Charcot-Marie-Tooth disease, dominant intermediate G

Summary

Charcot-Marie-Tooth disease, dominant intermediate G (MONDO:0036484) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease, dominant intermediate G
Mondo ID	MONDO:0036484
OMIM	617882
DOID	DOID:0080294
UMLS	C4693509
MedGen	1642893
GARD	0025819
Is cancer (heuristic)	no

Also known as: Charcot-Marie-Tooth disease, dominant intermediate G · CMTDIG

Data availability: 15 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › hereditary peripheral neuropathy › Charcot-Marie-Tooth disease › intermediate Charcot-Marie-Tooth disease › Charcot-Marie-Tooth disease, dominant intermediate G

Related subtypes (2): autosomal recessive intermediate Charcot-Marie-Tooth disease, autosomal dominant intermediate Charcot-Marie-Tooth disease

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

15 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 6 conflicting classifications of pathogenicity, 1 likely pathogenic, 1 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
41236	NM_006158.5(NEFL):c.293A>G (p.Asn98Ser)	NEFL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
66671	NM_006158.5(NEFL):c.1186G>A (p.Glu396Lys)	NEFL	Pathogenic	criteria provided, multiple submitters, no conflicts
2579045	NM_006158.5(NEFL):c.292A>C (p.Asn98His)	NEFL	Likely pathogenic	criteria provided, multiple submitters, no conflicts
219429	NM_006158.5(NEFL):c.65C>A (p.Pro22His)	NEFL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
220209	NM_006158.5(NEFL):c.1610A>G (p.Gln537Arg)	NEFL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
234913	NM_006158.5(NEFL):c.986T>C (p.Leu329Pro)	NEFL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
447763	NM_006158.5(NEFL):c.793T>G (p.Tyr265Asp)	NEFL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
464926	NM_006158.5(NEFL):c.338_339delinsCC (p.Gln113Pro)	NEFL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
66684	NM_006158.5(NEFL):c.19G>A (p.Glu7Lys)	NEFL	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1012265	NM_006158.5(NEFL):c.943_948dup (p.Lys315_Thr316dup)	NEFL	Uncertain significance	criteria provided, single submitter
1709291	NM_006158.5(NEFL):c.796G>C (p.Glu266Gln)	NEFL	Uncertain significance	criteria provided, single submitter
3891823	NM_006158.5(NEFL):c.923G>C (p.Ser308Thr)	NEFL	Uncertain significance	criteria provided, single submitter
444743	NM_006158.5(NEFL):c.146C>T (p.Ser49Phe)	NEFL	Uncertain significance	criteria provided, multiple submitters, no conflicts
533511	NM_006158.5(NEFL):c.1462G>A (p.Glu488Lys)	NEFL	Uncertain significance	criteria provided, multiple submitters, no conflicts
568307	NM_006158.5(NEFL):c.418G>A (p.Glu140Lys)	NEFL	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NEFL	Orphanet:101085	Charcot-Marie-Tooth disease type 1F
NEFL	Orphanet:228374	Charcot-Marie-Tooth disease type 2B5
NEFL	Orphanet:99939	Autosomal dominant Charcot-Marie-Tooth disease type 2E

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
NEFL	HGNC:7739	ENSG00000277586	P07196	Neurofilament light polypeptide	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NEFL	Neurofilament light polypeptide	Neurofilaments usually contain three intermediate filament proteins: NEFL, NEFM, and NEFH which are involved in the maintenance of neuronal caliber.

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)
NEFL	Other/Unknown	no		Intermed_filament_DNA-bd, IF_conserved, IF_rod_dom

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
dorsal root ganglion	1
lateral nuclear group of thalamus	1
pons	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NEFL	214	broad	marker	dorsal root ganglion, pons, lateral nuclear group of thalamus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NEFL	4,644

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NEFL	P07196	73.66

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. 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
Ras activation upon Ca2+ influx through NMDA receptor	1	571.0×	0.003	NEFL
Unblocking of NMDA receptors, glutamate binding and activation	1	543.8×	0.003	NEFL
Negative regulation of NMDA receptor-mediated neuronal transmission	1	543.8×	0.003	NEFL
Long-term potentiation	1	475.8×	0.003	NEFL
Assembly and cell surface presentation of NMDA receptors	1	253.8×	0.005	NEFL
RAF/MAP kinase cascade	1	61.1×	0.016	NEFL

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
intermediate filament polymerization or depolymerization	1	16852.0×	0.001	NEFL
response to sodium arsenite	1	8426.0×	0.001	NEFL
response to acrylamide	1	8426.0×	0.001	NEFL
neurofilament bundle assembly	1	5617.3×	0.001	NEFL
regulation of axon diameter	1	3370.4×	0.002	NEFL
peripheral nervous system axon regeneration	1	2106.5×	0.002	NEFL
neurofilament cytoskeleton organization	1	1685.2×	0.002	NEFL
retrograde axonal transport	1	1532.0×	0.002	NEFL
locomotion	1	1532.0×	0.002	NEFL
negative regulation of motor neuron apoptotic process	1	1532.0×	0.002	NEFL
axonal transport of mitochondrion	1	1404.3×	0.002	NEFL
response to corticosterone	1	1123.5×	0.002	NEFL
motor neuron apoptotic process	1	1123.5×	0.002	NEFL
protein polymerization	1	991.3×	0.002	NEFL
regulation of synapse maturation	1	936.2×	0.002	NEFL
postsynaptic modulation of chemical synaptic transmission	1	674.1×	0.003	NEFL
anterograde axonal transport	1	581.1×	0.003	NEFL
positive regulation of axonogenesis	1	581.1×	0.003	NEFL
spinal cord development	1	510.7×	0.003	NEFL
response to peptide hormone	1	391.9×	0.003	NEFL
neuromuscular process controlling balance	1	330.4×	0.004	NEFL
intermediate filament organization	1	240.7×	0.005	NEFL
hippocampus development	1	230.8×	0.005	NEFL
response to toxic substance	1	210.7×	0.005	NEFL
cerebral cortex development	1	205.5×	0.005	NEFL
axonogenesis	1	160.5×	0.006	NEFL
microtubule cytoskeleton organization	1	121.2×	0.008	NEFL

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NEFL	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	NEFL

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)
NEFL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.