ACO2

Chr 22ARAD

aconitase 2

Also known as: ACONM, HEL-S-284, ICRD, OCA8, OPA9

NCBI Gene: 50ENSG00000100412UniProt: Q99798

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. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Infantile cerebellar-retinal degenerationMIM #614559
AR
Optic atrophy 9MIM #616289
ADAR
285
ClinVar variants
24
Pathogenic / LP
0.21
pLI score
0
Active trials
Clinical Summary— ACO2
🧬
Gene-Disease Validity (ClinGen)
mitochondrial disease · ADStrong

Strong evidence — appropriate for clinical testing

3 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.
📋
ClinVar Variants
24 Pathogenic / Likely Pathogenic· 157 VUS of 285 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.42LOEUF
pLI 0.208
Z-score 4.33
OE 0.24 (0.14–0.42)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.92Z-score
OE missense 0.63 (0.57–0.69)
304 obs / 485.0 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.24 (0.14–0.42)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.63 (0.57–0.69)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.99
0≤1.21.6
LoF obs/exp: 9 / 37.7Missense obs/exp: 304 / 485.0Syn Z: 0.09

ClinVar Variant Classifications

285 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic16
Likely Pathogenic8
VUS157
Likely Benign102
Benign2
16
Pathogenic
8
Likely Pathogenic
157
VUS
102
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
7
0
9
0
16
Likely Pathogenic
4
4
0
0
8
VUS
3
124
24
6
157
Likely Benign
0
0
44
58
102
Benign
0
0
2
0
2
Total141287964285

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

ACO2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

ACO2-related infantile cerebellar-retinal degeneration

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. DisordersEye
G2P ↗

ACO2-related optic atrophy

strong
ARUndeterminedAltered Gene Product Structure
Eye
G2P ↗
missense variantinframe deletioninframe insertion

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
ACONITASE 2; ACO2
MIM #100850 · *

Infantile cerebellar-retinal degeneration

MIM #614559

Molecular basis of disorder known

Autosomal recessive

Optic atrophy 9

MIM #616289

Molecular basis of disorder known

Autosomal dominantAutosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Episodic Ataxias: Primary and Secondary Etiologies, Treatment, and Classification Approaches.
Hassan A·Tremor Other Hyperkinet Mov (N Y)
2023Case report
AFG3L2 and ACO2-Linked Dominant Optic Atrophy: Genotype-Phenotype Characterization Compared to OPA1 Patients.
Amore G et al.·Am J Ophthalmol
2024Cohort
Clinical and genetic landscape of optic atrophy in 826 families: insights from 50 nuclear genes.
Zheng Y et al.·Brain
2025
Unveiling migraine subtype heterogeneity and risk loci: integrated genome-wide association study and single-cell transcriptomics discovery.
Wei S et al.·J Headache Pain
2025
Target oxidative stress-induced disulfidptosis: novel therapeutic avenues in Parkinson's disease.
Zhang J et al.·Mol Brain
2025
The top 10 most frequently involved genes in hereditary optic neuropathies in 2186 probands.
Rocatcher A et al.·Brain
2023
Expanding the clinical and phenotypic heterogeneity associated with biallelic variants in ACO2.
Blackburn PR et al.·Ann Clin Transl Neurol
2020
The Prognostic Role of ACO2 in Renal Cell Carcinoma.
Jaworski D et al.·Anticancer Res
2023
ACO2 and ANPEP as novel prognostic markers for gallbladder squamous cell/adenosquamous carcinomas and adenocarcinomas.
Liu Z et al.·Int J Clin Oncol
2020
LONP1 Promotes Hepatocarcinogenesis by Degrading ACO2 to Alleviate Ferroptosis.
Zhong Y et al.·Front Biosci (Landmark Ed)
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools