MFN2

Chr 1ADAR

mitofusin 2

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

NCBI Gene: 9927ENSG00000116688UniProt: O95140

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]

Primary Disease Associations & Inheritance

Charcot-Marie-Tooth disease, axonal, type 2A2AMIM #609260
AD
Charcot-Marie-Tooth disease, axonal, type 2A2BMIM #617087
AR
Hereditary motor and sensory neuropathy VIAMIM #601152
AD
Lipomatosis, multiple symmetric, with or without peripheral neuropathyMIM #151800
AR
UniProtNeuropathy, hereditary motor and sensory, 6A, with optic atrophy
699
ClinVar variants
99
Pathogenic / LP
0.99
pLI score· haploinsufficient
2
Active trials
Clinical Summary— MFN2
🧬
Gene-Disease Validity (ClinGen)
obsolete axonal hereditary motor and sensory neuropathy · SDDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
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.
📋
ClinVar Variants
99 Pathogenic / Likely Pathogenic· 332 VUS of 699 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
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.
0.28LOEUF
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?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.
1.66Z-score
OE missense 0.77 (0.70–0.85)
326 obs / 421.8 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.0.13 (0.07–0.28)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.77 (0.70–0.85)
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.1.05
0≤1.21.6
LoF obs/exp: 5 / 37.3Missense obs/exp: 326 / 421.8Syn Z: -0.53

ClinVar Variant Classifications

699 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic45
Likely Pathogenic54
VUS332
Likely Benign210
Benign34
Conflicting24
45
Pathogenic
54
Likely Pathogenic
332
VUS
210
Likely Benign
34
Benign
24
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
17
12
16
0
45
Likely Pathogenic
4
42
8
0
54
VUS
11
271
45
5
332
Likely Benign
0
1
96
113
210
Benign
0
0
32
2
34
Conflicting
—24
Total32326197120699

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

View in ClinVar →

Protein Context — Lollipop Plot

MFN2 · protein map & ClinVar variants

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

Gene2Phenotype Curations

MFN2-related developmental disorder

moderate
ADUndeterminedAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variantinframe deletioninframe insertion

MFN2-related Charcot-Marie-Tooth disease, axonal

definitive
ARUndeterminedUncertain
Eye
G2P ↗

MFN2-related hereditary motor and sensory neuropathy

definitive
ADUndeterminedUncertain
Eye
G2P ↗

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
MITOFUSIN 2; MFN2
MIM #608507 · *

Charcot-Marie-Tooth disease, axonal, type 2A2A

MIM #609260

Molecular basis of disorder known

Autosomal dominant

Charcot-Marie-Tooth disease, axonal, type 2A2B

MIM #617087

Molecular basis of disorder known

Autosomal recessive

Hereditary motor and sensory neuropathy VIA

MIM #601152

Molecular basis of disorder known

Autosomal dominant

Lipomatosis, multiple symmetric, with or without peripheral neuropathy

MIM #151800

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — MFN2
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Charcot-Marie-Tooth: From Molecules to Therapy.
Morena J et al.·Int J Mol Sci
2019Review
Mfn2/Hsc70 Complex Mediates the Formation of Mitochondria-Lipid Droplets Membrane Contact and Regulates Myocardial Lipid Metabolism.
Hu L et al.·Adv Sci (Weinh)
2024
Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease.
Hernández-Alvarez MI et al.·Cell
2019
Mitochondrial DNA maintenance defects.
El-Hattab AW et al.·Biochim Biophys Acta Mol Basis Dis
2017Review
Hereditary neuropathy.
Pisciotta C et al.·Handb Clin Neurol
2023Review
Endothelial FIS1 DeSUMOylation Protects Against Hypoxic Pulmonary Hypertension.
Zhou X et al.·Circ Res
2023
TREM2 sustains macrophage-hepatocyte metabolic coordination in nonalcoholic fatty liver disease and sepsis.
Hou J et al.·J Clin Invest
2021
Release of mitochondrial dsRNA into the cytosol is a key driver of the inflammatory phenotype of senescent cells.
López-Polo V et al.·Nat Commun
2024
Evaluating the efficacy and safety of Alzheimer's disease drugs: A meta-analysis and systematic review.
Chen Y et al.·Medicine (Baltimore)
2024Meta-analysis
Whole genome sequencing increases the diagnostic rate in Charcot-Marie-Tooth disease.
Record CJ et al.·Brain
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Carnosic acid protects against mitochondrial dysfunction and ferroptosis in myocardial ischemia/reperfusion injury through mediating Mfn2.
Wang XQ et al.·Eur J Pharmacol
2026
USP30 alleviates intestinal ischemia-reperfusion injury by deubiquitinating MFN2 mediating the mitochondrial endoplasmic reticulum pathway.
Weng Z et al.·Biochem Pharmacol
2026
Mitofusin MFN2 acts as a molecular sensor preventing protein aggregation and mitophagy, with a protective effect against apoptosis in Charcot-Marie-Tooth type 2A disease.
Joaquim M et al.·Autophagy Rep
2026🔓 Open Access
Deletion of Mfn2 in endothelial cells triggers a mitohormetic response that improves systemic metabolism and healthspan in mice.
Chivite I et al.·Cell Metab
2026
MFN2-CD36 interaction regulates mitochondrial lipid digestion in cancer-associated fibroblasts and promotes esophageal squamous cell carcinoma progression.
Shi X et al.·Cancer Lett
2026
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Lipomatosis, Multiple Symmetrical

Evaluation of Safety and Efficiency of Metreleptin Treatment for Patients With Multiple Symmetric Lipomatosis (MSL)

ACTIVE NOT RECRUITING
NCT05351164Phase PHASE2University of MichiganStarted 2023-08-01
Metreleptin
Aortic Aneurysm and Dissection

MITAORTA - Role of Mitochondrial Dynamic in Aneurysm and Dissection of Ascending Thoracic Aorta

ACTIVE NOT RECRUITING
NCT05434481Phase NAUniversity Hospital, AngersStarted 2022-09-07
Mitochondrial dynamic analysis in the aorta samples and metabolomic profiling in the aortic diseases

External Resources

Links to major genomics databases and tools