AFG3L2

Summary

AFG3L2 (AFG3 like matrix AAA peptidase subunit 2, HGNC:315) is a protein-coding gene on chromosome 18p11.21, encoding Mitochondrial inner membrane m-AAA protease component AFG3L2 (Q9Y4W6). Catalytic component of the m-AAA protease, a protease that plays a key role in proteostasis of inner mitochondrial membrane proteins, and which is essential for axonal and neuron development. It is a common-essential gene (DepMap: required in 97.2% of cancer cell lines).

This gene encodes a protein localized in mitochondria and closely related to paraplegin. The paraplegin gene is responsible for an autosomal recessive form of hereditary spastic paraplegia. This gene is a candidate gene for other hereditary spastic paraplegias or neurodegenerative disorders.

Source: NCBI Gene 10939 — RefSeq curated summary.

At a glance

• Gene–disease (curated): AFG3L2-related optic atrophy and/or spastic ataxia spectrum (Definitive, ClinGen) — +3 more curated relationships
• Clinical variants (ClinVar): 614 total — 44 pathogenic, 32 likely-pathogenic
• Phenotypes (HPO): 88
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 97.2% of screened cell lines (common-essential)
• MANE Select transcript: NM_006796

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:315
Approved symbol	AFG3L2
Name	AFG3 like matrix AAA peptidase subunit 2
Location	18p11.21
Locus type	gene with protein product
Status	Approved
Aliases	SPAX5
Ensembl gene	ENSG00000141385
Ensembl biotype	protein_coding
OMIM	604581
Entrez	10939

Gene structure

Transcript identifiers

Ensembl transcripts: 50 — 42 protein_coding, 4 retained_intron, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000269143, ENST00000588893, ENST00000590811, ENST00000591848, ENST00000683671, ENST00000687337, ENST00000687477, ENST00000688199, ENST00000691179, ENST00000691970, ENST00000692497, ENST00000692988, ENST00000889391, ENST00000889392, ENST00000889393, ENST00000889394, ENST00000889395, ENST00000889396, ENST00000889397, ENST00000889398, ENST00000889399, ENST00000889400, ENST00000889401, ENST00000889402, ENST00000889403, ENST00000889404, ENST00000889405, ENST00000889406, ENST00000889407, ENST00000889408, ENST00000889409, ENST00000889410, ENST00000889411, ENST00000889412, ENST00000918896, ENST00000918897, ENST00000918898, ENST00000918899, ENST00000918900, ENST00000918901, ENST00000964852, ENST00000964853, ENST00000964854, ENST00000964855, ENST00000964856, ENST00000964857, ENST00000964858, ENST00000964859, ENST00000964860, ENST00000964861

RefSeq mRNA: 1 — MANE Select: NM_006796 NM_006796

CCDS: CCDS11859

Canonical transcript exons

ENST00000269143 — 17 exons

Exon	Start	End
ENSE00001018385	12359927	12360051
ENSE00001018386	12366965	12367117
ENSE00001018387	12358670	12358943
ENSE00001018389	12370849	12370926
ENSE00001120659	12367276	12367382
ENSE00001183718	12363782	12363856
ENSE00001183731	12356694	12356831
ENSE00001255259	12337341	12337535
ENSE00001255265	12340201	12340401
ENSE00001255270	12344132	12344247
ENSE00001255275	12348273	12348383
ENSE00001255282	12351085	12351210
ENSE00001255288	12351306	12351413
ENSE00001255297	12353005	12353158
ENSE00001255347	12371592	12371691
ENSE00001255359	12328944	12329783
ENSE00001255364	12376969	12377227

Expression profiles

Bgee: expression breadth ubiquitous, 288 present calls, max score 99.50.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 49.2279 / max 401.3310, expressed in 1824 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
171235	39.3487	1823
171231	4.6019	1648
171232	1.7400	979
171234	1.4716	929
171233	1.1021	721
171236	0.9636	605

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
Brodmann (1909) area 23	UBERON:0013554	99.50	gold quality
endothelial cell	CL:0000115	99.28	gold quality
jejunal mucosa	UBERON:0000399	99.21	gold quality
parietal pleura	UBERON:0002400	99.05	gold quality
esophagus squamous epithelium	UBERON:0006920	98.98	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.92	gold quality
renal medulla	UBERON:0000362	98.88	gold quality
gingival epithelium	UBERON:0001949	98.85	gold quality
biceps brachii	UBERON:0001507	98.83	gold quality
heart right ventricle	UBERON:0002080	98.82	gold quality
germinal epithelium of ovary	UBERON:0001304	98.81	gold quality
jejunum	UBERON:0002115	98.81	gold quality
tibia	UBERON:0000979	98.65	gold quality
visceral pleura	UBERON:0002401	98.60	gold quality
mucosa of sigmoid colon	UBERON:0004993	98.51	gold quality
body of tongue	UBERON:0011876	98.45	gold quality
gingiva	UBERON:0001828	98.41	gold quality
middle temporal gyrus	UBERON:0002771	98.38	gold quality
colonic mucosa	UBERON:0000317	98.34	gold quality
amniotic fluid	UBERON:0000173	98.10	gold quality
epithelium of nasopharynx	UBERON:0001951	98.10	gold quality
nasopharynx	UBERON:0001728	98.07	gold quality
pleura	UBERON:0000977	98.03	gold quality
oral cavity	UBERON:0000167	97.89	gold quality
lateral nuclear group of thalamus	UBERON:0002736	97.88	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.83	gold quality
pharyngeal mucosa	UBERON:0000355	97.63	gold quality
pigmented layer of retina	UBERON:0001782	97.61	gold quality
skin of hip	UBERON:0001554	97.60	gold quality
penis	UBERON:0000989	97.59	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	8.11

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

36 targeting AFG3L2, 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-4262	100.00	73.26	3931
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-548AA	99.96	70.64	3753
HSA-MIR-548AP-3P	99.96	70.64	3753
HSA-MIR-548T-3P	99.96	70.64	3753
HSA-MIR-4495	99.82	72.08	3080
HSA-MIR-374C-5P	99.80	72.06	2910
HSA-MIR-655-3P	99.80	72.19	2909
HSA-MIR-3617-5P	99.75	69.41	1968
HSA-MIR-641	99.75	69.35	1975
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-1825	99.72	68.11	1089
HSA-MIR-4699-3P	99.71	70.15	3142
HSA-MIR-3975	99.62	65.97	697
HSA-MIR-548AV-5P	99.60	70.84	2107
HSA-MIR-548K	99.60	70.84	2107
HSA-MIR-3120-3P	99.54	70.28	2669
HSA-MIR-5007-3P	99.51	68.14	1242
HSA-MIR-302B-5P	99.50	69.49	1857
HSA-MIR-302D-5P	99.50	69.34	1863
HSA-MIR-8054	99.48	70.81	2084
HSA-MIR-2116-5P	99.32	69.34	1273
HSA-MIR-4784	99.15	67.41	1733
HSA-MIR-485-5P	99.10	64.78	1889
HSA-MIR-6884-5P	99.10	64.50	1987
HSA-MIR-4478	99.07	65.16	2320

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 97.2% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 29)

• An intersubunit signaling network coordinates ATP hydrolysis by m-AAA protease AGG3L2. (PMID:19748354)
• work identifies AFG3L2 as a novel cause of dominant neurodegenerative disease and indicates a previously unknown role for this component of the mitochondrial protein quality control machinery in protecting the human cerebellum against neurodegeneration. (PMID:20208537)
• in spinocerebellar ataxia type 28 patients study found novel missense mutation at an evolutionarily conserved amino-acid position; amino-acid exchange p.E700K was detected in a 4-generation family and was not observed in chromosomes of controls (PMID:20354562)
• We further confirm both the involvement of AFG3L2 gene in Spinocerebellar ataxia type 28 (SCA28) and the presence of a mutational hotspot in exons 15-16. (PMID:20725928)
• The mutations of SCA28 are associated with amino acid changes in evolutionarily conserved residues of the alleged SCA28 gene, and indicate SCA28 as the sixth recognized SCA genotype caused by point mutations. (PMID:21827917)
• These findings expand the phenotype associated with AFG3L2 mutations and suggest that AFG3L2-related disease should be considered in the differential diagnosis of spastic ataxias. (PMID:22022284)
• Both full-length and truncated COX1 proteins physically interact with AFG3L2. (PMID:22252130)
• Here, we report on a novel AFG3L2 mutation in a patient with slowly progressive ataxia and a positive family history. (PMID:24293060)
• StAR proteolysis is executed by at least 2 mitochondrial proteases, the matrix LON protease and the inner membrane complexes of the metalloproteases AFG3L2 and AFG3L2:SPG7/paraplegin. (PMID:24422629)
• Identification of a partial AFG3L2 deletion and subsequent functional studies reveal loss of function as the most likely disease mechanism. (PMID:24814845)
• Deletion of AFG3L2 associated with spinocerebellar ataxia type 28 in the context of multiple genomic anomalies. (PMID:25251419)
• This study that AFG3L2 mutations are another important cause, albeit rare, of a late-onset ataxic PEO phenotype due to a disturbance of mtDNA maintenance. (PMID:25420100)
• AOA2 with myoclonus associated with mutations in SETX and AFG3L2 (PMID:25927548)
• we identify AFG3L2 [matrix (m)-AAA complex] as the major protease mediating this event, which acts by maturing the 60 kDa pre-pro-OMA1 to the 40 kDa pro-OMA1 form by severing the N-terminal portion without recognizing a specific consensus sequence. (PMID:29545505)
• Created are solubilized forms of AFG3L2 to examine the enzyme’s substrate specificity mechanisms. The study shows that conserved residues within the presequence of the mitochondrial ribosomal protein, MrpL32, target the subunit to the protease for processing into a mature form. Moreover, these residues can act as a degron, delivering diverse model proteins to AFG3L2 for degradation. (PMID:29932645)
• Data report here co-occurrence of a heterozygous de novo AFG3L2 missense mutation (p.R468C) and a maternally inherited heterozygous intragenic deletion of SPG7 in a patient with a complex ataxic and extrapyramidal phenotype with early-onset optic atrophy. Functional analysis in yeast demonstrated the pathogenic role of AFG3L2 p.R468C mutation shedding light on its pathogenic mechanism. (PMID:30252181)
• Mice harbouring a SCA28 patient mutation in AFG3L2 develop late-onset ataxia associated with enhanced mitochondrial proteotoxicity. (PMID:30389403)
• Our data identify the earliest events in SCA28 pathogenesis and open new perspectives for therapy. By identifying similar mitochondrial phenotypes between SCA28 cells and AFG3L2(+/-) cells, our results support haploinsufficiency as the mechanism for the studied pathogenic variants. (PMID:30910913)
• AFG3L2 variants should be considered in both slowly progressive ataxias and phenotypes with clinical features reminiscent of mitochondrial disease (PMID:31111429)
• results provide a molecular basis for neurological phenotypes associated with different AFG3L2 mutations and establish a structural framework to understand how different members of the AAA+ superfamily achieve specialized biological functions. (PMID:31327635)
• ATPase Domain AFG3L2 Mutations Alter OPA1 Processing and Cause Optic Neuropathy. (PMID:32219868)
• Spastic ataxia with eye-of-the-tiger-like sign in 4 siblings due to novel compound heterozygous AFG3L2 mutation. (PMID:32248051)
• A novel AFG3L2 mutation close to AAA domain leads to aberrant OMA1 and OPA1 processing in a family with optic atrophy. (PMID:32600459)
• Inactivation of the mitochondrial protease Afg3l2 results in severely diminished respiratory chain activity and widespread defects in mitochondrial gene expression. (PMID:33075064)
• Expanding the phenotype of AFG3L2 mutations: Late-onset autosomal recessive spinocerebellar ataxia. (PMID:34333379)
• AFG3L2 Biallelic Mutation: Clinical Heterogeneity in Two Italian Patients. (PMID:36447112)
• Autoregulatory control of mitochondrial glutathione homeostasis. (PMID:37917749)
• Dual regulation of SLC25A39 by AFG3L2 and iron controls mitochondrial glutathione homeostasis. (PMID:38157846)
• AFG3L2 and ACO2-Linked Dominant Optic Atrophy: Genotype-Phenotype Characterization Compared to OPA1 Patients. (PMID:38278202)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	afg3l2	ENSDARG00000062272
mus_musculus	Afg3l2	ENSMUSG00000024527
rattus_norvegicus	Afg3l2	ENSRNOG00000017965

