AFG3L2

Chr 18ADAR

AFG3 like matrix AAA peptidase subunit 2

Also known as: OPA12, SCA28, SPAX5

NCBI Gene: 10939 ENSG00000141385 UniProt: Q9Y4W6 OMIM: 604581

The protein functions as a catalytic component of the mitochondrial m-AAA protease, which degrades misfolded proteins and processes mitochondrial proteins essential for neuronal development and axonal function. Mutations cause optic atrophy 12, spastic ataxia 5, and spinocerebellar ataxia 28 through both autosomal dominant and autosomal recessive inheritance patterns. The pathogenic mechanism involves dominant-negative effects that disrupt mitochondrial protein quality control and processing.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

This gene encodes a protein localized in mitochondria and closely related to paraplegin. The paraplegin gene is responsible for an autosomal recessive form of hereditary spastic paraplegia. This gene is a candidate gene for other hereditary spastic paraplegias or neurodegenerative disorders. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Optic atrophy 12MIM #618977

Spastic ataxia 5, autosomal recessiveMIM #614487

Spinocerebellar ataxia 28MIM #610246

Clinical highlights

Gene-disease validity (ClinGen)

AFG3L2-related optic atrophy and/or spastic ataxia spectrum · SDDefinitivesufficient evidence for diagnostic panels

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.70

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — AFG3L2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.70LOEUF

pLI 0.000

Z-score 3.13

OE 0.49 (0.34–0.70)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.99Z-score

OE missense 0.73 (0.66–0.80)

303 obs / 417.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.49 (0.34–0.70)

0≤0.351.4

Missense OE?0.73 (0.66–0.80)

0≤0.61.4

Synonymous OE?1.07

0≤1.21.6

LoF obs/exp: 21 / 43.2Missense obs/exp: 303 / 417.3Syn Z: -0.64

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

AFG3L2 · protein map & ClinVar variants

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

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

📖

GeneReview available — AFG3L2

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Rare DisordersUndiagnosed DisordersDisorders of Unknown Prevalence

Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford

RECRUITING

NCT01793168Sanford HealthStarted 2010-07

Clinical Literature

Open Research Assistant →

Landmark / reviewRecent case evidence

Full-Text Mentions

NLP-detected gene mentions in article bodies · via PubTator3

PubTator3

Spasmodic Dysphonia in a Patient with Spinocerebellar Ataxia Associated with a Rare AFG3L2 Variant (ATX-AFG3L2).

Reyes NGD et al.·Mov Disord Clin Pract

2023

Expanding the AFG3L2 Spectrum: A Link to Axonal Neuropathy.

Rocco A et al.·Neurol Genet

2026

AFG3L2 Biallelic Mutation: Clinical Heterogeneity in Two Italian Patients.

Colucci F et al.·Cerebellum

2022Cohort

Optic Neuropathy AFG3L2 Related in a Patient Affected by Congenital Stationary Night Blindness

Cammarata G et al.·Case Rep Ophthalmol Med

2024

Expanding the phenotype of AFG3L2 mutations: Late-onset autosomal recessive spinocerebellar ataxia.

Chiang HL et al.·J Neurol Sci

2021

Top 5 full-text resultsSearch PubTator3 ↗

Key Publications

Landmark & review papers · by relevance

PubMed

Multifaceted Roles of AFG3L2, a Mitochondrial ATPase in Relation to Neurological Disorders.

Ghosh Dastidar R et al.·Mol Neurobiol

2024Review

The top 10 most frequently involved genes in hereditary optic neuropathies in 2186 probands.

Rocatcher A et al.·Brain

2023

Extreme phenotypic heterogeneity in non-expansion spinocerebellar ataxias.

Cunha P et al.·Am J Hum Genet

2023

[Type 28 spinocerebellar ataxia].

Krasakov IV et al.·Zh Nevrol Psikhiatr Im S S Korsakova

2025Case report

Sustained OMA1-mediated integrated stress response is beneficial for spastic ataxia type 5.

Franchino CA et al.·Brain

2024

Top 5 results · since 2015Search PubMed ↗

Recent Gene-Specific Literature

Gene in title · MEDLINE · newest first

Europe PMC

Rare AFG3L2 and POLG Variants Suggest a Role for Mitochondrial Dysfunction in Enteric Neuronal Vulnerability in Idiopathic Achalasia.

Latiano A et al.·Int J Mol Sci

2026Open Access

Loss of Function of AFG3L2 Leading to Developmental and Epileptic Encephalopathy.

Pan Z et al.·CNS Neurosci Ther

2026Open Access

Phenotypic Exploration in Patients with Heterozygous Variant in AFG3L2 Gene: A Case-Series and Literature Review.

Yoganathan S et al.·Mov Disord Clin Pract

2026Open AccessReview

Expanding the Spectrum of AFG3L2 Mutations: A Case with Late-Onset Autosomal Recessive Spinocerebellar Ataxia from Iran.

Salari M et al.·Cerebellum

2026

Digenic inheritance of mutations in SPG7 and AFG3L2 causes motor neuron and cerebellar disorders.

Estiar MA et al.·BMC Med

2026Open Access

Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox

AI-powered variant curation and clinical analysis

DECIPHER

Genomic variants and phenotypes in rare disease patients

AFG3L2

Primary Disease Associations & Inheritance

Clinical highlights

Population Genetics & Constraint

ClinVar Variant Classifications

Protein Context — Lollipop Plot

Mechanism of Pathogenicity

Tissue Expression

Transcripts & Isoforms

Transcript architecture

DECIPHER · Gene2Phenotype

OMIM — Genotype-Phenotype Relationships

Gene Overview

ClinGen Curation

Disease Associations

External Resources

Clinical Trials

External Resources

Mechanism of Pathogenicity

Transcripts & Isoforms