ACO1

Chr 9

aconitase 1

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

NCBI Gene: 48ENSG00000122729UniProt: P21399OMIM: 100880

The encoded protein functions as both a cytosolic aconitase that catalyzes the conversion of citrate to isocitrate in the TCA cycle and as an iron-responsive element-binding protein that regulates cellular iron homeostasis by controlling translation and stability of iron-related mRNAs. Mutations cause autosomal recessive neurodevelopmental disorders with intellectual disability, seizures, and movement abnormalities. The phenotypes reflect disruption of both mitochondrial energy metabolism and cellular iron regulation affecting primarily the nervous system.

OMIMResearchSummary from RefSeq, UniProt
DNmechanismLOEUF 0.93
Clinical Summary— ACO1
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
4 unique Pathogenic / Likely Pathogenic· 55 VUS of 100 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

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

Typical tolerance to LoF variation

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

Mild missense constraint

Observed / Expected Ratios
LoF OE0.70 (0.54–0.93)
0≤0.351.4
Missense OE0.89 (0.82–0.96)
0≤0.61.4
Synonymous OE1.01
0≤1.21.6
LoF obs/exp: 35 / 49.8Missense obs/exp: 454 / 512.5Syn Z: -0.13
DN
0.6356th %ile
GOF
0.5856th %ile
LOF
0.3939th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

100 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2
Likely Pathogenic2
VUS55
Likely Benign6
Benign7
2
Pathogenic
2
Likely Pathogenic
55
VUS
6
Likely Benign
7
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
2
0
2
Likely Pathogenic
0
0
2
0
2
VUS
1
52
2
0
55
Likely Benign
0
3
1
2
6
Benign
0
2
0
5
7
Total1577772

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.

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
An endometrial tissue-based predictive model for polycystic ovary syndrome constructed from immuno-metabolic dysregulation features mediated by ACO1
Yi P et al.·J Ovarian Res
2026Functional
Aberrant Expression of ACO1 in Vasculatures Parallels Progression of Idiopathic Pulmonary Fibrosis
Fukumoto J et al.·Front Pharmacol
2022
Comprehensive analysis of mitochondrial energy metabolism-related genes and immune infiltration in intervertebral disk degeneration
Lv J et al.·Medicine (Baltimore)
2025
Characterization of MicroRNAs and Gene Expression in ACC Oxidase RNA Interference-Based Transgenic Bananas
Xia Y et al.·Plants (Basel)
2023
Gene Co-expression Network Analysis of the Comparative Transcriptome Identifies Hub Genes Associated With Resistance to Aspergillus flavus L. in Cultivated Peanut (Arachis hypogaea L.)
Cui M et al.·Front Plant Sci
2022
Top 5 full-text resultsSearch PubTator3 ↗
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
2025Open Access
SlERF109-like and SlNAC1 Coordinately Regulated Tomato Ripening by Inhibiting ACO1 Transcription.
Sun C et al.·Int J Mol Sci
2024Open 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
2024Open 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
2022Open Access
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients