Optic atrophy 3

Summary

Optic atrophy 3 (MONDO:0008133) is a disease caused by OPA3 (GenCC Definitive), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: OPA3 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 516
• Phenotypes (HPO): 35

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

35 HPO clinical features (Orphanet curated; top 35 by frequency):

HPO ID	Term	Frequency
HP:0000505	Visual impairment	Obligate (100%)
HP:0000648	Optic atrophy	Very frequent (80-99%)
HP:0007663	Reduced visual acuity	Very frequent (80-99%)
HP:0000518	Cataract	Frequent (30-79%)
HP:0000603	Central scotoma	Frequent (30-79%)
HP:0000639	Nystagmus	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001272	Cerebellar atrophy	Frequent (30-79%)
HP:0001284	Areflexia	Frequent (30-79%)
HP:0002174	Postural tremor	Frequent (30-79%)
HP:0002317	Unsteady gait	Frequent (30-79%)
HP:0002522	Areflexia of lower limbs	Frequent (30-79%)
HP:0003394	Muscle spasm	Frequent (30-79%)
HP:0003401	Paresthesia	Frequent (30-79%)
HP:0003474	Somatic sensory dysfunction	Frequent (30-79%)
HP:0010924	Posterior cortical cataract	Frequent (30-79%)
HP:0012531	Pain	Frequent (30-79%)
HP:0000552	Tritanomaly	Occasional (5-29%)
HP:0000618	Blindness	Occasional (5-29%)
HP:0000642	Red-green dyschromatopsia	Occasional (5-29%)
HP:0001172	Abnormal thumb morphology	Occasional (5-29%)
HP:0001315	Reduced tendon reflexes	Occasional (5-29%)
HP:0001377	Limited elbow extension	Occasional (5-29%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0002322	Resting tremor	Occasional (5-29%)
HP:0002403	Positive Romberg sign	Occasional (5-29%)
HP:0003438	Absent Achilles reflex	Occasional (5-29%)
HP:0006248	Limited wrist movement	Occasional (5-29%)
HP:0007076	Extrapyramidal muscular rigidity	Occasional (5-29%)
HP:0007787	Posterior subcapsular cataract	Occasional (5-29%)
HP:0007795	Anterior cortical cataract	Occasional (5-29%)
HP:0007976	Cerulean cataract	Occasional (5-29%)
HP:0009468	Deviation of the 2nd finger	Occasional (5-29%)
HP:0010522	Dyslexia	Occasional (5-29%)
HP:0010923	Anterior subcapsular cataract	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	optic atrophy 3
Mondo ID	MONDO:0008133
MeSH	C537128
OMIM	165300
Orphanet	67036
DOID	DOID:0111433
SNOMED CT	719517009
UMLS	C1833809
MedGen	371657
GARD	0010203
Is cancer (heuristic)	no

Also known as: autosomal dominant optic atrophy type 3 · OPA3 · OPA3, autosomal dominant · optic atrophy 3 · optic atrophy 3 with cataract · optic atrophy 3, autosomal dominant · optic atrophy, cataract, and neurologic disorder

Data availability: 516 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › inborn mitochondrial metabolism disorder › mitochondrial oxidative phosphorylation disorder › optic atrophy 3

Related subtypes (47): mitochondrial respiratory chain complex deficiency, combined oxidative phosphorylation deficiency, myopathy, lactic acidosis, and sideroblastic anemia, autosomal dominant optic atrophy, classic form, Leigh syndrome, mitochondrial non-syndromic sensorineural hearing loss, maternally-inherited diabetes and deafness, chronic diarrhea with villous atrophy, Kearns-Sayre syndrome, Leber hereditary optic neuropathy, NARP syndrome, deafness, aminoglycoside-induced, hereditary spastic paraplegia 7, spinocerebellar ataxia type 28, leukoencephalopathy with brain stem and spinal cord involvement-high lactate syndrome, spastic ataxia 3, pontocerebellar hypoplasia type 6, autosomal recessive optic atrophy, OPA7 type, acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins, congenital cataract-progressive muscular hypotonia-hearing loss-developmental delay syndrome, spastic ataxia 4, hyperuricemia-pulmonary hypertension-renal failure-alkalosis syndrome, hereditary spastic paraplegia 55, cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome, Charcot-Marie-Tooth disease recessive intermediate D, autosomal dominant mitochondrial myopathy with exercise intolerance, Charcot-Marie-Tooth disease type 4K, hydrops-lactic acidosis-sideroblastic anemia-multisystemic failure syndrome, hereditary spastic paraplegia 77, fatal infantile encephalocardiomyopathy, FASTKD2-related infantile mitochondrial encephalomyopathy, autosomal dominant optic atrophy and peripheral neuropathy, ataxia neuropathy spectrum, maternally-inherited mitochondrial dystonia, Perrault syndrome, hypertrophic cardiomyopathy and renal tubular disease due to mitochondrial DNA mutation, adult-onset chronic progressive external ophthalmoplegia with mitochondrial myopathy, mitochondrial DNA maintenance syndrome, coenzyme Q10 deficiency, mitochondrial DNA depletion syndrome, periodic paralysis with later-onset distal motor neuropathy, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, Zellweger-like syndrome without peroxisomal anomalies, maternally-inherited progressive external ophthalmoplegia, Leber plus disease, encephalopathy due to mitochondrial and peroxisomal fission defect, severe neonatal lactic acidosis due to NFS1-ISD11 complex deficiency

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

516 retrieved; paginated sample, class counts are floors:

244 uncertain significance, 150 likely benign, 56 conflicting classifications of pathogenicity, 27 benign, 18 benign/likely benign, 9 likely pathogenic, 9 pathogenic, 2 not provided, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
3754912	NM_025136.4(OPA3):c.39C>G (p.Tyr13Ter)	LOC130064709	Pathogenic	criteria provided, single submitter
1727235	NM_025136.4(OPA3):c.143-1G>A	OPA3	Pathogenic	criteria provided, multiple submitters, no conflicts
2128878	NM_025136.4(OPA3):c.103G>T (p.Glu35Ter)	OPA3	Pathogenic	criteria provided, single submitter
3248433	NC_000019.9:g.(?46056772)(46088022_?)del	OPA3	Pathogenic	criteria provided, single submitter
4239	NM_025136.4(OPA3):c.143-1G>C	OPA3	Pathogenic	criteria provided, multiple submitters, no conflicts
4240	NM_025136.4(OPA3):c.277G>A (p.Gly93Ser)	OPA3	Pathogenic	no assertion criteria provided
4241	NM_025136.4(OPA3):c.313C>G (p.Gln105Glu)	OPA3	Pathogenic	criteria provided, multiple submitters, no conflicts
620409	NM_025136.4(OPA3):c.52C>T (p.Gln18Ter)	OPA3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
831267	NC_000019.10:g.(?45584613)(45584774_?)del	OPA3	Pathogenic	criteria provided, single submitter
952107	NM_025136.4(OPA3):c.143-2_143-1delinsCC	OPA3	Pathogenic	criteria provided, single submitter
1067581	NM_025136.4(OPA3):c.1A>G (p.Met1Val)	OPA3	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2190228	NM_025136.4(OPA3):c.152G>A (p.Trp51Ter)	OPA3	Likely pathogenic	criteria provided, single submitter
225178	NM_025136.4(OPA3):c.235C>G (p.Leu79Val)	OPA3	Likely pathogenic	criteria provided, single submitter
3248434	NC_000019.9:g.(?46056772)(46057189_?)del	OPA3	Likely pathogenic	criteria provided, single submitter
3583954	NM_025136.4(OPA3):c.308_312del (p.Arg103fs)	OPA3	Likely pathogenic	criteria provided, single submitter
3760447	NM_025136.4(OPA3):c.140A>G (p.Gln47Arg)	OPA3	Likely pathogenic	criteria provided, single submitter
531189	NM_025136.4(OPA3):c.142+2_142+3dup	OPA3	Likely pathogenic	criteria provided, single submitter
552615	NM_001017989.3(OPA3):c.313C>T (p.Gln105Ter)	OPA3	Likely pathogenic	criteria provided, single submitter
557552	NC_000019.10:g.45529163G>A	OPA3	Likely pathogenic	criteria provided, single submitter
1485991	NM_025136.4(OPA3):c.206A>C (p.Lys69Thr)	OPA3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1969576	NM_025136.4(OPA3):c.244G>T (p.Glu82Ter)	OPA3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2083156	NM_025136.4(OPA3):c.484C>T (p.Gln162Ter)	OPA3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214925	NM_025136.4(OPA3):c.508G>A (p.Ala170Thr)	OPA3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214926	NM_025136.4(OPA3):c.532A>G (p.Lys178Glu)	OPA3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214928	NM_025136.4(OPA3):c.540G>C (p.Ter180Tyr)	OPA3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214929	NM_001017989.3(OPA3):c.184G>A (p.Gly62Ser)	OPA3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2677420	NM_025136.4(OPA3):c.313C>T (p.Gln105Ter)	OPA3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2683843	NM_025136.4(OPA3):c.439_440del (p.Gly147fs)	OPA3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
284628	NM_025136.4(OPA3):c.33G>T (p.Leu11=)	OPA3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
329551	NM_025136.4(OPA3):c.*7181G>A	OPA3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

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
OPA3	Definitive	Autosomal dominant	optic atrophy 3	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
OPA3	Orphanet:67036	Autosomal dominant optic atrophy and cataract
OPA3	Orphanet:67047	3-methylglutaconic aciduria type 3

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
OPA3	HGNC:8142	ENSG00000125741	Q9H6K4	Optic atrophy 3 protein	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
OPA3	Optic atrophy 3 protein	May play some role in mitochondrial processes.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
OPA3	Other/Unknown	no		OPA3-like

Expression context

Cohort genes with no expression data: 0.

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
hindlimb stylopod muscle	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
OPA3	213	ubiquitous	yes	tendon of biceps brachii, hindlimb stylopod muscle, apex of heart

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
OPA3	87

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
OPA3	Q9H6K4	83.13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 0. Enrichment computed across 1 evidence-associated genes (0 with Reactome annotation).

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
regulation of growth	1	936.2×	0.005	OPA3
neuromuscular process	1	526.6×	0.005	OPA3
regulation of lipid metabolic process	1	432.1×	0.005	OPA3
bone development	1	276.3×	0.006	OPA3
fat cell differentiation	1	181.2×	0.008	OPA3
mitochondrion organization	1	151.8×	0.008	OPA3
visual perception	1	79.5×	0.013	OPA3

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
OPA3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
E	Difficult family or no structure, no drug	1	OPA3

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)
OPA3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.