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

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

79 unique Pathogenic / Likely Pathogenic· 247 VUS of 499 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 OE0.49 (0.34–0.70)

0≤0.351.4

Missense OE0.73 (0.66–0.80)

0≤0.61.4

Synonymous OE1.07

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

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 PMID:20208537

LOFPathogenic variants in the AFG3L2 proteolytic domain cause SCA28 through haploinsufficiency and proteostatic stress-driven OMA1 activation.PMID:30910913

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