C9orf72

Summary

C9orf72 (C9orf72-SMCR8 complex subunit, HGNC:28337) is a protein-coding gene on chromosome 9p21.2, encoding Guanine nucleotide exchange factor C9orf72 (Q96LT7). 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.

The protein encoded by this gene plays an important role in the regulation of endosomal trafficking, and has been shown to interact with Rab proteins that are involved in autophagy and endocytic transport. Expansion of a GGGGCC repeat from 2-22 copies to 700-1600 copies in the intronic sequence between alternate 5’ exons in transcripts from this gene is associated with 9p-linked ALS (amyotrophic lateral sclerosis) and FTD (frontotemporal dementia) (PMID: 21944778, 21944779). Studies suggest that hexanucleotide expansions could result in the selective stabilization of repeat-containing pre-mRNA, and the accumulation of insoluble dipeptide repeat protein aggregates that could be pathogenic in FTD-ALS patients (PMID: 23393093). Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 203228 — RefSeq curated summary.

At a glance

• Gene–disease (curated): frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 13
• Clinical variants (ClinVar): 112 total — 3 pathogenic
• Phenotypes (HPO): 24
• MANE Select transcript: NM_018325

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28337
Approved symbol	C9orf72
Name	C9orf72-SMCR8 complex subunit
Location	9p21.2
Locus type	gene with protein product
Status	Approved
Aliases	MGC23980, DENNL72, DENND9
Ensembl gene	ENSG00000147894
Ensembl biotype	protein_coding
OMIM	614260
Entrez	203228

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 21 protein_coding, 1 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000379995, ENST00000379997, ENST00000380003, ENST00000488117, ENST00000619707, ENST00000644136, ENST00000647196, ENST00000673600, ENST00000874868, ENST00000874869, ENST00000874870, ENST00000874871, ENST00000874872, ENST00000965246, ENST00000965247, ENST00000965248, ENST00000965249, ENST00000965250, ENST00000965251, ENST00000965252, ENST00000965253, ENST00000965254, ENST00000965255

RefSeq mRNA: 3 — MANE Select: NM_018325 NM_001256054, NM_018325, NM_145005

CCDS: CCDS6522, CCDS6523

Canonical transcript exons

ENST00000380003 — 11 exons

Exon	Start	End
ENSE00000982274	27546546	27548422
ENSE00001372610	27560227	27560299
ENSE00001380088	27558491	27558607
ENSE00001483368	27573431	27573481
ENSE00003497899	27548557	27548666
ENSE00003517144	27565531	27565590
ENSE00003519484	27566677	27567164
ENSE00003537908	27556561	27556796
ENSE00003558542	27562381	27562476
ENSE00003597147	27561585	27561649
ENSE00003693357	27550650	27550707

Expression profiles

Bgee: expression breadth ubiquitous, 250 present calls, max score 98.03.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 6.7533 / max 615.5481, expressed in 1224 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
100355	3.1698	454
100356	2.6497	1101
100357	0.5062	118
100354	0.2874	86
100353	0.1401	70

Top tissues by expression

255 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	98.03	gold quality
leukocyte	CL:0000738	97.42	gold quality
mucosa of paranasal sinus	UBERON:0005030	95.51	gold quality
bronchial epithelial cell	CL:0002328	95.49	gold quality
cerebellar vermis	UBERON:0004720	95.43	gold quality
bronchus	UBERON:0002185	94.87	gold quality
right lung	UBERON:0002167	94.70	gold quality
adrenal tissue	UBERON:0018303	94.17	gold quality
right uterine tube	UBERON:0001302	94.01	gold quality
cerebellar cortex	UBERON:0002129	93.55	gold quality
cerebellar hemisphere	UBERON:0002245	93.52	gold quality
oviduct epithelium	UBERON:0004804	93.47	gold quality
cerebellum	UBERON:0002037	93.42	gold quality
Brodmann (1909) area 23	UBERON:0013554	93.25	gold quality
right hemisphere of cerebellum	UBERON:0014890	93.21	gold quality
blood	UBERON:0000178	91.99	gold quality
granulocyte	CL:0000094	91.82	gold quality
left ovary	UBERON:0002119	91.56	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	91.54	gold quality
calcaneal tendon	UBERON:0003701	91.25	gold quality
superior vestibular nucleus	UBERON:0007227	91.23	gold quality
fallopian tube	UBERON:0003889	90.82	gold quality
epithelial cell of pancreas	CL:0000083	90.56	silver quality
right ovary	UBERON:0002118	90.37	gold quality
ovary	UBERON:0000992	90.24	gold quality
epithelium of nasopharynx	UBERON:0001951	90.17	gold quality
pons	UBERON:0000988	90.08	gold quality
germinal epithelium of ovary	UBERON:0001304	90.01	gold quality
thymus	UBERON:0002370	89.68	gold quality
corpus callosum	UBERON:0002336	89.53	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-6678	yes	24.12
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

128 targeting C9orf72, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-196A-5P	100.00	68.16	684
HSA-MIR-196B-5P	100.00	68.16	681
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-4789-3P	99.99	70.75	2484
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-570-3P	99.96	72.41	4910
HSA-MIR-146A-5P	99.96	68.93	988
HSA-MIR-146B-5P	99.96	69.13	977
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-7153-5P	99.94	68.89	1006
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-515-5P	99.92	69.82	2343
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267

Literature-anchored findings (GeneRIF, showing 40)

• Our findings indicate that repeat expansion in C9ORF72 is a major cause of both frontotemporal dementia and amyotrophic lateral sclerosis. (PMID:21944778)
• A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked amyotrophic lateral sclerosis-frontotemporal dementia. (PMID:21944779)
• Clinical and neuropathologic heterogeneity of c9FTD/ALS is associated with hexanucleotide repeat expansion in C9ORF72. (PMID:22083254)
• all four of the cases did show a repeat expansion of C9orf72, the recently reported cause of chromosome 9-linked motor neuron disease/amyotrophic lateral sclerosis (PMID:22181065)
• We found that C9ORF72 large repeat expansions were present in 3 of 342 families apparently affected with Alzheimer’s disease. The hexanucleotide expansion was seen in 6 of 771 subjects in whom probable Alzheimer’s disease was diagnosed. (PMID:22216764)
• These findings support the C9ORF72 mutation as an important newly recognized cause of amyotrophic lateral sclerosis. (PMID:22228244)
• Mutations in the C9ORF72 gene may be a major cause not only of frontotemporal dementia with motor neuron disease but also of late onset psychosis (PMID:22300873)
• The hexanucleotide repeat expansion in C9orf72 is an important cause of frontotemporal dementia with and without amyotrophic lateral sclerosis (PMID:22300876)
• patients with amyotrophic lateral sclerosis and the C9orf72 repeat expansion seem to present a recognisable phenotype characterised by earlier onset,presence of cognitive and behavioural impairment, specific neuroimaging changes, a family history of neurodegeneration with autosomal dominant inheritance and reduced survival (PMID:22305801)
• (GGGGCC)n repeat expansions in C9orf72 as a cause of familial amyotrophic lateral sclerosis (PMID:22343411)
• Our findings indicate that the C9ORF72 mutation is a major cause of familial frontotemporal dementia with TDP-43 pathology (PMID:22344582)
• These findings corroborate the clinical importance of the C9ORF72 mutation in frontotemporal lobar degeneration (PMID:22366791)
• clinically, C9ORF72 cases show the features of a relatively rapidly progressive, but otherwise typical, variant of amyotrophic lateral sclerosis (PMID:22366792)
• Clinical diagnoses of subjects with repeat expansion in C9ORF72 included behavioural variant frontotemporal dementia with or without parkinsonism, amyotrophic lateral sclerosis, frontotemporal dementia/amyotrophic lateral sclerosis (PMID:22366793)
• C9ORF72 hexanucleotide repeat expansions were the most frequent mutation in our large cohort of patients with familial amyotrophic lateral sclerosis of Italian, Sardinian and German ancestry (PMID:22366794)
• Patterns of atrophy therefore differed across subjects with C9ORF72, tau and progranulin mutations and sporadic frontotemporal dementia (PMID:22366795)
• We recently published that a large hexanucleotide repeat expansion within the C9ORF72 gene causes chromosome 9p-linked amyotrophic lateral sclerosis (ALS)/fronto-temporal dementia (FTD). Here, I describe how the chromosome 9p21 locus was first identified (PMID:22399792)
• C9ORF72 mutations can present with a behavioral variant FrontoTemporalDdementia-SP phenotype. (PMID:22399793)
• A common Mendelian genetic lesion in C9orf72 hexanucleotide repeat expansion causes sporadic amyotrophic lateral sclerosis and sporadic frontotemporal dementia in 17 regions world-wide. (PMID:22406228)
• We conclude that the hexanucleotide repeat expansion is specific to the FTLD/ALS disease spectrum. (PMID:22410647)
• In conclusion, we found that C9ORF72 hexanucleotide repeat expansions represents a sizeable proportion of apparent sporadic ALS in the Italian and Sardinian population. (PMID:22418734)
• Found a pathophysiological link between C9ORF72 expansions and ubiquilin-2 (UBQLN) proteins in amyotrophic lateral sclerosis and frontotemporal lobar degeneration that is associated with a highly characteristic pattern of UBQLN pathology. (PMID:22426854)
• Expansions in the C9ORF72 gene therefore represent a common cause of ALS in Greece and this test will be diagnostically very important to implement in the Greek population. (PMID:22445326)
• In summary, our findings suggest that the hexanucleotide expansion is probably associated with ALS, FTD, or FTD-ALS and occasional comorbid conditions such as Alzheimer’s disease. (PMID:22459598)
• Here we show that the large Lund pedigree with behavioral variant of frontotemporal dementia previously described with this disorder has an expansion in the recently described C9ORF72 locus on chromosome 9. (PMID:22483864)
• The C9orf72 hexanucleotide repeat expansion in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. (PMID:22487746)
• Our results confirm the major role of expanded repeats in C9ORF72 as causative for ALS and provide evidence for specific phenotypic aspects compared to patients with other ALS-related genes. (PMID:22499346)
• In conclusion, plasma GRN levels are not influenced by the hexanucleotide repeat expansion in C9ORF72 gene, and therefore, cannot be used as a reliable biomarker to detect mutation carriers. (PMID:22502998)
• amyotrophic lateral sclerosis/frontotemporal dementia in Sardinian families carrying both hexanucleotide repeat expansion and TARDBP missense mutation (PMID:22550220)
• Results suggest that a simple monogenic mechanism is not likely to be the cause of C9orf72 repeat-related sporadic amyotrophic lateral sclerosis. (PMID:22564974)
• The hexanucleotide repeat expansion in chromosome 9 (C9ORF72) could be associated with early onset psychiatric presentations. (PMID:22571983)
• Data indicate that the hexanucleotide expansion as a prevalent cause of frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) disorders. (PMID:22650353)
• This study demonstrated the existence and importance of the C9ORF72 hexanucleotide repeat expansion in a Taiwanese ALS cohort of Chinese origin, and supports the global presence of the C9ORF72 repeat expansion in ALS. (PMID:22673113)
• all C9ORF72 hexanucleotide repeat expansion mutation cases derive from a single common founder and are now the most common cause of familial and sporadic amyotrophic lateral sclerosis in Western Europe (PMID:22692064)
• A C9ORF72 mutation modifies the pathologic phenotype of frontotemporal lobar degeneration with motor neuron disease (FTLD-TDP) type B. (PMID:22702520)
• We describe a patient with a complex phenotype characterized by behavioural variant of FTD, Parkinsonism and ALS with predominant lower motor neuron involvement in which the C9ORF72 expansion was detected. (PMID:22708871)
• The data showed that the C9orf72 expansion is not commonly associated with Parkinson’s disease. (PMID:22721568)
• C9orf72 repeat expansion was found in 2 patients and 0 patients with sporadic or familial amyotrophic lateral sclerosis. The frequency of the C9orf72 repeat expansion among Japanese patients is much lower than in Western populations. (PMID:22727276)
• Abnormal expansion of a hexanucleotide repeat in the gene C9orf72 was found to be the most common genetic cause of both frontotemporal dementia and amyotrophic lateral sclerosis. (PMID:22732773)
• coding and noncoding variants located in the 3’-UTR region of the SIGMAR1 gene are not the cause of FTLD-MND in our cohort, and more than half of this targeted cohort is genetically explained by C9ORF72 repeat expansions. (PMID:22739338)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	C13H9orf72	ENSDARG00000011837
mus_musculus	C9orf72	ENSMUSG00000028300
rattus_norvegicus	RGD1359108	ENSRNOG00000009478
caenorhabditis_elegans		WBGENE00017547

Protein

Protein identifiers

Guanine nucleotide exchange factor C9orf72 — Q96LT7 (reviewed: Q96LT7)

All UniProt accessions (4): Q96LT7, A0A2R8Y5K2, A0A2R8Y5U5, A0A5F9ZHW7

UniProt curated annotations — full annotation on UniProt →

Function. 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. Acts as a GEF for RAB39A which enables HOPS-mediated autophagosome-lysosome membrane tethering and fusion in mammalian autophagy. Component of the C9orf72-SMCR8 complex where both subunits display GEF activity and that regulates autophagy. As part of the C9orf72-SMCR8-WDR41 (CSW) complex, functions as GEF for RAB8A and RAB39B, thereby promoting autophagosome maturation. As part of the C9orf72-SMCR8 complex, also functions as GTPase activating protein (GAP) for RAB8A and RAB11A in vitro. The C9orf72-SMCR8 complex also acts as a regulator of autophagy initiation by interacting with the ULK1/ATG1 kinase complex and modulating its protein kinase activity. Promotes initiation of autophagy by regulating the RAB1A-dependent trafficking of the ULK1/ATG1 kinase complex to the phagophore which leads to autophagosome formation. Acts as a regulator of mTORC1 signaling by promoting phosphorylation of mTORC1 substrates. Plays a role in endosomal trafficking. May be involved in regulating the maturation of phagosomes to lysosomes. Promotes the lysosomal localization and lysosome-mediated degradation of CARM1 which leads to inhibition of starvation-induced lipid metabolism. Regulates actin dynamics in motor neurons by inhibiting the GTP-binding activity of ARF6, leading to ARF6 inactivation. This reduces the activity of the LIMK1 and LIMK2 kinases which are responsible for phosphorylation and inactivation of cofilin, leading to CFL1/cofilin activation. Positively regulates axon extension and axon growth cone size in spinal motor neurons. Required for SMCR8 protein expression and localization at pre- and post-synaptic compartments in the forebrain, also regulates protein abundance of RAB3A and GRIA1/GLUR1 in post-synaptic compartments in the forebrain and hippocampus. Plays a role within the hematopoietic system in restricting inflammation and the development of autoimmunity. Regulates stress granule assembly in response to cellular stress. Does not play a role in regulation of stress granule assembly in response to cellular stress.

Subunit / interactions. Component of the C9orf72-SMCR8 complex, at least composed of C9orf72, SMCR8 and WDR41. The complex is formed of two protomers, each individually consisting of one molecule each of C9orf72, SMCR8 and WDR41. The protomers homodimerize via an interaction between C9orf72 (via C-terminus) and SMCR8 (via N-terminus). Within each protomer SMCR8 (via DENN domain) acts as a bridging protein between WDR41 (via C-terminus and N-terminus) and C9orf72 (via C-terminus). The C9orf72-SMCR8 complex associates with the ULK1/ATG1 kinase complex. Interacts with ULK1/ATG1 kinase complex members ULK1, ATG13 and RB1CC1. Interacts with SMCR8; the interaction is direct. Interacts with HNRNPA1, HNRNPA2B1 and UBQLN2. Interacts with small Rab GTPase RAB1A; the interaction mediates recruitment of RAB1A to the ULK1/ATG1 kinase complex. Also interacts with small Rab GTPase RAB7A. Interacts with cofilin. Interacts with GTP-binding proteins ARF1 and ARF6. Interacts with the DLG4/PSD-95. Interacts with CARM1 (via PH domain-like fold). Interacts with RAB39A and RAB39B (in GDP-bound forms); functions as GEF for RAB39A and RAB39B.

Subcellular location. Cytoplasm. Nucleus. P-body. Stress granule. Endosome. Lysosome. Cytoplasmic vesicle. Autophagosome. Autolysosome. Secreted. Cell projection. Axon. Growth cone. Perikaryon Perikaryon. Dendrite. Presynapse. Postsynapse Nucleus membrane.

Tissue specificity. Both isoforms are widely expressed, including kidney, lung, liver, heart, testis and several brain regions, such as cerebellum. Also expressed in the frontal cortex and in lymphoblasts (at protein level).

Disease relevance. Frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (FTDALS1) [MIM:105550] An autosomal dominant neurodegenerative disorder characterized by adult onset of frontotemporal dementia and/or amyotrophic lateral sclerosis in an affected individual. There is high intrafamilial variation. Frontotemporal dementia is characterized by frontal and temporal lobe atrophy associated with neuronal loss, gliosis, and dementia. Patients exhibit progressive changes in social, behavioral, and/or language function. Amyotrophic lateral sclerosis is characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. The disease is caused by variants affecting the gene represented in this entry. In the first intron of the gene, the expansion of a GGGGCC hexanucleotide that can vary from 10 to thousands of repeats, represents the most common genetic cause of both familial and sporadic FTDALS. The hexanucleotide repeat expansion (HRE) is structurally polymorphic and during transcription, is responsible for the formation of RNA and DNA G-quadruplexes resulting in the production of aborted transcripts at the expense of functional transcripts. The accumulation of those aborted transcripts may cause nucleolar stress and indirectly cell death. The expanded GGGGCC repeats are bidirectionally transcribed into repetitive RNA, which forms sense and antisense RNA foci. Remarkably, despite being within a non-coding region, these repetitive RNAs can be translated in every reading frame to form five different dipeptide repeat proteins (DPRs) – poly-GA, poly-GP, poly-GR, poly-PA and poly-PR – via a non-canonical mechanism known as repeat-associated non-ATG (RAN) translation. These dipeptide repeat proteins (DPRs) co-aggregate in the characteristic SQSTM1-positive TARDBP negative inclusions found in FTLD/ALS patients with C9orf72 repeat expansion.

Miscellaneous. Encoded by 2 transcripts differing in the 5’ non-coding region.

Isoforms (2)

UniProt ID	Names	Canonical?
Q96LT7-1	1, C9-L, C9(LF)	yes
Q96LT7-2	2, C9-S, C9(SF)

RefSeq proteins (3): NP_001242983, NP_060795, NP_659442 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR027819	C9orf72	Family

Pfam: PF15019

UniProt features (43 total): helix 16, strand 15, turn 4, domain 3, splice variant 2, chain 1, region of interest 1, sequence variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
6LT0	ELECTRON MICROSCOPY	3.2
6V4U	ELECTRON MICROSCOPY	3.8
7O2W	ELECTRON MICROSCOPY	3.8
7MGE	ELECTRON MICROSCOPY	3.94

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96LT7-F1	83.48	0.49

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 367 (showing top): RNGTGGGC_UNKNOWN, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_LYSOSOMAL_TRANSPORT, GOBP_NEURON_PROJECTION_EXTENSION, GOBP_VACUOLE_ORGANIZATION, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_VESICLE_ORGANIZATION, STARK_PREFRONTAL_CORTEX_22Q11_DELETION_DN, GOBP_MEMBRANE_FUSION, GOBP_GROWTH, GOBP_REGULATION_OF_EXOCYTOSIS, GOBP_VACUOLAR_TRANSPORT, GOBP_NEUROGENESIS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_REGULATION_OF_VACUOLE_ORGANIZATION

GO Biological Process (16): negative regulation of protein phosphorylation (GO:0001933), endocytosis (GO:0006897), autophagy (GO:0006914), regulation of autophagy (GO:0010506), positive regulation of macroautophagy (GO:0016239), regulation of protein localization (GO:0032880), stress granule assembly (GO:0034063), negative regulation of exocytosis (GO:0045920), axon extension (GO:0048675), negative regulation of immune response (GO:0050777), autophagosome-lysosome fusion (GO:0061909), regulation of synaptic vesicle cycle (GO:0098693), regulation of actin filament organization (GO:0110053), late endosome to lysosome transport (GO:1902774), regulation of TORC1 signaling (GO:1903432), regulation of autophagosome assembly (GO:2000785)

GO Molecular Function (4): guanyl-nucleotide exchange factor activity (GO:0005085), GTPase activator activity (GO:0005096), small GTPase binding (GO:0031267), protein binding (GO:0005515)

GO Cellular Component (31): P-body (GO:0000932), obsolete extracellular space (GO:0005615), nucleus (GO:0005634), cytoplasm (GO:0005737), lysosome (GO:0005764), endosome (GO:0005768), autophagosome (GO:0005776), cytosol (GO:0005829), cytoplasmic stress granule (GO:0010494), dendrite (GO:0030425), nuclear membrane (GO:0031965), guanyl-nucleotide exchange factor complex (GO:0032045), perikaryon (GO:0043204), axonal growth cone (GO:0044295), main axon (GO:0044304), autolysosome (GO:0044754), Flemming body (GO:0090543), hippocampal mossy fiber to CA3 synapse (GO:0098686), postsynapse (GO:0098794), glutamatergic synapse (GO:0098978), presynaptic cytosol (GO:0099523), extracellular region (GO:0005576), membrane (GO:0016020), axon (GO:0030424), growth cone (GO:0030426), cytoplasmic vesicle (GO:0031410), cell projection (GO:0042995), neuron projection (GO:0043005), synapse (GO:0045202), presynapse (GO:0098793), Atg1/ULK1 kinase complex (GO:1990316)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
macroautophagy	2
GTPase regulator activity	2
cytoplasmic ribonucleoprotein granule	2
synapse	2
regulation of protein phosphorylation	1
protein phosphorylation	1
negative regulation of protein modification process	1
negative regulation of phosphorylation	1
vesicle budding from membrane	1
membrane invagination	1
vesicle-mediated transport	1
import into cell	1
catabolic process	1
transmembrane transport	1
process utilizing autophagic mechanism	1
autophagy	1
regulation of catabolic process	1
positive regulation of autophagy	1
regulation of macroautophagy	1
intracellular protein localization	1
regulation of localization	1
membraneless organelle assembly	1
exocytosis	1
regulation of exocytosis	1
negative regulation of secretion by cell	1
axonogenesis	1
neuron projection extension	1
negative regulation of immune system process	1
immune response	1
negative regulation of response to stimulus	1
regulation of immune response	1
vesicle fusion	1
regulation of vesicle-mediated transport	1
synaptic vesicle cycle	1
actin filament organization	1
regulation of actin cytoskeleton organization	1
regulation of supramolecular fiber organization	1
lysosomal transport	1
intercellular transport	1

Protein interactions and networks

STRING

1626 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
C9orf72	SMCR8	Q8TEV9	996
C9orf72	WDR41	Q9HAD4	995
C9orf72	TARDBP	Q13148	944
C9orf72	FUS	P35637	919
C9orf72	A0A087WTZ4	A0A087WTZ4	919
C9orf72	SOD1	P00441	898
C9orf72	GRN	P23781	888
C9orf72	UBQLN2	Q9UHD9	871
C9orf72	RAB1A	P11476	863
C9orf72	ATXN2	Q99700	857
C9orf72	MAPT	P10636	852
C9orf72	VCP	P55072	852
C9orf72	CHMP2B	Q9UQN3	826
C9orf72	TBK1	Q9UHD2	824
C9orf72	SQSTM1	Q13501	821

IntAct

76 interactions, top by confidence:

A	B	Type	Score
C9orf72	SMCR8	psi-mi:“MI:0915”(physical association)	0.850
SMCR8	C9orf72	psi-mi:“MI:0915”(physical association)	0.850
C9orf72	SMCR8	psi-mi:“MI:2252”(guanine nucleotide exchange factor reaction)	0.850
C9orf72	SMCR8	psi-mi:“MI:0217”(phosphorylation reaction)	0.850
C9orf72	SMCR8	psi-mi:“MI:0914”(association)	0.850
RB1CC1	ATG13	psi-mi:“MI:0914”(association)	0.820
EIF2B2	C9orf72	psi-mi:“MI:0915”(physical association)	0.670
FAM90A1	KPNA3	psi-mi:“MI:0914”(association)	0.670
C9orf72	VRTN	psi-mi:“MI:0915”(physical association)	0.600
VRTN	C9orf72	psi-mi:“MI:0915”(physical association)	0.600
C9orf72	ULK1	psi-mi:“MI:2364”(proximity)	0.570
C9orf72	ULK1	psi-mi:“MI:0217”(phosphorylation reaction)	0.570
C9orf72	CRX	psi-mi:“MI:0915”(physical association)	0.560
C9orf72	REL	psi-mi:“MI:0915”(physical association)	0.560
C9orf72	NMI	psi-mi:“MI:0915”(physical association)	0.560
C9orf72	EIF2B2	psi-mi:“MI:0915”(physical association)	0.560
EIF2B2	C9orf72	psi-mi:“MI:0915”(physical association)	0.560
REL	C9orf72	psi-mi:“MI:0915”(physical association)	0.560
NMI	C9orf72	psi-mi:“MI:0915”(physical association)	0.560
CRX	C9orf72	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (1424): C9orf72 (Two-hybrid), C9orf72 (Two-hybrid), C9orf72 (Two-hybrid), C9orf72 (Two-hybrid), EIF2B2 (Two-hybrid), C9orf72 (Affinity Capture-MS), Smcr8 (Affinity Capture-MS), Wdr41 (Affinity Capture-MS), Hspa8 (Affinity Capture-MS), Setx (Affinity Capture-MS), Jak1 (Affinity Capture-MS), Dync1h1 (Affinity Capture-MS), Ubr4 (Affinity Capture-MS), Hsp90aa1 (Affinity Capture-MS), Bag3 (Affinity Capture-MS)

ESM2 similar proteins: A4D1B5, A5PKN5, A7RV13, D3IUT5, O70167, O70173, O75747, P42695, Q12769, Q28HN9, Q3MHH2, Q3TCV3, Q3UPC7, Q3URV1, Q5BKL1, Q5EA76, Q5R8P3, Q5RB52, Q5RC62, Q5RD58, Q5SUD9, Q5ZK21, Q5ZL79, Q63517, Q66H58, Q66HC3, Q66KD9, Q6DFW0, Q6GN08, Q6ZQK0, Q6ZW61, Q8BJW5, Q8BKN5, Q8IV33, Q8K1K4, Q8N957, Q8NB91, Q8R3P6, Q8TAM1, Q91YN0

Diamond homologs: Q66HC3, Q6DFW0, Q96LT7

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
C9orf72	“up-regulates activity”	ULK1/Atg13/Fip200	binding
RAB1A	“up-regulates activity”	C9orf72	binding
C9orf72	“up-regulates activity”	RAB1A	binding
HNRNPA3	“down-regulates quantity”	C9orf72

Disease & clinical

Clinical variants and AI predictions

ClinVar

112 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	59
Likely benign	8
Benign	22

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
1343330	NC_000009.12:g.27573529_27573534GGCCCC[60_?]	Pathogenic
151162	GRCh38/hg38 9p22.1-21.1(chr9:19564275-28106622)x1	Pathogenic
31151	NM_001256054.1(C9orf72):c.-45+163GGGGCC[>24]	Pathogenic

SpliceAI

2000 predictions. Top by Δscore:

Variant	Effect	Δscore
9:27548555:A:AC	donor_gain	1.0000
9:27548556:C:CC	donor_gain	1.0000
9:27556560:CAAAT:C	donor_gain	1.0000
9:27556795:TC:T	acceptor_gain	1.0000
9:27556795:TCC:T	acceptor_loss	1.0000
9:27556796:CC:C	acceptor_gain	1.0000
9:27556796:CCTG:C	acceptor_loss	1.0000
9:27556797:C:CC	acceptor_gain	1.0000
9:27561583:A:AC	donor_gain	1.0000
9:27561584:C:CC	donor_gain	1.0000
9:27561646:CTAT:C	acceptor_gain	1.0000
9:27561650:C:CC	acceptor_gain	1.0000
9:27562374:AACTT:A	donor_loss	1.0000
9:27562375:ACTT:A	donor_loss	1.0000
9:27562376:CTTA:C	donor_loss	1.0000
9:27562377:TTA:T	donor_loss	1.0000
9:27562378:TACAT:T	donor_loss	1.0000
9:27562379:A:AC	donor_gain	1.0000
9:27562379:AC:A	donor_loss	1.0000
9:27562380:C:CC	donor_gain	1.0000
9:27562380:CA:C	donor_gain	1.0000
9:27562380:CAT:C	donor_gain	1.0000
9:27562380:CATCT:C	donor_gain	1.0000
9:27562475:CC:C	acceptor_gain	1.0000
9:27562476:CC:C	acceptor_gain	1.0000
9:27549884:CCCAT:C	acceptor_gain	0.9900
9:27549885:CCAT:C	acceptor_gain	0.9900
9:27549886:C:T	acceptor_gain	0.9900
9:27549886:CAT:C	acceptor_gain	0.9900
9:27549897:C:CT	acceptor_gain	0.9900

AlphaMissense

3166 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:27566777:A:T	I115K	1.000
9:27566786:A:G	L112P	1.000
9:27566824:A:C	F99L	1.000
9:27566824:A:T	F99L	1.000
9:27566826:A:G	F99L	1.000
9:27566903:C:G	R73P	1.000
9:27566915:C:A	G69V	1.000
9:27566915:C:T	G69E	1.000
9:27566916:C:G	G69R	1.000
9:27566916:C:T	G69R	1.000
9:27566921:A:G	L67P	1.000
9:27566927:T:G	H65P	1.000
9:27566928:G:C	H65D	1.000
9:27566933:G:T	A63D	1.000
9:27566986:C:A	W45C	1.000
9:27566986:C:G	W45C	1.000
9:27566988:A:G	W45R	1.000
9:27566988:A:T	W45R	1.000
9:27567005:G:T	P39H	1.000
9:27567006:G:A	P39S	1.000
9:27567008:C:A	G38V	1.000
9:27567008:C:T	G38D	1.000
9:27567009:C:A	G38C	1.000
9:27567009:C:G	G38R	1.000
9:27567016:A:C	N35K	1.000
9:27567016:A:T	N35K	1.000
9:27567020:T:A	D34V	1.000
9:27567020:T:G	D34A	1.000
9:27567021:C:G	D34H	1.000
9:27567022:C:A	W33C	1.000

dbSNP variants (sampled 300 via entrez): RS1000210811 (9:27560811 A>C,G), RS1000340839 (9:27557752 T>C), RS1000345009 (9:27549791 A>C), RS1000572489 (9:27551692 T>C), RS1000630837 (9:27554326 T>C), RS1000662028 (9:27553974 C>T), RS1000707393 (9:27555881 A>C,G), RS1000836311 (9:27570826 GCCACTGCACT>G), RS1000845701 (9:27548946 G>A), RS1000972511 (9:27567801 T>C), RS1001021709 (9:27550076 T>C), RS1001171851 (9:27574308 AGTT>A), RS1001234397 (9:27573924 G>A), RS1001248210 (9:27561900 G>A,C), RS1001277994 (9:27548824 C>T)

Disease associations

OMIM: gene MIM:614260 | disease phenotypes: MIM:105550

GenCC curated gene-disease

Disease	Classification	Inheritance
frontotemporal dementia and/or amyotrophic lateral sclerosis 1	Definitive	Autosomal dominant
progressive myoclonus epilepsy	Limited	Autosomal dominant

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
frontotemporal dementia and/or amyotrophic lateral sclerosis 1	Definitive	AD

Mondo (4): frontotemporal dementia and/or amyotrophic lateral sclerosis 1 (MONDO:0007105), amyotrophic lateral sclerosis (MONDO:0004976), autism spectrum disorder (MONDO:0005258), progressive myoclonus epilepsy (MONDO:0020074)

Orphanet (3): Frontotemporal dementia with motor neuron disease (Orphanet:275872), Amyotrophic lateral sclerosis (Orphanet:803), NON RARE IN EUROPE: Autism (Orphanet:106)

HPO phenotypes

24 total (24 of 24 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000605	Supranuclear gaze palsy
HP:0000716	Depression
HP:0000726	Dementia
HP:0000738	Hallucinations
HP:0000741	Apathy
HP:0000746	Delusion
HP:0001260	Dysarthria
HP:0001300	Parkinsonism
HP:0001324	Muscle weakness
HP:0002059	Cerebral atrophy
HP:0002145	Frontotemporal dementia
HP:0002171	Gliosis
HP:0002186	Apraxia
HP:0002273	Tetraparesis
HP:0002366	Abnormal lower motor neuron morphology
HP:0002385	Paraparesis
HP:0002442	Dyscalculia
HP:0002529	Neuronal loss in central nervous system
HP:0003202	Skeletal muscle atrophy
HP:0003581	Adult onset
HP:0003678	Rapidly progressive
HP:0007308	Extrapyramidal dyskinesia
HP:0007354	Amyotrophic lateral sclerosis

GWAS associations

13 associations (top):

Study	Trait	p-value
GCST000481_2	Amyotrophic lateral sclerosis	1.000000e-08
GCST000481_7	Amyotrophic lateral sclerosis	7.000000e-09
GCST000781_1	Amyotrophic lateral sclerosis	9.000000e-11
GCST001664_7	Amyotrophic lateral sclerosis	4.000000e-07
GCST001946_1	PCA3 expression level	2.000000e-07
GCST002509_1	Amyotrophic lateral sclerosis	6.000000e-10
GCST004692_5	Amyotrophic lateral sclerosis	4.000000e-19
GCST004901_2	Amyotrophic lateral sclerosis (sporadic)	3.000000e-23
GCST005647_2	Amyotrophic lateral sclerosis	4.000000e-30
GCST005851_12	Delirium	9.000000e-07
GCST007146_1	Amyotrophic lateral sclerosis	3.000000e-15
GCST008978_1	Amyotrophic lateral sclerosis	2.000000e-06
GCST009391_1297	Metabolite levels	5.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0005127	cancer biomarker measurement
EFO:0010549	xanthosine measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D000690	Amyotrophic Lateral Sclerosis	C10.228.854.139; C10.574.562.250; C10.574.950.050; C10.668.467.250; C18.452.845.800.050
D020191	Myoclonic Epilepsies, Progressive	C10.228.140.490.375.130.650; C10.228.140.490.493.063.650

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

2 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs3849942	Efficacy	3	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Rheumatoid arthritis
rs774359	Efficacy	3	Tumor necrosis factor alpha (TNF-alpha) inhibitors	Rheumatoid arthritis

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs774359	C9orf72	3	2.25	1	Tumor necrosis factor alpha (TNF-alpha) inhibitors
rs3849942	C9orf72	3	0.00	1	Tumor necrosis factor alpha (TNF-alpha) inhibitors

