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…

LOFmechanismAD/ARLOEUF 0.703 OMIM phenotypes

Clinical Summary— AFG3L2

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Gene-Disease Validity (ClinGen)

AFG3L2-related optic atrophy and/or spastic ataxia spectrum · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

71 unique Pathogenic / Likely Pathogenic· 288 VUS of 604 total submissions

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Clinical Trials

1 active or recruiting trial — potential therapeutic options may be available

Explore recent and relevant literature in Research Assistant →

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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

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveAFG3L2-related ataxia and seizuresLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.81top 10%

GOF

0.6150th %ile

LOF

0.2872th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Literature Evidence

DNNotably, introducing AFG3L2WT into cells carrying mutant AFG3L2E691K or AFG3L2N432T resulted in only a limited correction of the yta10Îyta12Î respiratory phenotype, with an intermediately reduced growth rate of AFG3L2WT-AFG3L2mut cells, clearly indicating a dominant negative effect of these fully 1

LOFPathogenic variants in the AFG3L2 proteolytic domain cause SCA28 through haploinsufficiency and proteostatic stress-driven OMA1 activation.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References

ClinVar Variant Classifications

604 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic39

Likely Pathogenic32

VUS288

Likely Benign143

Benign54

Conflicting31

Pathogenic

Likely Pathogenic

288

VUS

143

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	20	18	1	0	39
Likely Pathogenic	8	24	0	0	32
VUS	9	243	25	11	288
Likely Benign	0	1	77	65	143
Benign	0	0	46	8	54
Conflicting	—				31
Total	37	286	149	84	587

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

View in ClinVar →

89 pathogenic / likely-pathogenic (of 105) ClinVar copy-number / structural variants overlap AFG3L2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →