OPA3

Chr 19

outer mitochondrial membrane lipid metabolism regulator OPA3

Also known as: MGA3

NCBI Gene: 80207ENSG00000125741UniProt: Q9H6K4

The mouse ortholog of this protein co-purifies with the mitochondrial inner membrane. Mutations in this gene have been shown to result in 3-methylglutaconic aciduria type III and autosomal dominant optic atrophy and cataract. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2009]

Primary Disease Associations & Inheritance

UniProt3-methylglutaconic aciduria 3
UniProtOptic atrophy 3
644
ClinVar variants
23
Pathogenic / LP
0.57
pLI score
0
Active trials
Clinical Summary— OPA3
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.57) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
23 Pathogenic / Likely Pathogenic· 160 VUS of 644 total submissions
Some data sources returned errors (2)

clinvar: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
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.
1.13LOEUF
pLI 0.566
Z-score 1.48
OE 0.00 (0.00–1.13)
Moderately constrained

Highly tolerant — LoF variants common in population

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.
0.05Z-score
OE missense 0.99 (0.84–1.16)
109 obs / 110.5 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.0.00 (0.00–1.13)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.99 (0.84–1.16)
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.0.98
0≤1.21.6
LoF obs/exp: 0 / 2.5Missense obs/exp: 109 / 110.5Syn Z: 0.12

ClinVar Variant Classifications

644 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10
Likely Pathogenic13
VUS160
Likely Benign121
Benign11
Conflicting28
10
Pathogenic
13
Likely Pathogenic
160
VUS
121
Likely Benign
11
Benign
28
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
3
3
4
0
10
Likely Pathogenic
4
3
6
0
13
VUS
5
101
54
0
160
Likely Benign
0
1
35
85
121
Benign
0
0
10
1
11
Conflicting
—28
Total1210810986343

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

View in ClinVar →

Protein Context — Lollipop Plot

OPA3 · protein map & ClinVar variants

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

Gene2Phenotype Curations

OPA3-related optic atrophy with cataract

definitive
ADUndeterminedAltered Gene Product Structure
Eye
G2P ↗
missense variantinframe deletioninframe insertion

OPA3-related 3-methylglutaconic aciduria, type III

definitive
ARLoss Of FunctionAbsent Gene Product
Eye
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Dominant optic atrophy.
Lenaers G et al.·Orphanet J Rare Dis
2012Review
Expression status and prognostic significance of mitochondrial dynamics OPA3 in human ovarian cancer.
Tsai HW et al.·Aging (Albany NY)
2022
Clinical and molecular genetic findings in autosomal dominant OPA3-related optic neuropathy.
Sergouniotis PI et al.·Neurogenetics
2015
Neuro-Ophthalmic Phenotype of OPA3.
Huna-Baron R et al.·J Neuroophthalmol
2022
Genetic screening for OPA1 and OPA3 mutations in patients with suspected inherited optic neuropathies.
Yu-Wai-Man P et al.·Ophthalmology
2011Cohort
Novel heterozygous OPA3 variant in a family with congenital cataracts, sensorineural hearing loss and neuropathy, without optic atrophy and comparison of pathogenic and population variants.
Penon-Portmann M et al.·Am J Med Genet A
2025Case report
Mitochondrial Membrane Dynamics and Inherited Optic Neuropathies.
Bagli E et al.·In Vivo
2017Review
A novel OPA3 mutation revealed by exome sequencing: an example of reverse phenotyping.
Arif B et al.·JAMA Neurol
2013Case report
Disrupted mitochondrial function in the Opa3L122P mouse model for Costeff Syndrome impairs skeletal integrity.
Navein AE et al.·Hum Mol Genet
2016Functional
Molecular genetic basis of primary inherited optic neuropathies.
Votruba M·Eye (Lond)
2004Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
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