neuropathy, hereditary motor and sensory, type 6A

Summary

neuropathy, hereditary motor and sensory, type 6A (MONDO:0011002) is a disease caused by MFN2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: MFN2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 36

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neuropathy, hereditary motor and sensory, type 6A
Mondo ID	MONDO:0011002
OMIM	601152
GARD	0018091
Is cancer (heuristic)	no

Also known as: Charcot-Marie-Tooth disease, type 6 · Charcot-Marie-Tooth disease, type 6A · hereditary motor and sensory neuropathy type 6 caused by mutation in MFN2 · hereditary motor and sensory neuropathy VIA · HMSN6A · MFN2 hereditary motor and sensory neuropathy type 6 · neuropathy, hereditary motor and sensory, type 6 · neuropathy, hereditary motor and sensory, type VIA · peripheral neuropathy and optic atrophy

Data availability: 36 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › motor peripheral neuropathy › neuropathy, hereditary motor and sensory, type 6A

Related subtypes (8): motor nerve neuritis, glossopharyngeal motor neuropathy, Charcot-Marie-Tooth disease type 5, hereditary motor and sensory neuropathy, Okinawa type, Charcot-Marie-Tooth disease type 4G, Charcot-Marie-Tooth disease axonal type 2C, neuropathy, hereditary motor and sensory, type 6B, peripheral motor neuropathy, childhood-onset, biotin-responsive

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

36 retrieved; paginated sample, class counts are floors:

15 uncertain significance, 6 pathogenic/likely pathogenic, 5 benign/likely benign, 5 conflicting classifications of pathogenicity, 5 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
214652	NM_014874.4(MFN2):c.314C>T (p.Thr105Met)	MFN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
217164	NM_014874.4(MFN2):c.494A>G (p.His165Arg)	MFN2	Pathogenic	criteria provided, multiple submitters, no conflicts
2268	NM_014874.4(MFN2):c.281G>A (p.Arg94Gln)	MFN2	Pathogenic	criteria provided, multiple submitters, no conflicts
2271	NM_014874.4(MFN2):c.839G>A (p.Arg280His)	MFN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2276	NM_014874.4(MFN2):c.280C>T (p.Arg94Trp)	MFN2	Pathogenic	criteria provided, multiple submitters, no conflicts
2280	NM_014874.4(MFN2):c.2119C>T (p.Arg707Trp)	MFN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2281	NM_014874.4(MFN2):c.310C>T (p.Arg104Trp)	MFN2	Pathogenic	criteria provided, multiple submitters, no conflicts
245768	NM_014874.4(MFN2):c.1198C>T (p.Arg400Ter)	MFN2	Pathogenic	criteria provided, multiple submitters, no conflicts
30738	NM_014874.4(MFN2):c.1085C>T (p.Thr362Met)	MFN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372790	NM_014874.4(MFN2):c.1252C>T (p.Arg418Ter)	MFN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
835548	NM_014874.4(MFN2):c.629A>G (p.Asp210Gly)	MFN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1806999	NM_014874.4(MFN2):c.2120G>A (p.Arg707Gln)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214653	NM_014874.4(MFN2):c.749G>A (p.Arg250Gln)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
420586	NM_014874.4(MFN2):c.2230G>A (p.Glu744Lys)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
543219	NM_014874.4(MFN2):c.748C>T (p.Arg250Trp)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
999667	NM_014874.4(MFN2):c.2232G>T (p.Glu744Asp)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1377782	NM_014874.4(MFN2):c.1253G>A (p.Arg418Gln)	MFN2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1478913	NM_014874.4(MFN2):c.1385A>G (p.Tyr462Cys)	MFN2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1519303	NM_014874.4(MFN2):c.2147C>T (p.Ala716Val)	MFN2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1691310	NM_014874.4(MFN2):c.2229T>G (p.Ser743Arg)	MFN2	Uncertain significance	criteria provided, single submitter
1710174	NM_014874.4(MFN2):c.404G>T (p.Arg135Leu)	MFN2	Uncertain significance	no assertion criteria provided
2683931	NM_014874.4(MFN2):c.1615G>A (p.Glu539Lys)	MFN2	Uncertain significance	criteria provided, single submitter
3767957	NM_014874.4(MFN2):c.1508C>G (p.Pro503Arg)	MFN2	Uncertain significance	criteria provided, single submitter
3896912	NM_014874.4(MFN2):c.2176T>C (p.Ser726Pro)	MFN2	Uncertain significance	criteria provided, single submitter
4077141	NM_014874.4(MFN2):c.1945C>T (p.Arg649Cys)	MFN2	Uncertain significance	criteria provided, single submitter
446368	NM_014874.4(MFN2):c.1143GGC[1] (p.Ala383del)	MFN2	Uncertain significance	criteria provided, multiple submitters, no conflicts
522942	NM_014874.4(MFN2):c.1555C>T (p.Arg519Cys)	MFN2	Uncertain significance	criteria provided, multiple submitters, no conflicts
568120	NM_014874.4(MFN2):c.1181G>A (p.Arg394His)	MFN2	Uncertain significance	criteria provided, multiple submitters, no conflicts
806068	NM_014874.4(MFN2):c.1292C>T (p.Ser431Leu)	MFN2	Uncertain significance	criteria provided, multiple submitters, no conflicts
873748	NM_014874.4(MFN2):c.271G>A (p.Val91Met)	MFN2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
MFN2	Definitive	Semidominant	axonal hereditary motor and sensory neuropathy	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MFN2	Orphanet:2398	Multiple symmetric lipomatosis
MFN2	Orphanet:64751	Hereditary motor and sensory neuropathy type 5
MFN2	Orphanet:90118	Severe early-onset axonal neuropathy due to MFN2 deficiency
MFN2	Orphanet:90120	Hereditary motor and sensory neuropathy type 6
MFN2	Orphanet:99947	Autosomal dominant Charcot-Marie-Tooth disease type 2A2

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MFN2	HGNC:16877	ENSG00000116688	O95140	Mitofusin-2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MFN2	Mitofusin-2	Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MFN2	Other/Unknown	no		Fzo/mitofusin_HR2, Mitofusin_fam, P-loop_NTPase

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
apex of heart	1
cardiac ventricle	1
heart left ventricle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MFN2	297	ubiquitous	marker	apex of heart, heart left ventricle, cardiac ventricle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MFN2	3,853

Structural data

PDB: 1 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MFN2	O95140	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Miro GTPase Cycle	1	2284.0×	0.003	MFN2
RHOT2 GTPase cycle	1	1631.4×	0.003	MFN2
Mitophagy	1	1038.2×	0.004	MFN2
PINK1-PRKN Mediated Mitophagy	1	356.9×	0.008	MFN2
Selective autophagy	1	278.5×	0.008	MFN2
Autophagy	1	148.3×	0.012	MFN2
Macroautophagy	1	115.3×	0.014	MFN2
Factors involved in megakaryocyte development and platelet production	1	66.4×	0.021	MFN2
Hemostasis	1	36.0×	0.033	MFN2
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	33.5×	0.033	MFN2
Signal Transduction	1	10.2×	0.098	MFN2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
type 2 mitophagy	1	3370.4×	0.002	MFN2
mitochondrial membrane organization	1	2407.4×	0.002	MFN2
positive regulation of vascular associated smooth muscle cell apoptotic process	1	2106.5×	0.002	MFN2
mitochondrion localization	1	1685.2×	0.002	MFN2
protein localization to phagophore assembly site	1	991.3×	0.003	MFN2
mitochondrial fusion	1	842.6×	0.003	MFN2
blastocyst formation	1	766.0×	0.003	MFN2
camera-type eye morphogenesis	1	766.0×	0.003	MFN2
negative regulation of Ras protein signal transduction	1	674.1×	0.003	MFN2
negative regulation of smooth muscle cell proliferation	1	624.1×	0.003	MFN2
obsolete protein targeting to mitochondrion	1	581.1×	0.003	MFN2
positive regulation of vascular associated smooth muscle cell proliferation	1	432.1×	0.003	MFN2
response to unfolded protein	1	300.9×	0.004	MFN2
aerobic respiration	1	247.8×	0.005	MFN2
positive regulation of cold-induced thermogenesis	1	163.6×	0.007	MFN2
apoptotic process	1	28.7×	0.035	MFN2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MFN2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
MFN2	3	Binding:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	MFN2

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MFN2	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.