ACO2

Summary

ACO2 (aconitase 2, HGNC:118) is a protein-coding gene on chromosome 22q13.2, encoding Aconitate hydratase, mitochondrial (Q99798). Catalyzes the isomerization of citrate to isocitrate via cis-aconitate. It is a selective cancer dependency (DepMap: 64.2% of cell lines).

The protein encoded by this gene belongs to the aconitase/IPM isomerase family. It is an enzyme that catalyzes the interconversion of citrate to isocitrate via cis-aconitate in the second step of the TCA cycle. This protein is encoded in the nucleus and functions in the mitochondrion. It was found to be one of the mitochondrial matrix proteins that are preferentially degraded by the serine protease 15(PRSS15), also known as Lon protease, after oxidative modification.

Source: NCBI Gene 50 — RefSeq curated summary.

At a glance

• Gene–disease (curated): optic atrophy 9 (Definitive, ClinGen) — +3 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 905 total — 55 pathogenic, 26 likely-pathogenic
• Phenotypes (HPO): 32
• Cancer dependency (DepMap): dependent in 64.2% of screened cell lines
• MANE Select transcript: NM_001098

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:118
Approved symbol	ACO2
Name	aconitase 2
Location	22q13.2
Locus type	gene with protein product
Status	Approved
Aliases	ACONM
Ensembl gene	ENSG00000100412
Ensembl biotype	protein_coding
OMIM	100850
Entrez	50

Gene structure

Transcript identifiers

Ensembl transcripts: 50 — 28 protein_coding, 12 retained_intron, 9 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000216254, ENST00000396512, ENST00000466237, ENST00000471094, ENST00000478010, ENST00000482208, ENST00000676664, ENST00000676714, ENST00000676748, ENST00000676792, ENST00000676822, ENST00000676883, ENST00000676959, ENST00000677007, ENST00000677153, ENST00000677427, ENST00000677492, ENST00000677516, ENST00000677532, ENST00000677554, ENST00000677698, ENST00000678269, ENST00000678394, ENST00000678454, ENST00000678600, ENST00000678688, ENST00000678788, ENST00000678819, ENST00000679264, ENST00000679284, ENST00000679311, ENST00000679320, ENST00000878384, ENST00000878385, ENST00000878386, ENST00000878387, ENST00000878388, ENST00000878389, ENST00000878390, ENST00000878391, ENST00000923519, ENST00000923520, ENST00000953703, ENST00000953704, ENST00000953705, ENST00000953706, ENST00000953707, ENST00000953708, ENST00000953709, ENST00000953710

RefSeq mRNA: 1 — MANE Select: NM_001098 NM_001098

CCDS: CCDS14017

Canonical transcript exons

ENST00000216254 — 18 exons

Exon	Start	End
ENSE00000655866	41522830	41522987
ENSE00000655869	41523205	41523278
ENSE00000655874	41523830	41523941
ENSE00000655877	41524846	41524968
ENSE00000655880	41525193	41525348
ENSE00000655884	41526262	41526453
ENSE00000655886	41527288	41527420
ENSE00000655890	41527901	41528022
ENSE00001176200	41499726	41499862
ENSE00001340994	41469117	41469182
ENSE00003472516	41515767	41515917
ENSE00003509924	41520171	41520276
ENSE00003535455	41511876	41511968
ENSE00003540387	41515377	41515535
ENSE00003562818	41507791	41508049
ENSE00003607158	41517527	41517631
ENSE00003687143	41518481	41518572
ENSE00003848339	41528479	41528974

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 99.53.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 62.7078 / max 740.5226, expressed in 1826 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
192477	61.7790	1825
192476	0.7558	432
192478	0.1730	84

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
heart right ventricle	UBERON:0002080	99.53	gold quality
apex of heart	UBERON:0002098	99.41	gold quality
left ventricle myocardium	UBERON:0006566	99.30	gold quality
cardiac ventricle	UBERON:0002082	99.24	gold quality
heart left ventricle	UBERON:0002084	99.23	gold quality
gastrocnemius	UBERON:0001388	99.13	gold quality
hindlimb stylopod muscle	UBERON:0004252	99.12	gold quality
right atrium auricular region	UBERON:0006631	99.11	gold quality
cardiac atrium	UBERON:0002081	99.10	gold quality
myocardium	UBERON:0002349	99.06	gold quality
jejunal mucosa	UBERON:0000399	99.00	gold quality
cardiac muscle of right atrium	UBERON:0003379	98.98	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	98.84	gold quality
vastus lateralis	UBERON:0001379	98.80	gold quality
diaphragm	UBERON:0001103	98.75	gold quality
skeletal muscle tissue	UBERON:0001134	98.75	gold quality
right frontal lobe	UBERON:0002810	98.75	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.75	gold quality
muscle of leg	UBERON:0001383	98.70	gold quality
muscle organ	UBERON:0001630	98.65	gold quality
skeletal muscle organ	UBERON:0014892	98.65	gold quality
duodenum	UBERON:0002114	98.62	gold quality
triceps brachii	UBERON:0001509	98.60	gold quality
heart	UBERON:0000948	98.57	gold quality
deltoid	UBERON:0001476	98.56	gold quality
body of tongue	UBERON:0011876	98.56	gold quality
cingulate cortex	UBERON:0003027	98.55	gold quality
biceps brachii	UBERON:0001507	98.54	gold quality
anterior cingulate cortex	UBERON:0009835	98.52	gold quality
amygdala	UBERON:0001876	98.51	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	11.19

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

31 targeting ACO2, 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-4692	100.00	67.32	2066
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-4320	99.75	65.80	793
HSA-MIR-5004-3P	99.54	68.27	1371
HSA-MIR-671-5P	99.52	67.11	1277
HSA-MIR-4489	99.50	65.56	785
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-12113	99.32	67.54	1072
HSA-MIR-888-5P	99.30	70.15	1855
HSA-MIR-6846-5P	98.81	65.86	1121
HSA-MIR-6848-5P	98.81	65.49	1126
HSA-MIR-4539	98.78	67.18	888
HSA-MIR-502-5P	98.77	66.51	906
HSA-MIR-5011-3P	98.63	64.81	638
HSA-MIR-4720-3P	98.50	68.88	988
HSA-MIR-4704-3P	98.28	69.33	1300
HSA-MIR-4691-3P	98.11	66.83	1204
HSA-MIR-6841-3P	98.08	66.54	604
HSA-MIR-3157-5P	97.41	67.61	998
HSA-MIR-517-5P	97.13	68.43	781
HSA-MIR-664B-5P	96.74	67.50	509
HSA-MIR-4772-5P	95.60	68.04	617
HSA-MIR-184	94.24	64.40	152
HSA-MIR-127-3P	93.92	66.42	36
HSA-MIR-4749-5P	92.16	62.26	179

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 64.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 30)

• Gp50 was a class II ribonucleotide reductase having properties similar to that of the corresponding enzyme from Lactobacillus leichmanni. (PMID:18248423)
• Lon protease selectively recognizes and degrades the oxidized, hydrophobic form of aconitase after mild oxidative modification, but that severe oxidation results in aconitase aggregation, which makes it a poor substrate for Lon. (PMID:12198491)
• ACO2 is often deleted in colorectal cancer but is unlikely to be the true target of the deletions (PMID:12746427)
• The m-aconitase promoter is contained in a 153-bp 5’ fragment lacking a TATA or CAAT sequence. Sp1 binding to specific Sp1 site is needed for promoter activity. Other transcription factors are recruited through protein-protein interactions. (PMID:16598741)
• Manganese acts as an antagonist of iron, disrupting the enzymatic activity and gene expression of mACON and citrate metabolism in the prostate. (PMID:16625280)
• This protein has been found differentially expressed in the dorsolateral prefrontal cortex from patients with schizophrenia. (PMID:19110265)
• This protein has been found differentially expressed in the Wernicke’s Area from patients with schizophrenia. (PMID:19405953)
• abolishes oxidant-induced apoptosis (PMID:19524665)
• these results suggest that p53 downregulation of mACON gene expression in human prostate carcinoma cells may not occur through the putative consensus p53 response elements found within the mACON promoter. (PMID:20607720)
• Homozygosity mapping followed by whole-exome sequencing disclosed a Ser112Arg mutation in ACO2. (PMID:22405087)
• Gastric cancer patients with lower ACO2 expression have a shorter survival time than those with higher ACO2 expression. (PMID:23550275)
• Hypoxia upregulates the gene expression of mitochondrial aconitase in prostate carcinoma cells (PMID:23709747)
• Ogg1 chaperoning of Aco-2 in preventing oxidant-mediated mtDNA damage and apoptosis may afford an innovative target for the molecular events underlying oxidant-induced toxicity. (PMID:24429287)
• immunofluorescence staining localized ACO2 to the human sperm mid-piece. By immunoblotting, we demonstrated that the level of ACO2 protein in asthenozoospermic samples was significantly decreased compared with that in normal fertile men (PMID:24785945)
• Results suggest that ACO2 activity is reduced in peripheral lymphocytes of subjects with Alzheimer’s disease and mild cognitive impairment and correlates with antioxidant protection (PMID:25322927)
• Our study shows that autosomal recessive ACO2 mutations can cause either isolated or syndromic optic neuropathy. (PMID:25351951)
• Dysfunctional mitochondrail Aco2, among the other bioenergetic parameters, is a key factor that could promote neurodegeneration (PMID:28814227)
• Aco2 activity correlated significantly with motor score, independence scale, and functional capacity of the Unified Huntington’s Disease Rating Scale as well as disease duration. Our study provides a potential biomarker to assess the disease status of HD patients and PreHD carriers. (PMID:29160844)
• Mutation in ACO2 gene is associated with optic neuropathy. (PMID:30118607)
• The study provides the most extensive cohort of patients and further delineates the clinical, radiological, biochemical, and molecular features of ACO2 deficiency. (PMID:30689204)
• Study showed that the expression of ACO2 was significantly increased in prostate cancer (PC) tissues and identified a positive correlation between ACO2 expression and the malignancy of prostate cancer. ACO2 protein expression and activity was higher in paclitaxel-resistant PC3 cells than in PTX-sensitive DU145 cells. These results indicate that ACO2 plays an important role in the development and drug resistance of PC. (PMID:30972978)
• This work identifies ACO2 as a relevant gene in cancer metabolic rewiring of MCF-7 cells, promoting a different utilisation of pyruvate and revealing the potential metabolic vulnerability of ACO2-associated malignancies. (PMID:31819175)
• ACO2 and ANPEP as novel prognostic markers for gallbladder squamous cell/adenosquamous carcinomas and adenocarcinomas. (PMID:32249333)
• Recessive ACO2 variants as a cause of isolated ophthalmologic phenotypes. (PMID:32449285)
• Expanding the clinical and phenotypic heterogeneity associated with biallelic variants in ACO2. (PMID:32519519)
• Haploinsufficiency due to a novel ACO2 deletion causes mitochondrial dysfunction in fibroblasts from a patient with dominant optic nerve atrophy. (PMID:33028849)
• Loss of mitochondrial aconitase promotes colorectal cancer progression via SCD1-mediated lipid remodeling. (PMID:33676027)
• ACO2 deficiency increases vulnerability to Parkinson’s disease via dysregulating mitochondrial function and histone acetylation-mediated transcription of autophagy genes. (PMID:38007539)
• AFG3L2 and ACO2-Linked Dominant Optic Atrophy: Genotype-Phenotype Characterization Compared to OPA1 Patients. (PMID:38278202)
• Mitochondrial Aconitase and Its Contribution to the Pathogenesis of Neurodegenerative Diseases. (PMID:39337438)

Cross-species orthologs

6 orthologs

Organism	Symbol	Gene ID
danio_rerio	aco2	ENSDARG00000007294
mus_musculus	Aco2	ENSMUSG00000022477
rattus_norvegicus	Aco2	ENSRNOG00000024128
drosophila_melanogaster	mAcon1	FBGN0010100
drosophila_melanogaster	mAcon2	FBGN0037862
caenorhabditis_elegans		WBGENE00000041

Paralogs (2): ACO1 (ENSG00000122729), IREB2 (ENSG00000136381)

Protein

Protein identifiers

Aconitate hydratase, mitochondrial — Q99798 (reviewed: Q99798)

Alternative names: Citrate hydro-lyase

All UniProt accessions (17): Q99798, A0A7I2V2Y4, A0A7I2V3C8, A0A7I2V3F1, A0A7I2V3U0, A0A7I2V3U7, A0A7I2V499, A0A7I2V4I8, A0A7I2V538, A0A7I2V586, A0A7I2V5A1, A0A7I2V5T4, A0A7I2V5U4, A0A7I2V5W7, A0A7I2V614, A0A7I2V6A6, A2A274

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the isomerization of citrate to isocitrate via cis-aconitate.

Subunit / interactions. Monomer.

Subcellular location. Mitochondrion.

Post-translational modifications. Forms covalent cross-links mediated by transglutaminase TGM2, between a glutamine and the epsilon-amino group of a lysine residue, forming homopolymers and heteropolymers.

Disease relevance. Infantile cerebellar-retinal degeneration (ICRD) [MIM:614559] A severe autosomal recessive neurodegenerative disorder characterized by onset between ages 2 and 6 months of truncal hypotonia, athetosis, seizures, and ophthalmologic abnormalities, particularly optic atrophy and retinal degeneration. Affected individuals show profound psychomotor retardation, with only some achieving rolling, sitting, or recognition of family. Brain MRI shows progressive cerebral and cerebellar degeneration. The disease is caused by variants affecting the gene represented in this entry. Optic atrophy 9 (OPA9) [MIM:616289] A condition that features 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. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 [4Fe-4S] cluster per subunit. Binding of a [3Fe-4S] cluster leads to an inactive enzyme.

Pathway. Carbohydrate metabolism; tricarboxylic acid cycle; isocitrate from oxaloacetate: step 2/2.

Similarity. Belongs to the aconitase/IPM isomerase family.

RefSeq proteins (1): NP_001089* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000573	AconitaseA/IPMdHydase_ssu_swvl	Domain
IPR001030	Acoase/IPM_deHydtase_lsu_aba	Domain
IPR006248	Aconitase_mito-like	Family
IPR015928	Aconitase/3IPM_dehydase_swvl	Homologous_superfamily
IPR015931	Acnase/IPM_dHydase_lsu_aba_1/3	Homologous_superfamily
IPR015932	Aconitase_dom2	Homologous_superfamily
IPR018136	Aconitase_4Fe-4S_BS	Binding_site
IPR036008	Aconitase_4Fe-4S_dom	Homologous_superfamily
IPR050926	Aconitase/IPM_isomerase	Family

Pfam: PF00330, PF00694

Enzyme classification (BRENDA):

• EC 4.2.1.3 — aconitate hydratase (BRENDA: 53 organisms, 72 substrates, 96 inhibitors, 82 Km, 22 kcat entries)

Substrate kinetics (BRENDA)

7 substrates with measured Km, best-characterized 7. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
CITRATE	0.12–21.1	27
ISOCITRATE	0.012–3.79	25
CIS-ACONITATE	0.0035–0.2	15
2-METHYL CIS-ACONITATE	0.0089–0.158	2
DL-ISOCITRATE	1.36–1.75	2
METHYLISOCITRATE	0.032–0.268	2
(2R,3S)-2-METHYLISOCITRATE	0.21	1

Catalyzed reactions (Rhea), 1 shown:

• citrate = D-threo-isocitrate (RHEA:10336)

UniProt features (61 total): modified residue 28, sequence conflict 12, binding site 9, sequence variant 7, compositionally biased region 2, transit peptide 1, chain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q99798-F1	95.44	0.95

Functional residue map

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

Ligand- & substrate-binding residues (9): 474; 479; 607; 670–671; 99; 192–194; 385; 448; 451

Post-translational modifications (28): 31, 50, 50, 138, 138, 144, 144, 233, 233, 411, 549, 559, 573, 573, 577, 591, 605, 605, 628, 670 …

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-1268020	Mitochondrial protein import
R-HSA-71403	Citric acid cycle (TCA cycle)
R-HSA-9837999	Mitochondrial protein degradation
R-HSA-9854311	Maturation of TCA enzymes and regulation of TCA cycle
R-HSA-1428517	Aerobic respiration and respiratory electron transport
R-HSA-1430728	Metabolism
R-HSA-392499	Metabolism of proteins
R-HSA-9609507	Protein localization

MSigDB gene sets: 270 (showing top): E2F_Q4, E2F4DP1_01, RORA1_01, ENK_UV_RESPONSE_KERATINOCYTE_UP, TGACCTY_ERR1_Q2, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY, NKX62_Q2, E2F1DP1_01, MCBRYAN_PUBERTAL_BREAST_4_5WK_DN, CATTTCA_MIR203, E2F1DP2_01, GOBP_TRICARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, FLECHNER_BIOPSY_KIDNEY_TRANSPLANT_REJECTED_VS_OK_DN, MODULE_295

GO Biological Process (3): generation of precursor metabolites and energy (GO:0006091), tricarboxylic acid cycle (GO:0006099), citrate metabolic process (GO:0006101)

GO Molecular Function (6): aconitate hydratase activity (GO:0003994), iron ion binding (GO:0005506), 4 iron, 4 sulfur cluster binding (GO:0051539), lyase activity (GO:0016829), metal ion binding (GO:0046872), iron-sulfur cluster binding (GO:0051536)

GO Cellular Component (3): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytosol (GO:0005829)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Protein localization	1
Aerobic respiration and respiratory electron transport	1
Metabolism of proteins	1
Citric acid cycle (TCA cycle)	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	2
metabolic process	1
aerobic respiration	1
primary metabolic process	1
tricarboxylic acid metabolic process	1
hydro-lyase activity	1
transition metal ion binding	1
iron-sulfur cluster binding	1
catalytic activity	1
cation binding	1
metal cluster binding	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
cellular anatomical structure	1

Protein interactions and networks

STRING

4466 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ACO2	FXN	Q16595	964
ACO2	IDH2	P48735	932
ACO2	ISCU	Q9H1K1	924
ACO2	IDH1	O75874	914
ACO2	MDH2	P40926	908
ACO2	CS	O75390	905
ACO2	FH	P07954	903
ACO2	NFS1	Q9Y697	887
ACO2	FECH	P22830	881
ACO2	F5H3C5	F5H3C5	876
ACO2	SOD2	P04179	876
ACO2	LONP1	P36776	851
ACO2	LYRM4	Q9HD34	838
ACO2	KLK15	Q9H2R5	818
ACO2	SDHA	P31040	808

IntAct

51 interactions, top by confidence:

A	B	Type	Score
VCAM1	PSMD11	psi-mi:“MI:0914”(association)	0.530
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
HSCB	NDUFS8	psi-mi:“MI:0914”(association)	0.460
TCIM	ACO2	psi-mi:“MI:0915”(physical association)	0.400
ACO2	C5AR2	psi-mi:“MI:0915”(physical association)	0.370
ACO2	MLH1	psi-mi:“MI:0915”(physical association)	0.370
HSCB	RBP5	psi-mi:“MI:0914”(association)	0.350
SOD1	NPEPPSL1	psi-mi:“MI:0914”(association)	0.350
KDM4C	SMCHD1	psi-mi:“MI:0914”(association)	0.350
ZDHHC5	IGKV2D-24	psi-mi:“MI:0914”(association)	0.350
rep	TAF4	psi-mi:“MI:0914”(association)	0.350
	CLIC1	psi-mi:“MI:0914”(association)	0.350
RIPK4	TBCA	psi-mi:“MI:0914”(association)	0.350
NEK7	SUPT5H	psi-mi:“MI:0914”(association)	0.350
TP53	DNAJA2	psi-mi:“MI:0914”(association)	0.350
EGFR	ENO1	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
	SHTN1	psi-mi:“MI:0914”(association)	0.350
SLC25A16	TOMM70	psi-mi:“MI:0914”(association)	0.350
FECH	GTPBP10	psi-mi:“MI:0914”(association)	0.350
DDX28	UBA6	psi-mi:“MI:0914”(association)	0.350
DNAJC30	UBA6	psi-mi:“MI:0914”(association)	0.350
GAB2	UBA6	psi-mi:“MI:0914”(association)	0.350
ITM2C	UBA6	psi-mi:“MI:0914”(association)	0.350
MRPL49	UBA6	psi-mi:“MI:0914”(association)	0.350
MRPS23	MYH7B	psi-mi:“MI:0914”(association)	0.350
OAS1	UBA6	psi-mi:“MI:0914”(association)	0.350

BioGRID (259): ACO2 (Co-fractionation), ACO2 (Co-fractionation), ACO2 (Co-fractionation), ACO2 (Co-fractionation), ACO2 (Co-fractionation), ALDH5A1 (Co-fractionation), ALDOA (Co-fractionation), ALDOC (Co-fractionation), ATP1B1 (Co-fractionation), ATP5F1 (Co-fractionation), ATP5J (Co-fractionation), ESD (Co-fractionation), GPD1 (Co-fractionation), GPD1L (Co-fractionation), GPD2 (Co-fractionation)

ESM2 similar proteins: A0A1U8QYZ5, A0A2Z4HPY5, A0A384JRP0, A1C7T5, A1DIF7, A8BQB4, A8J4S9, B0XUW3, B6HJA3, B8N6H2, C4R7Z3, C8V9Y5, D4AMT2, F4HTM3, G9NNY7, I1RNL0, J5K1E2, O42622, O42777, O42783, O42893, O47881, P0CT44, P14017, P16276, P20004, P32356, P35172, P49381, P52494, P93472, Q00314, Q0CVD7, Q10449, Q27128, Q2GN26, Q2UDE5, Q4HVQ9, Q4WUL6, Q4WZS1

Diamond homologs: A0ZZS7, A1K4A1, A1WAS7, A1WAT0, A3M1S8, A4IRH6, A5E8Z8, A5MZ75, A5UUP5, A6Q6J8, A6UDX5, A6VX34, A6X449, A7HT10, A7Z7B6, A8EQZ0, A8ILN3, A9BNH1, A9MCG4, A9VZG4, A9WC30, A9WVP8, B2I359, B2SAF6, B3PS18, B3Q845, B7GH21, B7H0T7, B7I4E1, B7KZ04, B9L5K2, B9LGN1, B9MDK8, B9MDL1, C0RM30, C3M9W6, C5D5L8, C8VG90, D4AT77, D9X0I3

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
ACO2	“down-regulates quantity”	citrate(3-)	“chemical modification”
ACO2	“up-regulates quantity”	D-threo-isocitrate(3-)	“chemical modification”
FGR	unknown	ACO2	phosphorylation

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	55
Likely pathogenic	26
Uncertain significance	406
Likely benign	336
Benign	36

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1063268	NM_001098.3(ACO2):c.952del (p.Asn317_Leu318insTer)	Pathogenic
1120200	NM_001098.3(ACO2):c.1091T>C (p.Val364Ala)	Pathogenic
1213918	NM_001098.3(ACO2):c.1507G>T (p.Gly503Ter)	Pathogenic
1390490	NM_001098.3(ACO2):c.1835dup (p.Asn612fs)	Pathogenic
1391740	NM_001098.3(ACO2):c.1534_1537del (p.Asp512fs)	Pathogenic
1395187	NM_001098.3(ACO2):c.1559del (p.Lys520fs)	Pathogenic
1401215	NM_001098.3(ACO2):c.1416C>G (p.Tyr472Ter)	Pathogenic
1413151	NM_001098.3(ACO2):c.1119G>A (p.Trp373Ter)	Pathogenic
1418195	NM_001098.3(ACO2):c.1128_1134dup (p.Val379fs)	Pathogenic
1420778	NM_001098.3(ACO2):c.499A>T (p.Lys167Ter)	Pathogenic
1435000	NM_001098.3(ACO2):c.1002T>A (p.Tyr334Ter)	Pathogenic
1451664	NM_001098.3(ACO2):c.1534_1537dup (p.Tyr513Ter)	Pathogenic
1454123	NM_001098.3(ACO2):c.1971G>A (p.Trp657Ter)	Pathogenic
1454488	NM_001098.3(ACO2):c.1666del (p.Val556fs)	Pathogenic
1470169	NM_001098.3(ACO2):c.525+1G>A	Pathogenic
147621	GRCh38/hg38 22q13.2(chr22:41277822-42414957)x3	Pathogenic
1679318	NM_001098.3(ACO2):c.1776T>A (p.Cys592Ter)	Pathogenic
1711154	NM_001098.3(ACO2):c.940+5G>C	Pathogenic
1711158	NM_001098.3(ACO2):c.1254dup (p.Gly419fs)	Pathogenic
189312	NM_001098.3(ACO2):c.776G>A (p.Gly259Asp)	Pathogenic
189313	NM_001098.3(ACO2):c.2208G>C (p.Lys736Asn)	Pathogenic
189314	NM_001098.3(ACO2):c.2328_2331del (p.Lys776fs)	Pathogenic
1994002	NM_001098.3(ACO2):c.397C>T (p.Gln133Ter)	Pathogenic
1998453	NM_001098.3(ACO2):c.1356del (p.Ile452fs)	Pathogenic
2027480	NM_001098.3(ACO2):c.2023_2084del (p.Ala675fs)	Pathogenic
2031049	NM_001098.3(ACO2):c.1912C>T (p.Gln638Ter)	Pathogenic
2043392	NM_001098.3(ACO2):c.135T>G (p.Tyr45Ter)	Pathogenic
2075825	NM_001098.3(ACO2):c.1239dup (p.Phe414fs)	Pathogenic
2128473	NM_001098.3(ACO2):c.1832del (p.Asp611fs)	Pathogenic
2185049	NM_001098.3(ACO2):c.708_723del (p.Ser237fs)	Pathogenic

SpliceAI

3777 predictions. Top by Δscore:

Variant	Effect	Δscore
22:41460484:CTCT:C	acceptor_gain	1.0000
22:41460486:CT:C	acceptor_gain	1.0000
22:41460487:TC:T	acceptor_loss	1.0000
22:41460488:C:CC	acceptor_gain	1.0000
22:41462681:CTGA:C	donor_gain	1.0000
22:41467441:CACTT:C	donor_loss	1.0000
22:41467442:ACTTA:A	donor_loss	1.0000
22:41467443:CTTAC:C	donor_loss	1.0000
22:41467444:TTA:T	donor_loss	1.0000
22:41467445:TA:T	donor_loss	1.0000
22:41467446:A:AC	donor_gain	1.0000
22:41467446:A:AT	donor_loss	1.0000
22:41467446:ACGT:A	donor_gain	1.0000
22:41467446:ACGTC:A	donor_gain	1.0000
22:41467447:C:CC	donor_gain	1.0000
22:41467447:CGT:C	donor_gain	1.0000
22:41467447:CGTC:C	donor_gain	1.0000
22:41467447:CGTCC:C	donor_gain	1.0000
22:41467449:T:TA	donor_gain	1.0000
22:41467611:TCACC:T	acceptor_loss	1.0000
22:41467613:ACCTG:A	acceptor_loss	1.0000
22:41467614:CCTG:C	acceptor_loss	1.0000
22:41467615:C:CG	acceptor_loss	1.0000
22:41468038:AAAGC:A	donor_gain	1.0000
22:41499725:GAAA:G	acceptor_gain	1.0000
22:41499861:CGGT:C	donor_loss	1.0000
22:41499862:GGTA:G	donor_loss	1.0000
22:41499863:GTA:G	donor_loss	1.0000
22:41499864:T:G	donor_loss	1.0000
22:41507785:CCACA:C	acceptor_loss	1.0000

AlphaMissense

5122 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:41507901:G:C	R95P	1.000
22:41507915:G:C	D100H	1.000
22:41507995:T:G	C126W	1.000
22:41507996:G:C	D127H	1.000
22:41507997:A:C	D127A	1.000
22:41507997:A:T	D127V	1.000
22:41507999:C:G	H128D	1.000
22:41508001:T:A	H128Q	1.000
22:41508001:T:G	H128Q	1.000
22:41508003:T:C	L129P	1.000
22:41511939:T:A	W166R	1.000
22:41511939:T:C	W166R	1.000
22:41511955:G:A	G171E	1.000
22:41511963:C:G	H174D	1.000
22:41515425:G:C	D192H	1.000
22:41515425:G:T	D192Y	1.000
22:41515426:A:C	D192A	1.000
22:41515426:A:G	D192G	1.000
22:41515426:A:T	D192V	1.000
22:41515427:C:A	D192E	1.000
22:41515427:C:G	D192E	1.000
22:41515428:T:C	S193P	1.000
22:41515431:C:G	H194D	1.000
22:41515433:C:A	H194Q	1.000
22:41515433:C:G	H194Q	1.000
22:41515470:G:A	G207R	1.000
22:41515470:G:C	G207R	1.000
22:41515471:G:A	G207E	1.000
22:41517543:C:G	C284W	1.000
22:41517546:C:A	N285K	1.000

dbSNP variants (sampled 300 via entrez): RS1000077957 (22:41517353 C>T), RS1000087751 (22:41476237 G>A), RS1000102728 (22:41491903 G>A,C), RS1000126653 (22:41506968 G>T), RS1000274792 (22:41482688 A>C), RS1000330414 (22:41494750 T>G), RS1000331804 (22:41494524 G>T), RS1000374381 (22:41500939 G>C), RS1000418410 (22:41475930 C>T), RS1000435885 (22:41488245 G>A), RS1000491903 (22:41488189 C>A,T), RS1000498163 (22:41498613 C>A,T), RS1000508145 (22:41510891 CA>C), RS1000562316 (22:41483445 T>G), RS1000567369 (22:41500338 T>G)

Disease associations

OMIM: gene MIM:100850 | disease phenotypes: MIM:614559, MIM:616289, MIM:613684, MIM:176000, MIM:613494

GenCC curated gene-disease

Disease	Classification	Inheritance
infantile cerebellar-retinal degeneration	Definitive	Autosomal recessive
optic atrophy 9	Strong	Semidominant
autosomal recessive optic atrophy	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (3)

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

Disease	Classification	Inheritance
optic atrophy 9	Definitive	SD
mitochondrial disease	Strong	AD
mitochondrial disease	Definitive	AR

Mondo (12): infantile cerebellar-retinal degeneration (MONDO:0013802), optic atrophy 9 (MONDO:0014571), mitochondrial disease (MONDO:0044970), optic nerve disorder (MONDO:0002135), isolated macular dystrophy (MONDO:0957048), inherited retinal dystrophy (MONDO:0019118), optic atrophy (MONDO:0003608), Rubinstein-Taybi syndrome due to EP300 haploinsufficiency (MONDO:0013364), neurodegenerative disease (MONDO:0005559), acute intermittent porphyria (MONDO:0008294), immunodeficiency, common variable, 4 (MONDO:0013284), (MONDO:0014753)

