Giant axonal neuropathy 2

Summary

Giant axonal neuropathy 2 (MONDO:0012411) is a disease with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 7

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		2	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	giant axonal neuropathy 2
Mondo ID	MONDO:0012411
OMIM	610100
Orphanet	401964
DOID	DOID:0090069
UMLS	C1864695
MedGen	400593
GARD	0012447
Is cancer (heuristic)	no

Also known as: autosomal dominant hereditary motor and sensory neuropathy type 2 with giant axons · CMT2 with giant axons · DCAF8 giant axonal neuropathy · GAN2 · giant axonal neuropathy 2, autosomal dominant · giant axonal neuropathy caused by mutation in DCAF8 · giant axonal neuropathy type 2 · HMSN2 with giant axons

Data availability: 7 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › axonal neuropathy › giant axonal neuropathy › giant axonal neuropathy 2

Related subtypes (1): giant axonal neuropathy 1

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

7 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 1 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
133348	NM_015726.4(DCAF8):c.949C>T (p.Arg317Cys)	DCAF8	Likely pathogenic	criteria provided, single submitter
2440710	NM_015726.4(DCAF8):c.364C>T (p.Arg122Trp)	DCAF8	Uncertain significance	criteria provided, multiple submitters, no conflicts
2442193	NM_015726.4(DCAF8):c.1727C>T (p.Ser576Phe)	DCAF8	Uncertain significance	criteria provided, single submitter
4078460	NM_015726.4(DCAF8):c.833G>A (p.Arg278His)	DCAF8	Uncertain significance	criteria provided, single submitter
4819653	NM_015726.4(DCAF8):c.385TCA[1] (p.Ser130del)	DCAF8	Uncertain significance	criteria provided, single submitter
930290	NM_015726.4(DCAF8):c.451C>T (p.Arg151Cys)	DCAF8	Uncertain significance	criteria provided, single submitter
788287	NM_015726.4(DCAF8):c.822G>A (p.Lys274=)	DCAF8	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 1 · 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
DCAF8	Moderate	Autosomal dominant	giant axonal neuropathy 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DCAF8	Orphanet:401964	Autosomal dominant Charcot-Marie-Tooth disease type 2 with giant axons

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
DCAF8	HGNC:24891	ENSG00000132716	Q5TAQ9	DDB1- and CUL4-associated factor 8	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DCAF8	DDB1- and CUL4-associated factor 8	May function as a substrate receptor for CUL4-DDB1 E3 ubiquitin-protein ligase complex.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 0 · 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
Scaffold/PPI	1	17.3×	0.058

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DCAF8	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, WD40_repeat_dom_sf

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
body of pancreas	1
right lobe of thyroid gland	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DCAF8	160	ubiquitous	marker	right uterine tube, right lobe of thyroid gland, body of pancreas

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DCAF8	1,244

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DCAF8	Q5TAQ9	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Neddylation	1	47.4×	0.021	DCAF8

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
myotube cell development	1	3370.4×	6e-04	DCAF8
protein ubiquitination	1	41.4×	0.024	DCAF8

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
DCAF8	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	DCAF8

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)
DCAF8	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.