CTD chemical–gene interactions

46 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression, increases expression, increases methylation, affects cotreatment	5
trichostatin A	affects cotreatment, decreases expression	3
Cyclosporine	increases expression	3
entinostat	decreases expression, affects cotreatment	2
Panobinostat	affects cotreatment, decreases expression	2
Nickel	increases expression	2
GSK-J4	increases expression	1
dicrotophos	decreases expression	1
alpha phellandrene	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
o,p’-DDT	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases abundance, increases expression, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
pentabromodiphenyl ether	increases expression	1
6-formylindolo(3,2-b)carbazole	increases expression	1
2-palmitoylglycerol	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	decreases expression	1
MT19c compound	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Leflunomide	increases expression	1
Acetaminophen	increases expression	1
Arsenic	increases abundance, increases expression, affects cotreatment	1
Benzo(a)pyrene	decreases expression	1
Calcitriol	increases expression	1

Cellosaurus cell lines

162 cell lines: 75 transformed cell line, 55 induced pluripotent stem cell, 22 finite cell line, 8 cancer cell line, 2 embryonic stem cell

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_1N98	ND42765	Induced pluripotent stem cell	Female
CVCL_1N99	ND43208	Induced pluripotent stem cell	Female
CVCL_9S54	UCLi001-A	Induced pluripotent stem cell	Male
CVCL_9S55	UCLi002-A	Induced pluripotent stem cell	Male
CVCL_A3KR	HEK293 C9orf72+/-	Transformed cell line	Female
CVCL_A3KS	HEK293 C9orf72-/- A	Transformed cell line	Female
CVCL_A3KT	HEK293 C9orf72-/- B	Transformed cell line	Female
CVCL_A4HP	U2OS C9orf72-/-	Cancer cell line	Female
CVCL_A9SR	F09229	Finite cell line	Male
CVCL_A9T5	F09128	Finite cell line	Male

Clinical trials (associated diseases)

302 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
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
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)
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
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
NCT00372879	PHASE3	COMPLETED	Clinical Trial of Vitamin E to Treat Muscular Cramps in Patients With ALS
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)
NCT00839033	PHASE3	TERMINATED	Evaluation of a Mechanical Device During Acute Respiratory Failure in Patients With Neuromuscular Disorders
NCT00868166	PHASE3	COMPLETED	Safety and Efficacy of TRO19622 as add-on Therapy to Riluzole Versus Placebo in Treatment of Patients Suffering From ALS
NCT00965497	PHASE3	COMPLETED	Escitalopram (Lexapro) for Depression MS or ALS
NCT01016522	PHASE3	TERMINATED	Safety and Tolerability of the Ketogenic Diet in Amyotrophic Lateral Sclerosis (ALS)
NCT01160263	PHASE3	COMPLETED	Study of Dopamine and Serotonin Transporters in Patients With Amyotrophic Lateral Sclerosis and Controls
NCT01281189	PHASE3	COMPLETED	Phase 3 Study of Dexpramipexole in ALS
NCT01492686	PHASE3	COMPLETED	Phase 3 Study of MCI-186 for Treatment of Amyotrophic Lateral Sclerosis
NCT01583088	PHASE3	TERMINATED	Early Stage Amyotrophic Lateral Sclerosis Phrenic Stimulation
NCT01622088	PHASE3	TERMINATED	Phase 3 Extension Study of Dexpramipexole in ALS
NCT02496767	PHASE3	COMPLETED	Ventilatory Investigation of Tirasemtiv and Assessment of Longitudinal Indices After Treatment for a Year
NCT02623699	PHASE3	COMPLETED	An Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of BIIB067 (Tofersen) in Adults With Inherited Amyotrophic Lateral Sclerosis (ALS)
NCT02936635	PHASE3	COMPLETED	A Study for Patients Who Completed VITALITY-ALS (CY 4031)
NCT03127267	PHASE3	RECRUITING	Efficacy and Safety of Masitinib Versus Placebo in the Treatment of ALS Patients
NCT03280056	PHASE3	COMPLETED	Safety and Efficacy of Repeated Administrations of NurOwn® in ALS Patients
NCT03491462	PHASE3	COMPLETED	Arimoclomol in Amyotropic Lateral Sclerosis
NCT03505021	PHASE3	COMPLETED	Effects of Oral Levosimendan (ODM-109) on Respiratory Function in Patients With ALS
NCT03548311	PHASE3	COMPLETED	Clinical Trial of Ultra-high Dose Methylcobalamin for ALS
NCT03690791	PHASE3	UNKNOWN	Efficacy of Cannabinoids in Amyotrophic Lateral Sclerosis or Motor Neurone Disease
NCT03800524	PHASE3	UNKNOWN	Safety and Efficacy of TUDCA as add-on Treatment in Patients Affected by ALS
NCT03836716	PHASE3	TERMINATED	Arimoclomol in Amyotropic Lateral Sclerosis - Open Label Extension Trial
NCT03948178	PHASE3	TERMINATED	Effects of Oral Levosimendan on Respiratory Function in Patients With Amyotrophic Lateral Sclerosis (ALS): Open-Label Extension
NCT04165824	PHASE3	COMPLETED	Safety Study of Oral Edaravone Administered in Subjects With ALS
NCT04248465	PHASE3	TERMINATED	An Efficacy and Safety Study of Ravulizumab in ALS Participants
NCT04569084	PHASE3	TERMINATED	Efficacy and Safety Study of Oral Edaravone Administered in Subjects With ALS