Paralogs (2): YME1L1 (ENSG00000136758), SPG7 (ENSG00000197912)

Protein

Protein identifiers

Mitochondrial inner membrane m-AAA protease component AFG3L2 — Q9Y4W6 (reviewed: Q9Y4W6)

Alternative names: AFG3-like protein 2, Paraplegin-like protein

All UniProt accessions (7): A0A8I5KRT8, A0A8I5KVV1, A0A8I5KXN0, A0A8I5KYF5, A0A8I5QJR7, Q9Y4W6, K7EP56

UniProt curated annotations — full annotation on UniProt →

Function. Catalytic component of the m-AAA protease, a protease that plays a key role in proteostasis of inner mitochondrial membrane proteins, and which is essential for axonal and neuron development. AFG3L2 possesses both ATPase and protease activities: the ATPase activity is required to unfold substrates, threading them into the internal proteolytic cavity for hydrolysis into small peptide fragments. The m-AAA protease carries out quality control in the inner membrane of the mitochondria by mediating degradation of mistranslated or misfolded polypeptides. The m-AAA protease complex also promotes the processing and maturation of mitochondrial proteins, such as MRPL32/bL32m, PINK1 and SP7. Mediates protein maturation of the mitochondrial ribosomal subunit MRPL32/bL32m by catalyzing the cleavage of the presequence of MRPL32/bL32m prior to assembly into the mitochondrial ribosome. Required for SPG7 maturation into its active mature form after SPG7 cleavage by mitochondrial-processing peptidase (MPP). Required for the maturation of PINK1 into its 52kDa mature form after its cleavage by mitochondrial-processing peptidase (MPP). Acts as a regulator of calcium in neurons by mediating degradation of SMDT1/EMRE before its assembly with the uniporter complex, limiting the availability of SMDT1/EMRE for MCU assembly and promoting efficient assembly of gatekeeper subunits with MCU. Promotes the proteolytic degradation of GHITM upon hyperpolarization of mitochondria: progressive GHITM degradation leads to respiratory complex I degradation and broad reshaping of the mitochondrial proteome by AFG3L2. Also acts as a regulator of mitochondrial glutathione homeostasis by mediating cleavage and degradation of SLC25A39. SLC25A39 cleavage is prevented when SLC25A39 binds iron-sulfur. Involved in the regulation of OMA1-dependent processing of OPA1. May act by mediating processing of OMA1 precursor, participating in OMA1 maturation.

Subunit / interactions. Homohexamer. Forms heterohexamers with SPG7. The m-AAA protease is either composed of homohexamers of AFG3L2 or heterohexamers of AFG3L2 and SPG7. Interacts with MAIP1. Interacts with DNAJC19. Interacts with PHB2.

Subcellular location. Mitochondrion inner membrane.

Tissue specificity. Ubiquitous. Highly expressed in the cerebellar Purkinje cells.

Post-translational modifications. Upon import into the mitochondrion, the N-terminal transit peptide is cleaved to generate an intermediate form which undergoes autocatalytic proteolytic processing to generate the proteolytically active mature form.

Disease relevance. Spinocerebellar ataxia 28 (SCA28) [MIM:610246] Spinocerebellar ataxia is a clinically and genetically heterogeneous group of cerebellar disorders. Patients show progressive incoordination of gait and often poor coordination of hands, speech and eye movements, due to degeneration of the cerebellum with variable involvement of the brainstem and spinal cord. SCA28 is an autosomal dominant cerebellar ataxia (ADCA) with a slow progressive course and no evidence of sensory involvement or cognitive impairment. The disease is caused by variants affecting the gene represented in this entry. Spastic ataxia 5, autosomal recessive (SPAX5) [MIM:614487] A neurodegenerative disorder characterized by early onset spasticity, peripheral neuropathy, ptosis, oculomotor apraxia, dystonia, cerebellar atrophy, and progressive myoclonic epilepsy. The disease is caused by variants affecting the gene represented in this entry. Optic atrophy 12 (OPA12) [MIM:618977] An autosomal dominant disease characterized by progressive visual loss in association with optic atrophy. Atrophy of the optic disk indicates a deficiency in the number of nerve fibers which arise in the retina and converge to form the optic disk, optic nerve, optic chiasm and optic tracts. OPA12 patients manifest slowly progressive visual impairment with onset usually in the first decade. Some patients may exhibit additional features including impaired intellectual development, dystonia, movement disorders, or ataxia. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 zinc ion per subunit.

Similarity. In the N-terminal section; belongs to the AAA ATPase family. In the C-terminal section; belongs to the peptidase M41 family.

RefSeq proteins (1): NP_006787* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000642	Peptidase_M41	Domain
IPR003593	AAA+_ATPase	Domain
IPR003959	ATPase_AAA_core	Domain
IPR003960	ATPase_AAA_CS	Conserved_site
IPR005936	FtsH	Family
IPR011546	Pept_M41_FtsH_extracell	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR037219	Peptidase_M41-like	Homologous_superfamily
IPR041569	AAA_lid_3	Domain
IPR050928	ATP-dep_Zn_Metalloprotease	Family

Pfam: PF00004, PF01434, PF06480, PF17862

Enzyme classification (BRENDA):

• EC 3.4.24.B18 — (BRENDA: organisms, substrates, inhibitors, Km, kcat entries)

Catalyzed reactions (Rhea), 1 shown:

• ATP + H2O = ADP + phosphate + H(+) (RHEA:13065)

UniProt features (122 total): sequence variant 36, helix 23, strand 17, binding site 11, turn 9, mutagenesis site 9, compositionally biased region 3, topological domain 3, transmembrane region 2, sequence conflict 2, region of interest 2, transit peptide 1, propeptide 1, active site 1, chain 1, modified residue 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6NYY	ELECTRON MICROSCOPY	3
2LNA	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y4W6-F1	77.07	0.39

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 575

Ligand- & substrate-binding residues (11): 310; 311; 352; 353; 354; 355; 356; 490; 574; 578; 649

Post-translational modifications (1): 117

Mutagenesis-validated functional residues (9):

Position	Phenotype
289	reduced rate of protein degradation.
299	reduced rate of protein degradation.
354	does not effect activity of the m-aaa protease complex.
380	abolished atpase and protease activities.
380	increased atp hydrolysis.
408	abolished atpase activity, leading to impaired activity of the m-aaa protease complex, preventing cleavage and degradati
421	impairted protease activity without affecting the atpase activity.
575	abolished protease activity. loss of autocatalytic processing. impaired proteolytic maturation of spg7.
779	impaired ability to degrade substrates without affecting the atpase activity.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-8949664	Processing of SMDT1
R-HSA-9837999	Mitochondrial protein degradation
R-HSA-382551	Transport of small molecules
R-HSA-392499	Metabolism of proteins
R-HSA-8949215	Mitochondrial calcium ion transport

MSigDB gene sets: 394 (showing top): MORF_MTA1, GOBP_NEUROMUSCULAR_JUNCTION_DEVELOPMENT, MORF_DNMT1, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, MORF_ESPL1, GOMF_METALLOPEPTIDASE_ACTIVITY, BASSO_B_LYMPHOCYTE_NETWORK, RORA1_01, GOBP_REGULATION_OF_DEVELOPMENTAL_GROWTH, MORF_RRM1, GOBP_GROWTH, MORF_HDAC1, GOBP_MACROMOLECULE_CATABOLIC_PROCESS, MORF_CDK2, GOBP_NEUROGENESIS

GO Biological Process (23): proteolysis (GO:0006508), axonogenesis (GO:0007409), neuromuscular junction development (GO:0007528), mitochondrial fusion (GO:0008053), protein processing (GO:0016485), protein autoprocessing (GO:0016540), nerve development (GO:0021675), protein catabolic process (GO:0030163), membrane protein proteolysis (GO:0033619), mitochondrial protein processing (GO:0034982), calcium import into the mitochondrion (GO:0036444), regulation of multicellular organism growth (GO:0040014), cristae formation (GO:0042407), myelination (GO:0042552), mitochondrial calcium ion homeostasis (GO:0051560), protein maturation (GO:0051604), muscle cell development (GO:0055001), righting reflex (GO:0060013), cellular response to glutathione (GO:0072753), regulation of calcium import into the mitochondrion (GO:0110097), mitochondrial protein quality control (GO:0141164), mitochondrion organization (GO:0007005), glutathione import into mitochondrion (GO:0160007)

GO Molecular Function (12): ATP-dependent peptidase activity (GO:0004176), metalloendopeptidase activity (GO:0004222), ATP binding (GO:0005524), metallopeptidase activity (GO:0008237), zinc ion binding (GO:0008270), ATP hydrolysis activity (GO:0016887), obsolete unfolded protein binding (GO:0051082), nucleotide binding (GO:0000166), protein binding (GO:0005515), peptidase activity (GO:0008233), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (10): mitochondrion (GO:0005739), mitochondrial inner membrane (GO:0005743), m-AAA complex (GO:0005745), perinuclear theca (GO:0033011), sperm midpiece (GO:0097225), sperm principal piece (GO:0097228), sperm head-tail coupling apparatus (GO:0120212), sperm glycocalyx (GO:0120238), membrane (GO:0016020), mitochondrial membrane (GO:0031966)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Mitochondrial calcium ion transport	1
Metabolism of proteins	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
protein metabolic process	3
mitochondrion	3
proteolysis	2
protein processing	2
peptidase activity	2
ATP-dependent activity	2
sperm flagellum	2
cell morphogenesis involved in neuron differentiation	1
neuron projection morphogenesis	1
axon development	1
synapse organization	1
mitochondrion organization	1
organelle fusion	1
protein maturation	1
nervous system development	1
anatomical structure development	1
macromolecule catabolic process	1
mitochondrial calcium ion transmembrane transport	1
intercellular transport	1
multicellular organism growth	1
regulation of developmental growth	1
regulation of multicellular organismal process	1
inner mitochondrial membrane organization	1
axon ensheathment	1
intracellular calcium ion homeostasis	1
gene expression	1
muscle cell differentiation	1
cell development	1
reflex	1
response to glutathione	1
cellular response to nitrogen compound	1
cellular response to oxygen-containing compound	1
calcium import into the mitochondrion	1
regulation of calcium ion transmembrane transport	1
endopeptidase activity	1
metallopeptidase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
transition metal ion binding	1

Protein interactions and networks

STRING

3671 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
AFG3L2	SPG7	Q9UQ90	927
AFG3L2	HSPA9	P30036	814
AFG3L2	OMA1	Q96E52	748
AFG3L2	LYRM4	Q9HD34	736
AFG3L2	HSPD1	P10809	727
AFG3L2	CLPP	Q16740	716
AFG3L2	LONP1	P36776	710
AFG3L2	SDHA	P31040	700
AFG3L2	PARL	Q9H300	685
AFG3L2	A0A1W2PP11	A0A1W2PP11	677
AFG3L2	FXN	Q16595	671
AFG3L2	CLPX	O76031	665
AFG3L2	ISCU	Q9H1K1	649
AFG3L2	ACO2	Q99798	631
AFG3L2	ATP5MG	O75964	625

IntAct

173 interactions, top by confidence:

A	B	Type	Score
MED20	MED19	psi-mi:“MI:0914”(association)	0.840
BECN1	ZWINT	psi-mi:“MI:0914”(association)	0.750
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
GBA2	ILVBL	psi-mi:“MI:0914”(association)	0.640
HTT	AFG3L2	psi-mi:“MI:0915”(physical association)	0.560
TIMMDC1	NDUFS8	psi-mi:“MI:0914”(association)	0.530
COQ2	SLC25A5	psi-mi:“MI:0914”(association)	0.530
sseJ	AGPS	psi-mi:“MI:0914”(association)	0.460
AIFM1	HAX1	psi-mi:“MI:2364”(proximity)	0.420
TUBA1A	TUBAL3	psi-mi:“MI:0914”(association)	0.420
HTRA2	HAX1	psi-mi:“MI:2364”(proximity)	0.420
GJA10	AFG3L2	psi-mi:“MI:0915”(physical association)	0.400
	AGPS	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
AFG3L2	HSPA2	psi-mi:“MI:0915”(physical association)	0.370
AFG3L2	MAPK8IP2	psi-mi:“MI:0915”(physical association)	0.370
AFG3L2	RAC2	psi-mi:“MI:0915”(physical association)	0.370
NDUFA11	NDUFS8	psi-mi:“MI:0914”(association)	0.350
NDUFA13	SLC22A20P	psi-mi:“MI:0914”(association)	0.350
Cenpe	BBX	psi-mi:“MI:0914”(association)	0.350
Bmpr1a	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
Hspa14	TDG	psi-mi:“MI:0914”(association)	0.350
Tnpo1	CCHCR1	psi-mi:“MI:0914”(association)	0.350
Kctd5		psi-mi:“MI:0914”(association)	0.350

BioGRID (416): AFG3L2 (Affinity Capture-MS), AFG3L2 (Affinity Capture-MS), AFG3L2 (Affinity Capture-MS), AFG3L2 (Affinity Capture-MS), AFG3L2 (Co-fractionation), AFG3L2 (Co-fractionation), AFG3L2 (Co-fractionation), AFG3L2 (Co-fractionation), AFG3L2 (Co-fractionation), AFG3L2 (Co-fractionation), AFG3L2 (Co-fractionation), AFG3L2 (Co-fractionation), AFG3L2 (Co-fractionation), ATP1A1 (Co-fractionation), ATP5A1 (Co-fractionation)

ESM2 similar proteins: A1A4J8, A6H784, D3ZS74, D4A6D7, E9QBI7, O42899, O43819, O60341, O75880, P00258, P10109, P23833, P24483, P30048, P38072, Q05B51, Q0VCH8, Q12931, Q2KHU5, Q2NKY8, Q2TBI4, Q3ULF4, Q4VAE3, Q5EA41, Q5REY3, Q5RH02, Q5SUC9, Q69ZP3, Q6DKK2, Q6PI78, Q6ZQ88, Q7ZUC7, Q8BMS4, Q8JZQ2, Q8LAL0, Q8N490, Q8VCL2, Q920A7, Q95N00, Q96HS1

Diamond homologs: A2T308, A6H5M5, P15821, P31568, P31569, P61243, Q2KJI7, Q4L3G8, Q5SCW3, Q67JH0, Q859W7, Q85B60, Q85WV5, Q8JZQ2, Q8WHW9, Q9Y4W6, A0L4S0, A0LN68, A0PXM8, A1URA3, A6LD25, A6TWP7, A8F7F7, A9BFL9, A9BHD3, A9BJK3, A9EXK6, B0B970, B0K5A3, B1GZK7, B2A3Q4, B2UE66, B2UMY1, B3DV46, B3DY14, B4SCV5, B8D065, B8G4Q6, B8H444, B8J992

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 187 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Mitochondrial protein degradation	9	8.9×	5e-04
Mitochondrial protein import	6	8.7×	7e-03
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	8	6.7×	4e-03
Respiratory electron transport	8	6.6×	4e-03
PIP3 activates AKT signaling	10	5.8×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
stress granule assembly	5	19.9×	6e-03
peptidyl-tyrosine phosphorylation	5	13.9×	6e-03
amino acid transport	6	12.4×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	44
Likely pathogenic	32
Uncertain significance	295
Likely benign	132
Benign	53

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1021242	NM_006796.3(AFG3L2):c.121C>T (p.Arg41Ter)	Pathogenic
1027438	NM_006796.3(AFG3L2):c.634dup (p.Val212fs)	Pathogenic
1077182	Single allele	Pathogenic
144318	GRCh38/hg38 18p11.21(chr18:12159446-12739785)	Pathogenic
147418	GRCh38/hg38 18p11.22-11.21(chr18:10077657-14081888)x3	Pathogenic
1526594	GRCh37/hg19 18p11.32-11.21(chr18:136226-15198990)	Pathogenic
1676883	NM_006796.3(AFG3L2):c.1378G>A (p.Asp460Asn)	Pathogenic
2014169	NM_006796.3(AFG3L2):c.1993G>C (p.Gly665Arg)	Pathogenic
214059	NM_006796.3(AFG3L2):c.2067_2068del (p.Tyr689_Ser690delinsTer)	Pathogenic
2192635	NM_006796.3(AFG3L2):c.633C>G (p.Tyr211Ter)	Pathogenic
253619	GRCh37/hg19 18p11.32-11.21(chr18:14316-15328499)x1	Pathogenic
2745883	NM_006796.3(AFG3L2):c.2155_2156del (p.Lys719fs)	Pathogenic
2790911	NM_006796.3(AFG3L2):c.2104C>T (p.Arg702Ter)	Pathogenic
2838891	NM_006796.3(AFG3L2):c.416del (p.Asp139fs)	Pathogenic
30424	NM_006796.3(AFG3L2):c.1997T>G (p.Met666Arg)	Pathogenic
30425	NM_006796.3(AFG3L2):c.2011G>A (p.Gly671Arg)	Pathogenic
30427	NM_006796.3(AFG3L2):c.1847A>G (p.Tyr616Cys)	Pathogenic
3063542	GRCh37/hg19 18p11.31-11.21(chr18:2922899-15198990)x3	Pathogenic
3239393	NM_006796.3(AFG3L2):c.753-1G>C	Pathogenic
3242801	NC_000018.9:g.(?12337320)(12340420_?)del	Pathogenic
3251301	NM_006796.3(AFG3L2):c.1651C>T (p.Arg551Ter)	Pathogenic
3255229	NM_006796.3(AFG3L2):c.245dup (p.Asn82fs)	Pathogenic
3377390	NM_006796.3(AFG3L2):c.1168C>T (p.Arg390Ter)	Pathogenic
38389	NM_006796.3(AFG3L2):c.1997T>C (p.Met666Thr)	Pathogenic
38393	NM_006796.3(AFG3L2):c.2098G>A (p.Glu700Lys)	Pathogenic
4771070	NM_006796.3(AFG3L2):c.325_332del (p.Gly109fs)	Pathogenic
4774506	NM_006796.3(AFG3L2):c.2150_2151del (p.Thr717fs)	Pathogenic
4847721	NM_006796.3(AFG3L2):c.271G>T (p.Glu91Ter)	Pathogenic
5470	NM_006796.3(AFG3L2):c.2071G>A (p.Glu691Lys)	Pathogenic
5471	NM_006796.3(AFG3L2):c.2021_2022delinsTA (p.Ser674Leu)	Pathogenic

SpliceAI

2925 predictions. Top by Δscore:

Variant	Effect	Δscore
18:12337336:CCTA:C	donor_loss	1.0000
18:12337337:CTA:C	donor_loss	1.0000
18:12337340:C:CT	donor_loss	1.0000
18:12337340:CCTT:C	donor_gain	1.0000
18:12337532:CAAT:C	acceptor_gain	1.0000
18:12337536:C:CG	acceptor_loss	1.0000
18:12340199:A:AC	donor_gain	1.0000
18:12340200:C:CC	donor_gain	1.0000
18:12348381:CACCT:C	acceptor_loss	1.0000
18:12348382:ACCTA:A	acceptor_loss	1.0000
18:12348384:C:CA	acceptor_loss	1.0000
18:12348384:C:CC	acceptor_gain	1.0000
18:12348385:T:A	acceptor_loss	1.0000
18:12351080:CTCA:C	donor_loss	1.0000
18:12351081:TCA:T	donor_loss	1.0000
18:12351082:CA:C	donor_loss	1.0000
18:12351210:CCTT:C	acceptor_gain	1.0000
18:12351213:T:TC	acceptor_gain	1.0000
18:12351221:CA:C	acceptor_gain	1.0000
18:12351222:A:C	acceptor_gain	1.0000
18:12351222:A:T	acceptor_gain	1.0000
18:12351224:T:C	acceptor_gain	1.0000
18:12351224:T:TC	acceptor_gain	1.0000
18:12351226:T:C	acceptor_gain	1.0000
18:12351226:T:TC	acceptor_gain	1.0000
18:12351409:AAAAC:A	acceptor_gain	1.0000
18:12351410:AAAC:A	acceptor_gain	1.0000
18:12351411:AAC:A	acceptor_gain	1.0000
18:12351411:AACC:A	acceptor_loss	1.0000
18:12351412:AC:A	acceptor_gain	1.0000

