ACO1

Chr 9

aconitase 1

Also known as: ACONS, HEL60, IREB1, IREBP, IREBP1, IRP1

NCBI Gene: 48ENSG00000122729UniProt: P21399

The protein encoded by this gene is a bifunctional, cytosolic protein that functions as an essential enzyme in the TCA cycle and interacts with mRNA to control the levels of iron inside cells. When cellular iron levels are high, this protein binds to a 4Fe-4S cluster and functions as an aconitase. Aconitases are iron-sulfur proteins that function to catalyze the conversion of citrate to isocitrate. When cellular iron levels are low, the protein binds to iron-responsive elements (IREs), which are stem-loop structures found in the 5' UTR of ferritin mRNA, and in the 3' UTR of transferrin receptor mRNA. When the protein binds to IRE, it results in repression of translation of ferritin mRNA, and inhibition of degradation of the otherwise rapidly degraded transferrin receptor mRNA. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. Alternative splicing results in multiple transcript variants [provided by RefSeq, Jan 2014]

227
ClinVar variants
67
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— ACO1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
67 Pathogenic / Likely Pathogenic· 111 VUS of 227 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.93LOEUF
pLI 0.000
Z-score 1.94
OE 0.70 (0.54–0.93)
Tolerant

Typical tolerance to LoF variation

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.
0.92Z-score
OE missense 0.89 (0.82–0.96)
454 obs / 512.5 exp
Tolerant

Mild missense constraint

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.0.70 (0.54–0.93)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.89 (0.82–0.96)
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.1.01
0≤1.21.6
LoF obs/exp: 35 / 49.8Missense obs/exp: 454 / 512.5Syn Z: -0.13

ClinVar Variant Classifications

227 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic59
Likely Pathogenic8
VUS111
Likely Benign11
Benign10
59
Pathogenic
8
Likely Pathogenic
111
VUS
11
Likely Benign
10
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
59
0
59
Likely Pathogenic
0
0
8
0
8
VUS
1
106
4
0
111
Likely Benign
0
5
1
5
11
Benign
0
2
0
8
10
Total11137213199

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

View in ClinVar →

Protein Context — Lollipop Plot

ACO1 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
ACONITASE 1; ACO1
MIM #100880 · *
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Identification of potential ferroptosis-associated biomarkers in rheumatoid arthritis.
He X et al.·Front Immunol
2023
Identification of ferroptosis-related genes associated with diffuse large B-cell lymphoma via bioinformatics and machine learning approaches.
Jia Z et al.·Int J Biol Macromol
2024
Impact of iron deficiency on therapeutic outcomes in colorectal cancer patients: a single-center cohort study.
Luo Y et al.·J Transl Med
2025Cohort
Prion Mutations in Republic of Republic of Korea, China, and Japan.
Kim DY et al.·Int J Mol Sci
2022Review
NFS1 Plays a Critical Role in Regulating Ferroptosis Homeostasis.
Sun S et al.·Biomolecules
2025Review
Bioinformatics-based exploration of the role of copper metabolism in chronic glomerulonephritis.
Sun L et al.·Medicine (Baltimore)
2025
[Omics Analysis of Ferroptosis and Establishment of Prognostic Model for multiple myeloma Patients].
Wang ZN et al.·Zhongguo Shi Yan Xue Ye Xue Za Zhi
2023Cohort
An immune-related prognostic signature for predicting breast cancer recurrence.
Tian Z et al.·Cancer Med
2020
Integrative Analysis of Core Genes and Biological Process Involved in Polycystic Ovary Syndrome.
Zhang Y et al.·Reprod Sci
2023
A novel and independent survival prognostic model for OSCC: the functions and prognostic values of RNA-binding proteins.
Wang S et al.·Eur Arch Otorhinolaryngol
2024Functional
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
MUSTN1 prevents muscle atrophy through ferroptosis suppression: A ACO1-dependent and exosome-mediated mechanism.
Hu Z et al.·Int J Biol Macromol
2026Functional
ACO1 OGDH axis drives mitochondrial immune crosstalk in preeclampsia through systems biology enabling dual target therapy.
Wu M et al.·Sci Rep
2025🔓 Open Access
SlERF109-like and SlNAC1 Coordinately Regulated Tomato Ripening by Inhibiting ACO1 Transcription.
Sun C et al.·Int J Mol Sci
2024🔓 Open Access
Characterization and Potential Action Mode Divergences of Homologous ACO1 Genes during the Organ Development and Ripening Process between Non-Climacteric Grape and Climacteric Peach.
Luo L et al.·Int J Mol Sci
2024🔓 Open Access
ACO1 and IREB2 downregulation confer poor prognosis and correlate with autophagy-related ferroptosis and immune infiltration in KIRC.
Zhu T et al.·Front Oncol
2022🔓 Open Access
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