-galactosyl-(1->3)-N-acetyl-beta-D-galactosaminide alpha-2,3-sialyltransferase, N-acetyllactosaminide alpha-2,3-sialyltransferase
SPTLC1	2.3.1.50	serine C-palmitoyltransferase
SQLE	1.14.14.17	squalene monooxygenase
HDAC4	3.5.1.98	histone deacetylase
CAMK1G	2.7.11.17	Ca2+/calmodulin-dependent protein kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TBK1	475
VCP	120
ERBB4	591
PPIA	155
TUBA4A	1,695
HDAC4	1,941
CAMK1G	137

Pharmacogenomics

Cohort genes with a PharmGKB record: 75; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

28 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)
MOMELOTINIB	4	TBK1
AMLEXANOX	4	TBK1
FEDRATINIB	4	CAMK1G, ERBB4, TBK1
RUXOLITINIB	4	CAMK1G, TBK1
ENTRECTINIB	4	TBK1
PACRITINIB	4	TBK1
BOSUTINIB	4	ERBB4, TBK1
FILGOTINIB	4	TBK1
NINTEDANIB	4	CAMK1G, TBK1
SUNITINIB	4	CAMK1G, TBK1
ERLOTINIB	4	ERBB4, TBK1
CRIZOTINIB	4	TBK1
MIDOSTAURIN	4	CAMK1G, ERBB4, TBK1
CLOTRIMAZOLE	4	VCP
GANCICLOVIR	4	VCP
HEXACHLOROPHENE	4	VCP
NIACINAMIDE	4	SARM1
PHENAZOPYRIDINE HYDROCHLORIDE	4	SARM1
DEXLANSOPRAZOLE	4	SARM1
NITROFURAZONE	4	SARM1
MOBOCERTINIB	4	ERBB4
AFATINIB	4	ERBB4
NERATINIB	4	ERBB4
IBRUTINIB	4	ERBB4
AFATINIB DIMALEATE	4	ERBB4
DACOMITINIB	4	ERBB4
DACOMITINIB ANHYDROUS	4	ERBB4
VANDETANIB	4	ERBB4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	16	TBK1, VCP, SARM1, DAO, ERBB4, AOC1, TARDBP, APEX1, PPIA, SCN7A (+6 more)
B	Phased (≥1) drug, not yet approved	4	DNAJC7, EWSR1, MATR3, SELL
C	Druggable family + PDB, no drug	6	SOD1, PON1, VAPB, CYLD, SPTLC1, VRK1
D	Druggable family + AlphaFold only, no drug	5	PON3, PON2, ST3GAL3, OR52K1, CAPN14
E	Difficult family or no structure, no drug	44	CFAP410, SQSTM1, TAF15, UBQLN2, CHCHD10, SS18L1, CCNF, FIG4, TNIP1, OPTN (+34 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SOD1	38	TARDBP
TAF15	1	TARDBP
UBQLN2	1	TARDBP, VCP
CHCHD10	0	MATR3
OPTN	0	TBK1
C9orf72	0	TARDBP
FUS	7	TARDBP
VAPB	1	TARDBP
HNRNPA1	7	TARDBP
HNRNPA2B1	12	TARDBP
ATXN2	5	TARDBP
CFAP410	1	—
SQSTM1	20	—
SS18L1	0	—
CCNF	0	—
FIG4	0	—
TNIP1	0	—
SCFD1	1	—
UNC13A	0	—
CHMP2B	0	—
GLE1	0	—
ANG	2	—
ANXA11	7	—
KIF5A	8	—
MOBP	0	—
NEFH	0	—
PFN1	1	—
PON1	11	—
PON3	1	—
PRPH	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 927.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	491
PHASE2	163
PHASE1	97
PHASE1/PHASE2	64
PHASE3	52
PHASE2/PHASE3	36
EARLY_PHASE1	18
PHASE4	6

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07223723	PHASE4	RECRUITING	A Study to Learn More About the Long-Term Safety of Tofersen (Qalsody) in Chinese Participants With SOD-1 Amyotrophic Lateral Sclerosis (ALS)
NCT00542412	PHASE4	COMPLETED	CARE Canadian ALS Riluzole Evaluation
NCT00560287	PHASE4	UNKNOWN	Non-Invasive Ventilation in Amyotrophic Lateral Sclerosis
NCT00613899	PHASE4	COMPLETED	Feasibility of Telesurveillance and Home Cough Assistance for Amyotrophic Lateral Patients (ALS)
NCT04997954	PHASE4	UNKNOWN	EMERALD TRIAL Open Label Extension Study
NCT06849115	PHASE4	COMPLETED	Effects of L-Carnitine in Amyotrophic Lateral Sclerosis Patients With CHCHD10 Mutations
NCT03127267	PHASE3	RECRUITING	Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients
NCT04057898	PHASE2/PHASE3	ACTIVE_NOT_RECRUITING	Evaluation of MN-166 (Ibudilast) for 12 Months Followed by an Open-label Extension for 6 Months in Patients With ALS
NCT04220190	PHASE2/PHASE3	RECRUITING	RAPA-501 Therapy for ALS
NCT04297683	PHASE2/PHASE3	RECRUITING	HEALEY ALS Platform Trial - Master Protocol
NCT04768972	PHASE3	ACTIVE_NOT_RECRUITING	FUSION: A Study to Evaluate the Efficacy, Safety, Pharmacokinetics and Pharmacodynamics of ION363 in Amyotrophic Lateral Sclerosis Participants With Fused in Sarcoma Mutations (FUS-ALS)
NCT05021536	PHASE3	ACTIVE_NOT_RECRUITING	Phase III Trial of AMX0035 for Amyotrophic Lateral Sclerosis Treatment
NCT06126315	PHASE2/PHASE3	RECRUITING	Trial on the Biological and Clinical Effects of Acetyl-L-carnitine in ALS
NCT06391645	PHASE2/PHASE3	NOT_YET_RECRUITING	Nerve Growth Factor Encapsulated With 2-methacryloyloxyethyl Phosphorylcholine Nanocapsules in the Treatment of Amyotrophic Lateral Sclerosis
NCT06719947	PHASE2/PHASE3	NOT_YET_RECRUITING	HD-tDCS in Amyotrophic Lateral Sclerosis: A Multicenter Randomized Controlled Trial
NCT06973629	PHASE3	NOT_YET_RECRUITING	Efficacy and Safety of MSC-NTF (NurOwn) in Participants With Early Symptomatic ALS and Moderate Disease Presentation in ALS (ENDURANCE STUDY)
NCT07082192	PHASE2/PHASE3	NOT_YET_RECRUITING	A Study to Evaluate the Efficacy and Safety of Different Doses of CB03-154 in Adult Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT07174492	PHASE3	NOT_YET_RECRUITING	Efficacy and Safety of Masitinib in Combination With SoC Versus Placebo in the Treatment of ALS Patients
NCT07321860	PHASE2/PHASE3	NOT_YET_RECRUITING	This Study Evaluates the Safety, Target Engagement, and Preliminary Efficacy of Galunisertib (TGF-βR1/ALK5 Inhibitor)Combined With Nerandomilast (PDE4 Inhibitor) in GREM2-positive ALS, a Biomarker-defined Subgroup Hypothesized to Reflect Heightened TGF-β/SMAD-driven Astrocytic and Fibrotic Signaling
NCT07322003	PHASE3	RECRUITING	Pridopidine Phase 3 Study to Evaluate Efficacy and Safety in ALS
NCT07325591	PHASE2/PHASE3	NOT_YET_RECRUITING	Efficacy and Safety of Tazbentetol in ALS Participants
NCT07410806	PHASE2/PHASE3	ENROLLING_BY_INVITATION	HEALEY ALS Platform Trial - Regimen I NUZ-001
NCT00021697	PHASE3	COMPLETED	Safety/Efficacy of AVP-923 in the Treatment of Emotional Lability (Uncontrolled Crying & Laughing) in Patients With ALS
NCT00035815	PHASE3	COMPLETED	Insulin-like Growth Factor-1 in Amyotrophic Lateral Sclerosis (ALS) Trial
NCT00047723	PHASE3	COMPLETED	Minocycline to Treat Amyotrophic Lateral Sclerosis
NCT00069186	PHASE3	UNKNOWN	Study of Creatine Monohydrate in Patients With Amyotrophic Lateral Sclerosis
NCT00125203	PHASE2/PHASE3	COMPLETED	Study of Myobloc in the Treatment of Sialorrhea (Drooling) in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00136110	PHASE3	COMPLETED	Trial of Sodium Valproate in Amyotrophic Lateral Sclerosis
NCT00330681	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS)
NCT00349622	PHASE3	COMPLETED	Clinical Trial Ceftriaxone in Subjects With ALS
NCT00353665	PHASE2/PHASE3	COMPLETED	Memantine for Disability in Amyotrophic Lateral Sclerosis (MEDALS)
NCT00372879	PHASE3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
NCT00386464	PHASE2/PHASE3	COMPLETED	Noninvasive Ventilation in ALS Patients With Mild Respiratory Involvement
NCT00415519	PHASE3	COMPLETED	Efficacy and Safety Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis (ALS) Who Met Severity Classification III
NCT00424463	PHASE3	COMPLETED	Expanded Controlled Study of Safety and Efficacy of MCI-186 in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00444613	PHASE2/PHASE3	COMPLETED	A Study in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00445172	PHASE2/PHASE3	COMPLETED	A Long-Term Study in Patients With Amyotrophic Lateral Sclerosis (ALS)
NCT00706147	PHASE2/PHASE3	COMPLETED	Phase II/III Randomized, Placebo-controlled Trial of Arimoclomol in SOD1 Positive Familial Amyotrophic Lateral Sclerosis
NCT00818389	PHASE2/PHASE3	TERMINATED	Study to Investigate the Safety and Efficacy of Lithium in Volunteers With Amyotrophic Lateral Sclerosis (ALS)
NCT00833820	PHASE2/PHASE3	COMPLETED	Repetitive Transcranial Magnetic Stimulation (rTMS) in Amyotrophic Lateral Sclerosis

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
RILUZOLE	4	23
ARIMOCLOMOL	4	5
EDARAVONE	4	5
IBUDILAST	4	4
PERAMPANEL	4	4
TOFERSEN	4	4
DEFERIPRONE	4	3
LITHIUM CARBONATE	4	3
RASAGILINE	4	3
ALBUMIN HUMAN	4	2
CAPSAICIN	4	2
MINOCYCLINE	4	2
RABEPRAZOLE	4	2
RANOLAZINE	4	2
TAMOXIFEN CITRATE	4	2
TAURURSODIOL	4	2
ACAMPROSATE	4	1
ACAMPROSATE CALCIUM	4	1
ANAKINRA	4	1
BARICITINIB	4	1
BASILIXIMAB	4	1
BIOTIN	4	1
CEFTRIAXONE	4	1
COPPER	4	1
CORTICOTROPIN	4	1
DARUNAVIR	4	1
DARUNAVIR ETHANOLATE	4	1
DEXTROMETHORPHAN HYDROBROMIDE	4	1
DIGOXIN	4	1
ENOXACIN	4	1