Orphanet (9): Infantile cerebellar-retinal degeneration (Orphanet:313850), Mitochondrial disease (Orphanet:68380), OBSOLETE: Isolated macular dystrophy (Orphanet:519302), OBSOLETE: Inherited retinal disorder (Orphanet:71862), Rubinstein-Taybi syndrome due to EP300 haploinsufficiency (Orphanet:353284), Rubinstein-Taybi syndrome (Orphanet:783), Acute intermittent porphyria (Orphanet:79276), OBSOLETE: Common variable immunodeficiency (Orphanet:1572), Adult-onset common variable immunodeficiency due to BAFF-receptor deficiency (Orphanet:696925)

HPO phenotypes

32 total (30 of 32 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000252	Microcephaly
HP:0000253	Progressive microcephaly
HP:0000407	Sensorineural hearing impairment
HP:0000486	Strabismus
HP:0000505	Visual impairment
HP:0000543	Optic disc pallor
HP:0000556	Retinal dystrophy
HP:0000639	Nystagmus
HP:0000642	Red-green dyschromatopsia
HP:0000648	Optic atrophy
HP:0001251	Ataxia
HP:0001252	Hypotonia
HP:0001265	Hyporeflexia
HP:0001272	Cerebellar atrophy
HP:0001284	Areflexia
HP:0001508	Failure to thrive
HP:0002069	Bilateral tonic-clonic seizure
HP:0002079	Hypoplasia of the corpus callosum
HP:0002120	Cerebral cortical atrophy
HP:0002305	Athetosis
HP:0002500	Abnormal cerebral white matter morphology
HP:0003593	Infantile onset
HP:0003621	Juvenile onset
HP:0004325	Decreased body weight
HP:0007108	Demyelinating peripheral neuropathy
HP:0007359	Focal-onset seizure
HP:0007663	Reduced visual acuity
HP:0010864	Severe intellectual disability
HP:0011344	Severe global developmental delay

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST005232_52	Neuroticism	3.000000e-18
GCST010002_83	Refractive error	2.000000e-27
GCST010043_44	Asthma	4.000000e-12
GCST010143_2	Meat-related diet	4.000000e-08
GCST010988_515	Adult body size	3.000000e-09

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0007660	neuroticism measurement
EFO:0008111	diet measurement

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D019636	Neurodegenerative Diseases	C10.574
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D009901	Optic Nerve Diseases	C10.292.700; C11.640
D017118	Porphyria, Acute Intermittent	C06.552.830.150; C16.320.850.742.150; C17.800.827.742.150; C18.452.811.400.150
D058499	Retinal Dystrophies	C11.768.585.658

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression, decreases methylation, increases expression	3
Doxorubicin	affects expression, decreases expression	2
bisphenol F	increases expression	1
2,4,6-tribromophenol	increases expression	1
lasiocarpine	decreases expression	1
nobiletin	decreases expression, decreases reaction	1
sodium arsenate	decreases expression, decreases reaction	1
pyrogallol 1,3-dimethyl ether	decreases expression, affects cotreatment, increases expression, affects localization	1
decabromobiphenyl ether	increases expression	1
ferric ammonium citrate	decreases activity, decreases reaction, increases activity	1
2,6-dichloro-4-nitrophenol	decreases expression	1
zinc chloride	affects cotreatment, decreases activity	1
cobaltous chloride	increases expression	1
linalool	increases expression	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
nickel chloride	decreases activity	1
perfluorooctanoic acid	increases expression	1
manganese chloride	decreases activity, decreases reaction, decreases expression	1
nickel sulfate	increases expression	1
CGP 52608	affects binding, increases reaction	1
nutlin 3	affects cotreatment, increases secretion	1
bisphenol B	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
bisphenol AF	increases expression	1
Temozolomide	decreases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	decreases expression	1
Acetaminophen	increases expression	1
Aluminum	decreases activity, decreases expression	1
Atrazine	decreases expression	1

