Optic atrophy 9

Summary

Optic atrophy 9 (MONDO:0014571) is a disease caused by ACO2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: ACO2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 36

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	optic atrophy 9
Mondo ID	MONDO:0014571
OMIM	616289
DOID	DOID:0111442
UMLS	C4225384
MedGen	898858
GARD	0018199
Is cancer (heuristic)	no

Also known as: ACO2 autosomal recessive isolated optic atrophy · autosomal recessive isolated optic atrophy caused by mutation in ACO2 · OPA9 · optic atrophy 9

Data availability: 36 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › optic nerve disorder › optic atrophy › primary optic atrophy › hereditary optic atrophy › ACO2-related optic atrophy with or without extraocular features › optic atrophy 9

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

36 retrieved; paginated sample, class counts are floors:

9 conflicting classifications of pathogenicity, 9 uncertain significance, 7 benign, 5 likely pathogenic, 4 pathogenic, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
830373	NM_001098.3(ACO2):c.[1894G>A];[487G>T]		Pathogenic	no assertion criteria provided
1213918	NM_001098.3(ACO2):c.1507G>T (p.Gly503Ter)	ACO2	Pathogenic	criteria provided, multiple submitters, no conflicts
1711158	NM_001098.3(ACO2):c.1254dup (p.Gly419fs)	ACO2	Pathogenic	no assertion criteria provided
931020	NM_001098.3(ACO2):c.2253dup (p.Ile752fs)	ACO2	Pathogenic	criteria provided, single submitter
1709577	NM_001098.3(ACO2):c.1823_1896dup (p.Arg633fs)	ACO2	Likely pathogenic	criteria provided, single submitter
2506954	NM_001098.3(ACO2):c.36G>A (p.Gln12=)	ACO2	Likely pathogenic	criteria provided, single submitter
2686036	NM_001098.3(ACO2):c.1831_1833delinsC (p.Asp611fs)	ACO2	Likely pathogenic	criteria provided, single submitter
3897935	NM_001098.3(ACO2):c.664T>C (p.Trp222Arg)	ACO2	Likely pathogenic	criteria provided, single submitter
4823908	NM_001098.3(ACO2):c.1364G>A (p.Trp455Ter)	ACO2	Likely pathogenic	criteria provided, single submitter
1031822	NM_001098.3(ACO2):c.2145CAA[1] (p.Asn716del)	ACO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1354645	NM_001098.3(ACO2):c.934C>T (p.Arg312Trp)	ACO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1400671	NM_001098.3(ACO2):c.2012G>A (p.Arg671Gln)	ACO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1810223	NM_001098.3(ACO2):c.1534G>A (p.Asp512Asn)	ACO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
189310	NM_001098.3(ACO2):c.220C>G (p.Leu74Val)	ACO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
218316	NM_001098.3(ACO2):c.1819C>T (p.Arg607Cys)	ACO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
374008	NM_001098.3(ACO2):c.76C>T (p.Leu26=)	ACO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
728759	NM_001098.3(ACO2):c.1387G>T (p.Gly463Trp)	ACO2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1436279	NM_001098.3(ACO2):c.1628C>T (p.Thr543Ile)	LOC130067544	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1213908	NM_001098.3(ACO2):c.317C>T (p.Ala106Val)	ACO2	Uncertain significance	criteria provided, single submitter
1704307	NM_001098.3(ACO2):c.2015A>C (p.Glu672Ala)	ACO2	Uncertain significance	criteria provided, single submitter
1709424	NM_001098.3(ACO2):c.1348C>T (p.Pro450Ser)	ACO2	Uncertain significance	criteria provided, single submitter
214018	NM_001098.3(ACO2):c.719G>C (p.Gly240Ala)	ACO2	Uncertain significance	criteria provided, multiple submitters, no conflicts
214022	NM_001098.3(ACO2):c.2051G>A (p.Arg684Gln)	ACO2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3064018	NM_001098.3(ACO2):c.1442A>C (p.Asp481Ala)	ACO2	Uncertain significance	criteria provided, single submitter
3370479	NM_001098.3(ACO2):c.36+262C>T	ACO2	Uncertain significance	criteria provided, single submitter
374009	NM_001098.3(ACO2):c.75C>T (p.Val25=)	ACO2	Uncertain significance	criteria provided, single submitter
562210	NM_001098.3(ACO2):c.2050C>T (p.Arg684Trp)	ACO2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1188855	NM_001098.3(ACO2):c.174-52G>T	ACO2	Benign	criteria provided, multiple submitters, no conflicts
1188888	NM_001098.3(ACO2):c.836-118C>T	ACO2	Benign	criteria provided, multiple submitters, no conflicts
1188889	NM_001098.3(ACO2):c.836-54T>C	ACO2	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
ACO2	Strong	Semidominant	optic atrophy 9	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACO2	Orphanet:313850	Infantile cerebellar-retinal degeneration
ACO2	Orphanet:98676	Autosomal recessive isolated optic atrophy

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ACO2	HGNC:118	ENSG00000100412	Q99798	Aconitate hydratase, mitochondrial	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACO2	Aconitate hydratase, mitochondrial	Catalyzes the isomerization of citrate to isocitrate via cis-aconitate.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ACO2	Enzyme (other)	yes	4.2.1.3	AconitaseA/IPMdHydase_ssu_swvl, Acoase/IPM_deHydtase_lsu_aba, Aconitase_mito-like

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
heart right ventricle	1
left ventricle myocardium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACO2	291	ubiquitous	marker	heart right ventricle, apex of heart, left ventricle myocardium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACO2	4,776

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ACO2	Q99798	95.44

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Maturation of TCA enzymes and regulation of TCA cycle	1	571.0×	0.009	ACO2
Citric acid cycle (TCA cycle)	1	423.0×	0.009	ACO2
Protein localization	1	190.3×	0.012	ACO2
Mitochondrial protein import	1	167.9×	0.012	ACO2
Mitochondrial protein degradation	1	114.2×	0.014	ACO2
Aerobic respiration and respiratory electron transport	1	88.5×	0.015	ACO2
Metabolism of proteins	1	12.4×	0.086	ACO2
Metabolism	1	11.6×	0.086	ACO2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
citrate metabolic process	1	4213.0×	7e-04	ACO2
tricarboxylic acid cycle	1	510.7×	0.003	ACO2
generation of precursor metabolites and energy	1	343.9×	0.003	ACO2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ACO2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ACO2	4.2.1.3	aconitate hydratase

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	ACO2
E	Difficult family or no structure, no drug	0

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
ACO2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.