OPA3

Chr 19ADAR

outer mitochondrial membrane lipid metabolism regulator OPA3

Also known as: MGA3

NCBI Gene: 80207 ENSG00000125741 UniProt: Q9H6K4 OMIM: 165300

This protein localizes to the mitochondrial inner membrane and is involved in mitochondrial processes. Mutations cause optic atrophy with cataract and 3-methylglutaconic aciduria type III, with both autosomal dominant and autosomal recessive inheritance patterns described. The gene shows intermediate constraint against loss-of-function variants (pLI 0.57, LOEUF 1.13).

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Optic atrophy 3 with cataractMIM #165300

3-methylglutaconic aciduria, type IIIMIM #258501

Clinical highlights

Gene–disease validity (ClinGen)

Moderate · optic atrophy 3 · AD · ClinGen 2024

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype) and the gene is intolerant of it in the population — truncating, frameshift and canonical splice variants carry more prior weight here than missense.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.13

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — OPA3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

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?

0.05Z-score

OE missense 0.99 (0.84–1.16)

109 obs / 110.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.00 (0.00–1.13)

0≤0.351.4

Missense OE?0.99 (0.84–1.16)

0≤0.61.4

Synonymous OE?0.98

0≤1.21.6

LoF obs/exp: 0 / 2.5Missense obs/exp: 109 / 110.5Syn Z: 0.12

Background carrier burden — how many people carry a rare variant somewhere in OPA3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 170

446 rare PASS variants

Rare truncating (LoF)

1 in 1,900

68 rare PASS variants

Rare synonymous (reference)

1 in 340

194 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for OPA3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 260	1 in 3,700
South Asian	~43k	1 in 210	1 in 500
Remaining (unassigned)	~30k	1 in 140	1 in 2,700
European (Finnish)	~27k	1 in 840	≈ 1 in 13,000
Admixed American	~22k	1 in 130	1 in 1,100
African / African American	~21k	1 in 140	1 in 1,600
East Asian	~20k	1 in 170	≈ 1 in 5,000
Ashkenazi Jewish	~13k	≈ 1 in 3,300	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 360	≈ 1 in 1,400

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 2 coding exons well covered in gnomAD exomes and genomes.? see exons ↓