ACO2

Chr 22

aconitase 2

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

NCBI Gene: 50 ENSG00000100412 UniProt: Q99798

The protein is a mitochondrial enzyme that catalyzes the conversion of citrate to isocitrate in the TCA cycle, essential for cellular energy production. Mutations cause infantile cerebellar-retinal degeneration and optic atrophy 9, affecting the central nervous system and visual system with early onset manifestations. The gene follows both autosomal recessive and autosomal dominant inheritance patterns and shows moderate constraint against loss-of-function variants (LOEUF 0.417).

ResearchSummary from RefSeq, OMIM, UniProt

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]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.42

Clinical Summary— ACO2

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Gene-Disease Validity (ClinGen)

mitochondrial disease · ADStrong

Strong evidence — appropriate for clinical testing

3 total gene-disease associations curated

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.

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ClinVar Variants

87 unique Pathogenic / Likely Pathogenic· 406 VUS of 915 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

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?

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?

LoF OE?0.24 (0.14–0.42)

0≤0.351.4

Missense OE?0.63 (0.57–0.69)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 9 / 37.7Missense obs/exp: 304 / 485.0Syn Z: 0.09

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveACO2-related infantile cerebellar-retinal degenerationLOFAR

strongACO2-related optic atrophyOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6455th %ile

GOF

0.5660th %ile

LOF

0.4628th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

915 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic55

Likely Pathogenic32

VUS406

Likely Benign349

Benign37

Conflicting20

Pathogenic

Likely Pathogenic

406

VUS

349

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	43	7	5	0	55
Likely Pathogenic	21	10	0	1	32
VUS	5	357	32	12	406
Likely Benign	0	1	157	191	349
Benign	0	1	30	6	37
Conflicting	—				20
Total	69	376	224	210	899

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

View in ClinVar →

21 pathogenic / likely-pathogenic (of 34) ClinVar copy-number / structural variants overlap ACO2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →