Charcot-Marie-Tooth disease type 2A2: genes and variants

Genes linked to Charcot-Marie-Tooth disease type 2A2

• MFN2: Mitofusin-2

  It promotes outer-mitochondrial-membrane fusion and coordinates mitochondrial transport, distribution, and contacts with other organelles. Pathogenic variants are a major cause of Charcot-Marie-Tooth disease type 2A and related axonal neuropathies.

  32 disease-causing and 37 uncertain variants in MFN2 are linked to Charcot-Marie-Tooth disease type 2A2.

Weakly linked (only a few uncertain records): ATP1A1.

Where Charcot-Marie-Tooth disease type 2A2 variants cluster

• MFN2 Dynamin-type G (positions 93–342): 20 of 32 disease-causing changes, 1.9× more than its size predicts.
• MFN2 Part of a helix bundle domain, formed by helices (positions 359–385): 4 of 32 disease-causing changes, 3.5× more than its size predicts.
• MFN2 Part of a helix bundle domain, formed by helices (positions 722–753): 3 of 32 disease-causing changes, 2.2× more than its size predicts.
• MFN2 Coiled coil (positions 695–738): 3 of 32 disease-causing changes, 1.6× more than its size predicts.

Known disease-causing variants in Charcot-Marie-Tooth disease type 2A2

Which prediction tools work for Charcot-Marie-Tooth disease type 2A2

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• MetaLR: 98 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CATVariant: 93 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 87 out of 100

Same protein, different disease

• Charcot-Marie-Tooth disease is also caused by MFN2 variants; they fall partly in the same places as the Charcot-Marie-Tooth disease type 2A2 variants (86 disease-causing).
• Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b; is also caused by MFN2 variants; they fall in the same places as the Charcot-Marie-Tooth disease type 2A2 variants (9 disease-causing).
• Neuropathy, hereditary motor and sensory, type 6A is also caused by MFN2 variants; they fall in the same places as the Charcot-Marie-Tooth disease type 2A2 variants (6 disease-causing).

Diseases related to Charcot-Marie-Tooth disease type 2A2

• Charcot-Marie-Tooth disease, also linked to MFN2
• Auditory neuropathy, also linked to MFN2
• Charcot-Marie-Tooth disease, axonal, autosomal recessive, type 2a2b;, also linked to MFN2
• Neuropathy, hereditary motor and sensory, type 6A, also linked to MFN2
• Peripheral neuropathy, also linked to MFN2
• Cerebellar ataxia, also linked to MFN2
• Hereditary motor and sensory neuropathy with optic atrophy, also linked to MFN2

Frequently asked questions

Which genes are linked to Charcot-Marie-Tooth disease type 2A2?

In CATVariant, Charcot-Marie-Tooth disease type 2A2 is linked to 1 analyzed protein: MFN2 (Mitofusin-2).

How many genetic variants are linked to Charcot-Marie-Tooth disease type 2A2?

96 variants: 32 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 40 are of uncertain significance or have conflicting reports.

Which uncertain variants in Charcot-Marie-Tooth disease type 2A2 look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Charcot-Marie-Tooth disease type 2A2?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.87, based on 29 disease-causing and 18 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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