Cellosaurus cell lines

3 cell lines: 2 cancer cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_SB24	HAP1 ACO2 (-) 1	Cancer cell line	Male
CVCL_SB25	HAP1 ACO2 (-) 2	Cancer cell line	Male
CVCL_XI73	IISHDOi006-A	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT03351998	PHASE4	COMPLETED	Impact of Statin Therapy on Muscle Mitochondrial Function and Aerobic Capacity
NCT00432744	PHASE3	COMPLETED	Phase III Trial of Coenzyme Q10 in Mitochondrial Disease
NCT05162768	PHASE3	COMPLETED	Study to Evaluate Efficacy and Safety of Elamipretide in Subjects With Primary Mitochondrial Disease From Nuclear DNA Mutations (nPMD)
NCT06451757	PHASE3	RECRUITING	KHENERFIN Study: A Trial to Evaluate the Efficacy and Safety of Sonlicromanol in Primary Mitochondrial Diseases
NCT04224207	PHASE3	COMPLETED	Management of Retinitis Pigmentosa by Mesenchymal Stem Cells by Wharton’s Jelly Derived Mesenchymal Stem Cells
NCT07082855	PHASE3	NOT_YET_RECRUITING	A Multicenter, Randomized, Double-Blind, Controlled Clinical Study of Minocycline for the Treatment of Retinitis Pigmentosa
NCT02398201	PHASE2	COMPLETED	A Study of Bezafibrate in Mitochondrial Myopathy
NCT02473445	PHASE2	TERMINATED	A Long-term Extension of Study RP103-MITO-001 (NCT02023866) to Assess Cysteamine Bitartrate Delayed-release Capsules (RP103) in Children With Inherited Mitochondrial Disease
NCT02500628	PHASE2	COMPLETED	Heart Rate Variability in Response to Metformin Challenge
NCT02805790	PHASE2	COMPLETED	Safety, Tolerability, Efficacy of MTP-131 for Treatment of Mitochondrial Disease in Subjects From the MMPOWER Study
NCT02909400	PHASE2	COMPLETED	The KHENERGY Study
NCT02976038	PHASE2	TERMINATED	Open-Label Extension Trial to Characterize the Long-term Safety and Tolerability of Elamipretide in Subjects With Genetically Confirmed Primary Mitochondrial Myopathy (PMM)
NCT03177798	PHASE2	COMPLETED	Mitochondria and Chronic Kidney Disease
NCT03866954	PHASE2	WITHDRAWN	Trial of Erythrocyte Encapsulated Thymidine Phosphorylase In Mitochondrial Neurogastrointestinal Encephalomyopathy
NCT04165239	PHASE2	COMPLETED	The KHENERGYZE Study
NCT04604548	PHASE2	COMPLETED	The KHENEREXT Study
NCT04802707	PHASE2	RECRUITING	Deoxynucleosides Pyrimidines as Treatment for Mitochondrial Depletion Syndrome
NCT04846036	PHASE2	SUSPENDED	The KHENERGYC Study
NCT05650229	PHASE2	RECRUITING	Efficacy of KL1333 in Adult Patients With Primary Mitochondrial Disease
NCT05972954	PHASE2	COMPLETED	OMT-28 in Patients With Primary Mitochondrial Disease (PMD) (PMD-OPTION)
NCT06017869	PHASE2	RECRUITING	Evaluate the Safety and Therapeutic Effects of a Single Intravenous Infusion (IV) of Autologous CD34+ Cells Enriched With Allogenic Placenta-derived Mitochondria in Patients With a Diagnosis of Pearson Syndrome (PS)
NCT07514338	PHASE2	NOT_YET_RECRUITING	Open Label Extension to Assess Long Term Safety and Efficacy of KL1333 in Patients With Primary Mitochondrial Disease
NCT03763227	PHASE2	COMPLETED	Intravitreal Ranibizumab (Lucentis®) in the Treatment of Non-leaking Macular Cysts in Retinal Dystrophy
NCT04068207	PHASE2	COMPLETED	Minocycline Treatment in Retinitis Pigmentosa
NCT04945772	PHASE2	COMPLETED	Efficacy and Safety of MCO-010 Optogenetic Therapy in Adults With Retinitis Pigmentosa [RESTORE]
NCT00060515	PHASE1	TERMINATED	RG2133 (2’,3’,5’-Tri-O-Acetyluridine) in Mitochondrial Disease
NCT02348125	PHASE1	UNKNOWN	Does Clinical Treatment of Mitochondrial Dysfunction Impact Autism Spectrum Disorder (ASD)?
NCT02544217	PHASE1	COMPLETED	A Dose-escalating Clinical Trial With KH176
NCT03888716	PHASE1	COMPLETED	A Phase Ia/Ib, SAD and MAD Study of of KL1333 in Healthy Subjects and Patients With Primary Mitochondrial Disease
NCT04086329	PHASE1	RECRUITING	Validation of Oxygen Nanosensor in Mitochondrial Myopathy
NCT04643249	PHASE1	COMPLETED	Drug-drug Interaction Study of KL1333 in Healthy Subjects
NCT05241262	PHASE1	RECRUITING	Study of N-acetylcysteine in the Treatment of Patients With the m.3243A>G Mutation and Low Brain Glutathione Levels
NCT05569122	PHASE1	RECRUITING	Applying pGz in Mitochondrial Disease
NCT06819683	PHASE1	RECRUITING	Validation of Nanosensor Oxygen Measurement
NCT07258667	PHASE1	NOT_YET_RECRUITING	Pilot Study of the Efficacy of Nicotinamide (Vitamin B3) in Leber’s Hereditary Optic Neuropathy
NCT05902962	PHASE1	COMPLETED	SAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects
NCT06319872	PHASE1	RECRUITING	The Effects of Disulfiram (Antabuse®) on Visual Acuity in Patients With Retinal Degeneration
NCT06455826	PHASE1	COMPLETED	MAD of IVT VP-001 in PRPF31 Mutation-Associated Retinal Dystrophy Subjects (Wallaby)
NCT01064505	PHASE1	COMPLETED	Safety Study of a Single IVT Injection of QPI-1007 in Chronic Optic Nerve Atrophy and Recent Onset NAION Patients
NCT05147701	PHASE1	RECRUITING	Safety of Cultured Allogeneic Adult Umbilical Cord Derived Mesenchymal Stem Cells for NAION