MFN2

Chr 1ADAR

mitofusin 2

Also known as: CMT2A, CMT2A2, CMT2A2A, CMT2A2B, CPRP1, HMSN6A, HSG, MARF

NCBI Gene: 9927 ENSG00000116688 UniProt: O95140 OMIM: 608507

The protein functions as a mitochondrial outer membrane protein that mediates mitochondrial fusion and maintains the mitochondrial network. Mutations cause autosomal dominant and autosomal recessive forms of Charcot-Marie-Tooth disease type 2A2 and hereditary motor and sensory neuropathy VI, both axonal peripheral neuropathies, as well as multiple symmetric lipomatosis. The high pLI score (0.99) and low LOEUF score (0.28) indicate the gene is highly intolerant to loss-of-function variants, suggesting pathogenicity occurs through haploinsufficiency or dominant-negative mechanisms.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a mitochondrial membrane protein that participates in mitochondrial fusion and contributes to the maintenance and operation of the mitochondrial network. This protein is involved in the regulation of vascular smooth muscle cell proliferation, and it may play a role in the pathophysiology of obesity. Mutations in this gene cause Charcot-Marie-Tooth disease type 2A2, and hereditary motor and sensory neuropathy VI, which are both disorders of the peripheral nervous system. Defects in this gene have also been associated with early-onset stroke. Two transcript variants encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismAD/ARLOEUF 0.284 OMIM phenotypes

Clinical Summary— MFN2

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Gene-Disease Validity (ClinGen)

obsolete axonal hereditary motor and sensory neuropathy · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

214 unique Pathogenic / Likely Pathogenic· 684 VUS of 1456 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 — MFN2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.28LOEUF

pLI 0.994

Z-score 4.90

OE 0.13 (0.07–0.28)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.66Z-score

OE missense 0.77 (0.70–0.85)

326 obs / 421.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.13 (0.07–0.28)

0≤0.351.4

Missense OE?0.77 (0.70–0.85)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 5 / 37.3Missense obs/exp: 326 / 421.8Syn Z: -0.53

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

moderateMFN2-related developmental disorderOTHERAD

definitiveMFN2-related Charcot-Marie-Tooth disease, axonalOTHERAR

definitiveMFN2-related hereditary motor and sensory neuropathyOTHERAD

This gene — mechanism propensity

0.5181th %ile

GOF

0.5269th %ile

LOF

0.59top 25%

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function, gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to loss-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF30% of P/LP variants are LoF · LOEUF 0.28

GOF1 literature citation

DN1 literature citation

Literature Evidence

DNWhile mitochondrial aggregates were labeled for mitophagy, mutant MFN2 did not inhibit Parkin-mediated degradation, but instead had a dominant negative effect on mitochondrial fusion only when MFN1 was at low levels, as occurs in neurons.1

GOFPich et al. (2005) showed that Mfn2 loss of function inhibited pyruvate, glucose, and fatty acid oxidation and reduced mitochondrial membrane potential, whereas Mfn2 gain of function increased glucose oxidation and mitochondrial membrane potential.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

1456 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic101

Likely Pathogenic113

VUS684

Likely Benign381

Benign71

Conflicting87

101

Pathogenic

113

Likely Pathogenic

684

VUS

381

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	46	42	13	0	101
Likely Pathogenic	18	88	7	0	113
VUS	15	582	79	8	684
Likely Benign	0	5	176	200	381
Benign	0	0	66	5	71
Conflicting	—				87
Total	79	717	341	213	1,437

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

View in ClinVar →

38 pathogenic / likely-pathogenic (of 58) ClinVar copy-number / structural variants overlap MFN2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →