AFG3L2

Chr 18ADAR

AFG3 like matrix AAA peptidase subunit 2

Also known as: OPA12, SCA28, SPAX5

NCBI Gene: 10939ENSG00000141385UniProt: Q9Y4W6

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]

Primary Disease Associations & Inheritance

Optic atrophy 12MIM #618977
AD
Spastic ataxia 5, autosomal recessiveMIM #614487
AR
Spinocerebellar ataxia 28MIM #610246
AD
581
ClinVar variants
103
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— AFG3L2
🧬
Gene-Disease Validity (ClinGen)
optic atrophy 12 · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
103 Pathogenic / Likely Pathogenic· 284 VUS of 581 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.70LOEUF
pLI 0.000
Z-score 3.13
OE 0.49 (0.34–0.70)
Tolerant

Typical tolerance to LoF variation

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.
1.99Z-score
OE missense 0.73 (0.66–0.80)
303 obs / 417.3 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.0.49 (0.34–0.70)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.73 (0.66–0.80)
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.1.07
0≤1.21.6
LoF obs/exp: 21 / 43.2Missense obs/exp: 303 / 417.3Syn Z: -0.64

ClinVar Variant Classifications

581 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic77
Likely Pathogenic26
VUS284
Likely Benign132
Benign40
Conflicting22
77
Pathogenic
26
Likely Pathogenic
284
VUS
132
Likely Benign
40
Benign
22
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
10
11
56
0
77
Likely Pathogenic
4
15
7
0
26
VUS
9
230
34
11
284
Likely Benign
0
1
67
64
132
Benign
0
0
35
5
40
Conflicting
—22
Total2325719980581

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

View in 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.

Gene2Phenotype Curations

AFG3L2-related ataxia and seizures

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Optic atrophy 12

MIM #618977

Molecular basis of disorder known

Autosomal dominant

Spastic ataxia 5, autosomal recessive

MIM #614487

Molecular basis of disorder known

Autosomal recessive

Spinocerebellar ataxia 28

MIM #610246

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — AFG3L2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
AFG3L2 and ACO2-Linked Dominant Optic Atrophy: Genotype-Phenotype Characterization Compared to OPA1 Patients.
Amore G et al.·Am J Ophthalmol
2024Cohort
Clinical and genetic landscape of optic atrophy in 826 families: insights from 50 nuclear genes.
Zheng Y et al.·Brain
2025
Extreme phenotypic heterogeneity in non-expansion spinocerebellar ataxias.
Cunha P et al.·Am J Hum Genet
2023
Multifaceted Roles of AFG3L2, a Mitochondrial ATPase in Relation to Neurological Disorders.
Ghosh Dastidar R et al.·Mol Neurobiol
2024Review
Sustained OMA1-mediated integrated stress response is beneficial for spastic ataxia type 5.
Franchino CA et al.·Brain
2024
Genetic overlap between ALS and other neurodegenerative or neuromuscular disorders.
Olsen CG et al.·Amyotroph Lateral Scler Frontotemporal Degener
2024
The top 10 most frequently involved genes in hereditary optic neuropathies in 2186 probands.
Rocatcher A et al.·Brain
2023
Expanding the phenotype of AFG3L2 mutations: Late-onset autosomal recessive spinocerebellar ataxia.
Chiang HL et al.·J Neurol Sci
2021
Pathogenic variants in the AFG3L2 proteolytic domain cause SCA28 through haploinsufficiency and proteostatic stress-driven OMA1 activation.
Tulli S et al.·J Med Genet
2019
Expanding the Phenotypic Spectrum of SPG7 Rare Damaging Variants: Insights From a Hungarian Cohort.
Jimoh IJ et al.·Clin Genet
2025Cohort
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
Rare DisordersUndiagnosed DisordersDisorders of Unknown Prevalence

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

RECRUITING
NCT01793168Sanford HealthStarted 2010-07

External Resources

Links to major genomics databases and tools