AlphaMissense

5190 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
18:12337522:C:T	G665D	1.000
18:12340212:C:G	A657P	1.000
18:12340234:G:C	D649E	1.000
18:12340234:G:T	D649E	1.000
18:12340235:T:A	D649V	1.000
18:12340235:T:C	D649G	1.000
18:12340235:T:G	D649A	1.000
18:12340236:C:G	D649H	1.000
18:12340244:G:T	A646D	1.000
18:12340247:C:T	G645D	1.000
18:12340248:C:G	G645R	1.000
18:12340289:C:T	G631D	1.000
18:12340290:C:A	G631C	1.000
18:12340290:C:G	G631R	1.000
18:12340292:C:T	G630D	1.000
18:12340364:G:T	A606D	1.000
18:12340370:C:T	G604D	1.000
18:12340371:C:A	G604C	1.000
18:12340371:C:G	G604R	1.000
18:12340373:A:G	L603P	1.000
18:12340373:A:T	L603Q	1.000
18:12340394:A:T	I596N	1.000
18:12340398:A:G	S595P	1.000
18:12344139:A:T	L591H	1.000
18:12344164:A:G	W583R	1.000
18:12344164:A:T	W583R	1.000
18:12344166:C:T	G582D	1.000
18:12344172:A:T	V580D	1.000
18:12344175:G:T	A579E	1.000
18:12344181:C:T	G577D	1.000

dbSNP variants (sampled 300 via entrez): RS1000017165 (18:12367994 C>G), RS1000141847 (18:12347466 C>T), RS1000166081 (18:12350005 G>A,T), RS1000270201 (18:12344328 T>C), RS1000295053 (18:12355828 A>G), RS1000358901 (18:12375607 C>G), RS1000471844 (18:12375820 C>A,G,T), RS1000536894 (18:12371246 G>A), RS1000584226 (18:12372493 G>T), RS1000712302 (18:12377387 C>G,T), RS1000729608 (18:12330632 G>C), RS1000743344 (18:12377242 T>A,C), RS1000766985 (18:12335120 T>A), RS1000852424 (18:12349707 G>T), RS1000860684 (18:12335764 C>T)

Disease associations

OMIM: gene MIM:604581 | disease phenotypes: MIM:108600, MIM:614487, MIM:610246, MIM:146390, MIM:618977, MIM:232400

GenCC curated gene-disease

Disease	Classification	Inheritance
spinocerebellar ataxia type 28	Definitive	Autosomal dominant
spastic ataxia 5	Definitive	Autosomal recessive
optic atrophy 12	Strong	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
AFG3L2-related optic atrophy and/or spastic ataxia spectrum	Definitive	SD

Mondo (13): spastic ataxia (MONDO:0017845), spastic ataxia 5 (MONDO:0013776), spinocerebellar ataxia type 28 (MONDO:0012450), chromosome 18p deletion syndrome (MONDO:0007800), optic atrophy 12 (MONDO:0033549), dystonic disorder (MONDO:0003441), intellectual disability (MONDO:0001071), glycogen storage disease III (MONDO:0009291), inherited retinal dystrophy (MONDO:0019118), optic atrophy (MONDO:0003608), retinal disorder (MONDO:0005283), sensorineural hearing loss disorder (MONDO:0020678), optic nerve disorder (MONDO:0002135)

Orphanet (8): Spastic ataxia (Orphanet:316226), Early-onset spastic ataxia-myoclonic epilepsy-neuropathy syndrome (Orphanet:313772), Spinocerebellar ataxia type 28 (Orphanet:101109), Monosomy 18p syndrome (Orphanet:1598), Partial deletion of the short arm of chromosome 18 syndrome (Orphanet:261974), Glycogen storage disease due to glycogen debranching enzyme deficiency (Orphanet:366), OBSOLETE: Inherited retinal disorder (Orphanet:71862), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

88 total (30 of 88 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000365	Hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000473	Torticollis
HP:0000501	Glaucoma
HP:0000508	Ptosis
HP:0000512	Abnormal electroretinogram
HP:0000514	Slow saccadic eye movements
HP:0000543	Optic disc pallor
HP:0000551	Color vision defect
HP:0000575	Scotoma
HP:0000597	Ophthalmoparesis
HP:0000613	Photophobia
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000640	Gaze-evoked nystagmus
HP:0000641	Dysmetric saccades
HP:0000642	Red-green dyschromatopsia
HP:0000648	Optic atrophy
HP:0000649	Abnormality of visual evoked potentials
HP:0000657	Oculomotor apraxia
HP:0000708	Atypical behavior
HP:0000716	Depression
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001256	Mild intellectual disability
HP:0001257	Spasticity
HP:0001260	Dysarthria
HP:0001272	Cerebellar atrophy

GWAS associations

0 associations (top):

MeSH disease descriptors (10)

Descriptor	Name	Tree numbers
D020821	Dystonic Disorders	C10.228.662.300
D006010	Glycogen Storage Disease Type III	C16.320.565.202.449.520; C18.452.648.202.449.520
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D009901	Optic Nerve Diseases	C10.292.700; C11.640
D012164	Retinal Diseases	C11.768
D058499	Retinal Dystrophies	C11.768.585.658
C538309	Chromosome 18p deletion syndrome (supp.)
C564815	Spastic Ataxia (supp.)
C537205	Spinocerebellar ataxia 28 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4802020 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 3 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.22	Kd	597.6	nM	CHEMBL5653589
6.22	ED50	597.6	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2147815: Binding affinity to human AFG3L2 incubated for 45 mins by Kinobead based pull down assay	kd	0.5976	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	increases expression, affects cotreatment, decreases expression	3
sodium arsenite	affects cotreatment, increases expression, decreases expression	3
Acetaminophen	increases expression	2
Air Pollutants	decreases expression, increases abundance	2
Smoke	decreases expression, increases abundance	2
Tretinoin	affects cotreatment, increases expression, decreases expression	2
Valproic Acid	affects cotreatment, increases expression, affects expression	2
bisphenol F	affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
lead acetate	affects cotreatment, increases expression	1
trichostatin A	increases expression	1
beta-methylcholine	affects expression	1
corosolic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
bisphenol B	increases expression	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, decreases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Atrazine	increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Doxorubicin	increases expression	1
Hydralazine	affects cotreatment, increases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Ivermectin	decreases expression	1
Plant Extracts	affects cotreatment, increases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
1-Methyl-3-isobutylxanthine	decreases expression, affects cotreatment	1
Particulate Matter	decreases expression, increases abundance	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4724685	Binding	Displacement of (1-(2-aminoethyl)-3,5-dimethyl-1H-pyrazol-4-yl)(4-((1-neopentyl-1H-benzo[d]imidazol-2-yl)methyl)piperazin-1-yl)methanone from AFG3L2 in vorinostat-stimulated human Jurkat 2C4 cells infected with latent HIV-1 by pull-down exp	Discovery of an Anion-Dependent Farnesyltransferase Inhibitor from a Phenotypic Screen. — ACS Med Chem Lett

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00142259	PHASE4	UNKNOWN	Efficacy and Safety of DBS of the GPi in Patients With Primary Generalized and Segmental Dystonia
NCT00950196	PHASE4	COMPLETED	Amantadine for Improving Neurologic Symptoms in Ataxia-Telangiectasia
NCT00998660	PHASE4	COMPLETED	RECHARGE Sub-Study to the Implantable Systems Performance Registry (ISPR)
NCT02263417	PHASE4	COMPLETED	A Randomized Controlled Trail Comparing Subthalamic and Pallidal Deep Brain Stimulation for Dystonia
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00169403	PHASE3	UNKNOWN	Pallidal Stimulation in Patients With Idiopathic Generalised Dystonia
NCT03232320	PHASE3	COMPLETED	Meditoxin® Treatment in Patients With Cervical Dystonia
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00001784	PHASE2	COMPLETED	Mexiletine for the Treatment of Focal Dystonia
NCT00105430	PHASE2	COMPLETED	Deep Brain Stimulation for Cervical Dystonia
NCT00106782	PHASE2	COMPLETED	Transcranial Electrical Polarization to Treat Focal Hand Dystonia
NCT00122044	PHASE2	COMPLETED	Childhood Hypertonia of Central Origin: A Trial of Anticholinergic Treatment Effects
NCT00169338	PHASE2	COMPLETED	Pallidal Stimulation in Patients With Post-anoxic and Idiopathic Dystonia
NCT00331669	PHASE2	UNKNOWN	Efficacy and Safety of Deep Brain Stimulation (DBS) of the Pallidal (GPi) in Patients With Tardive Dystonia
NCT02107261	PHASE2	COMPLETED	Incobotulinum Toxin A (Xeomin®) As A Treatment For Focal Task-Specific Dystonia Of The Musician’s Hand
NCT02470325	PHASE2	UNKNOWN	The Effects of Cannabis on Dystonia and Spasticity on Pediatric Patients
NCT05027997	PHASE2	COMPLETED	Exploratory Study of Dipraglurant (ADX48621) for the Treatment of Patients With Blepharospasm
NCT06412653	PHASE2	COMPLETED	Prospective Pilot Trial to Address Feasibility and Safety of Oral Zinc in GNAO1 Associated Disorders
NCT07304089	PHASE2	RECRUITING	A Study to Evaluate the Efficacy, Safety, and Tolerability of VIM0423 in Individuals With Isolated Dystonia
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT01433757	PHASE1	COMPLETED	Ampicillin for DYT-1 Dystonia Motor Symptoms
NCT01698450	PHASE1	COMPLETED	Magnetic Resonance (MR) Guided Functional Ultrasound-Neurosurgery for Movement Disorders
NCT02982304	PHASE1	UNKNOWN	Multi-Target Pallidal and Thalamic Deep Brain Stimulation for Hemi-Dystonia
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT06554288	PHASE1	RECRUITING	Pharmacogenomic Contributions to Trihexyphenidyl Biotransformation and Response in Children With Dystonic Cerebral Palsy
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT04297891	Not specified	UNKNOWN	Phenotypes, Biomarkers and Pathophysiology in Spastic Ataxias
NCT00004421	PHASE2/PHASE3	COMPLETED	Deep Brain Stimulation in Treating Patients With Dystonia
NCT00272246	PHASE2/PHASE3	UNKNOWN	Bilateral Internal Pallidum Stimulation in Primary Generalized Dystonia