C9ORF72

Chr 9AD

C9orf72-SMCR8 complex subunit

Also known as: ALSFTD, DENND9, DENNL72, FTDALS, FTDALS1

The C9ORF72 protein functions as a guanine nucleotide exchange factor for Rab GTPases and regulates autophagy, endosomal trafficking, and axon growth in motor neurons. Hexanucleotide repeat expansions in this gene cause frontotemporal dementia and amyotrophic lateral sclerosis, typically with adult onset. Inheritance is autosomal dominant.

OMIMResearchSummary from RefSeq, OMIM, UniProt
ADLOEUF 0.931 OMIM phenotype
Clinical SummaryC9ORF72
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Gene-Disease Validity (ClinGen)
frontotemporal dementia and/or amyotrophic lateral sclerosis 1 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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Clinical Trials
12 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint
0.93LOEUF
pLI 0.000
Z-score 1.82
OE 0.58 (0.380.93)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
0.24Z-score
OE missense 0.96 (0.861.06)
240 obs / 250.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.58 (0.380.93)
00.351.4
Missense OE0.96 (0.861.06)
00.61.4
Synonymous OE1.16
01.21.6
LoF obs/exp: 13 / 22.3Missense obs/exp: 240 / 250.9Syn Z: -1.20

ClinVar Variant Classifications

0 submitted variants in ClinVar

Protein Context — Lollipop Plot

C9ORF72 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

Amyotrophic Lateral SclerosisFrontotemporal DementiaALS-Frontotemporal Dementia

TRIAL READY (Clinical Trial Readiness)

ACTIVE NOT RECRUITING
NCT03912987University of MiamiStarted 2019-01-22
Amyotrophic Lateral Sclerosis

Development of Targeted RNA-Seq for Amyotrophic Lateral Sclerosis Diagnosis

RECRUITING
NCT06083584Centre Hospitalier Universitaire de NīmesStarted 2023-11-22
RNA sequencing
Amyotrophic Lateral Sclerosis

Needs of ALS Patients With C9orf72 Mutation and Their Caregivers

RECRUITING
NCT07302321Istituto Auxologico ItalianoStarted 2025-10-01
Survey for ALS patientsSurvey for Caregivers
Frontotemporal Lobar Degeneration (FTLD)Progressive Supranuclear Palsy (PSP)Corticobasal Degeneration (CBD)

ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD)

RECRUITING
NCT04363684Mayo ClinicStarted 2020-03-01
Frontotemporal DementiaFrontotemporal Lobar DegenerationFTD-GRN

Neurofilament Surveillance Project (NSP)

ACTIVE NOT RECRUITING
NCT04516499The Bluefield Project to Cure Frontotemporal DementiaStarted 2020-09-02
C9orf72 Amyotrophic Lateral Sclerosis (ALS)Frontotemporal Dementia

Safety and Therapeutic Potential of the FDA-approved Drug Metformin for C9orf72 ALS/FTD

ACTIVE NOT RECRUITING
NCT04220021Phase PHASE2University of FloridaStarted 2020-01-10
Metformin
Neurodegenerative DiseasesDementia

Neurofilament Light Chain And Voice Acoustic Analyses In Dementia Diagnosis

RECRUITING
NCT06339190Monash UniversityStarted 2021-08-01
Venepuncture
ALS

Amyotrophic Lateral Sclerosis (ALS) Families Project

RECRUITING
NCT03865420Columbia UniversityStarted 2018-09-11
Cerebellar Ataxias

The Benefits of Long-read High-throughput Genomic Sequencing for the Causal Diagnosis of Cerebellar Ataxias

RECRUITING
NCT06467175Phase NACentre Hospitalier Universitaire DijonStarted 2024-12-11
blood sampling for high molecular weight DNA extraction
Frontotemporal DementiaFTDFTD-GRN

A Study of PBFT02 in Participants With FTD and Mutations in the Granulin Precursor (GRN) or C9ORF72 Genes

RECRUITING
NCT04747431Phase PHASE1, PHASE2Passage Bio, Inc.Started 2021-09-14
PBFT02
Bipolar DisorderFrontotemporal Dementia, Behavioral Variant

A Study of the Behavioral Variant of Frontotemporal Dementia and Bipolar Disorder: a Neuroimaging and Epigenetics Integrated Approach

RECRUITING
NCT06706687Phase NAFondazione IRCCS Ca' Granda, Ospedale Maggiore PoliclinicoStarted 2021-05-19
DISBAND protocol
Corticobasal Syndrome(CBS)Primary Progressive Aphasia(PPA)Progressive Supranuclear Palsy(PSP)

Neuroinflammation in FTLD

ACTIVE NOT RECRUITING
NCT06870838Leiden University Medical CenterStarted 2023-07-25
7T MRI scanCSFBlood withdrawal
Clinical Literature
Open Research Assistant →
Key Publications
Landmark & review papers · by relevance
PubMed
The genetics of amyotrophic lateral sclerosis.
Nijs M et al.·Curr Opin Neurol
2024Review
C9orf72-mediated ALS and FTD: multiple pathways to disease.
Balendra R et al.·Nat Rev Neurol
2018Review
The Genetics of C9orf72 Expansions.
Gijselinck I et al.·Cold Spring Harb Perspect Med
2018Review
Chorea.
Termsarasab P·Continuum (Minneap Minn)
2019Review
Chorea.
Mestre TA·Continuum (Minneap Minn)
2016Review
Top 5 results · since 2015Search PubMed ↗