neuronopathy, distal hereditary motor, type 5B

Summary

neuronopathy, distal hereditary motor, type 5B (MONDO:0013884) is a disease caused by REEP1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: REEP1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 20

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neuronopathy, distal hereditary motor, type 5B
Mondo ID	MONDO:0013884
OMIM	614751
DOID	DOID:0111205
UMLS	C3553656
MedGen	766570
GARD	0018267
Is cancer (heuristic)	no

Also known as: HMN5B · neuronopathy, distal hereditary motor caused by mutation in REEP1 · neuronopathy, distal hereditary motor, type VB · REEP1 neuronopathy, distal hereditary motor

Data availability: 20 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › neuronopathy, distal hereditary motor, autosomal dominant › neuronopathy, distal hereditary motor, type 5 › neuronopathy, distal hereditary motor, type 5B

Related subtypes (2): neuronopathy, distal hereditary motor, type 5A, neuronopathy, distal hereditary motor, type 5C

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

20 retrieved; paginated sample, class counts are floors:

9 uncertain significance, 4 benign, 3 conflicting classifications of pathogenicity, 2 likely pathogenic, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1694461	NM_001164730.2(REEP1):c.40dup (p.Arg14fs)	REEP1	Pathogenic	criteria provided, single submitter
35598	NM_001371279.1(REEP1):c.304-2A>G	REEP1	Pathogenic	criteria provided, single submitter
1172760	NM_001371279.1(REEP1):c.248del (p.Gly83fs)	REEP1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1184484	NM_001371279.1(REEP1):c.67T>C (p.Ser23Pro)	REEP1	Likely pathogenic	no assertion criteria provided
474263	NM_001003800.2(BICD2):c.1687G>A (p.Gly563Arg)	BICD2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1092988	NM_001371279.1(REEP1):c.537C>T (p.Ser179=)	REEP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1861	NM_001371279.1(REEP1):c.837G>T (p.Ser279=)	REEP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1029867	NM_001371279.1(REEP1):c.206A>C (p.Lys69Thr)	REEP1	Uncertain significance	criteria provided, single submitter
2047524	NM_001371279.1(REEP1):c.503C>T (p.Ser168Leu)	REEP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2442048	NM_001371279.1(REEP1):c.160T>G (p.Phe54Val)	REEP1	Uncertain significance	criteria provided, single submitter
2442146	NM_001371279.1(REEP1):c.683A>C (p.Gln228Pro)	REEP1	Uncertain significance	criteria provided, single submitter
3892272	NM_001371279.1(REEP1):c.84A>T (p.Lys28Asn)	REEP1	Uncertain significance	criteria provided, single submitter
3896968	NM_001371279.1(REEP1):c.590G>T (p.Ser197Ile)	REEP1	Uncertain significance	criteria provided, single submitter
411803	NM_001371279.1(REEP1):c.166G>A (p.Asp56Asn)	REEP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
857719	NM_001371279.1(REEP1):c.164C>A (p.Thr55Lys)	REEP1	Uncertain significance	criteria provided, single submitter
932703	NM_001371279.1(REEP1):c.853T>G (p.Ter285Gly)	REEP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1290965	NM_001371279.1(REEP1):c.33-23A>C	REEP1	Benign	criteria provided, multiple submitters, no conflicts
1290966	NM_001371279.1(REEP1):c.417+45T>C	REEP1	Benign	criteria provided, multiple submitters, no conflicts
1290967	NM_001371279.1(REEP1):c.105+26C>T	REEP1	Benign	criteria provided, multiple submitters, no conflicts
130108	NM_001371279.1(REEP1):c.285G>A (p.Thr95=)	REEP1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 3 · 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
REEP1	Strong	Autosomal dominant	neuronopathy, distal hereditary motor, type 5B	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
REEP1	Orphanet:101011	Autosomal dominant spastic paraplegia type 31
REEP1	Orphanet:139536	Distal hereditary motor neuropathy type 5
BICD2	Orphanet:363454	BICD2-related autosomal dominant childhood-onset proximal spinal muscular atrophy

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
REEP1	HGNC:25786	ENSG00000068615	Q9H902	Receptor expression-enhancing protein 1	gencc,clinvar
BICD2	HGNC:17208	ENSG00000185963	Q8TD16	Protein bicaudal D homolog 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
REEP1	Receptor expression-enhancing protein 1	Required for endoplasmic reticulum (ER) network formation, shaping and remodeling; it links ER tubules to the cytoskeleton.
BICD2	Protein bicaudal D homolog 2	Acts as an adapter protein linking the dynein motor complex to various cargos and converts dynein from a non-processive to a highly processive motor in the presence of dynactin.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
REEP1	Other/Unknown	no		TB2_DP1_HVA22
BICD2	Other/Unknown	no		BICD

Expression context

Cohort genes with no expression data: 0.

2 cohort genes 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	1
dorsal root ganglion	1
middle temporal gyrus	1
gingiva	1
gingival epithelium	1
hair follicle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
REEP1	284	broad	marker	dorsal root ganglion, middle temporal gyrus, cortical plate
BICD2	290	ubiquitous	marker	gingival epithelium, gingiva, hair follicle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
BICD2	2,275
REEP1	1,295

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BICD2	Q8TD16	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
REEP1	Q9H902	67.91

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
COPI-independent Golgi-to-ER retrograde traffic	1	103.8×	0.038	BICD2
Golgi-to-ER retrograde transport	1	66.4×	0.038	BICD2
Intra-Golgi and retrograde Golgi-to-ER traffic	1	52.4×	0.038	BICD2
Membrane Trafficking	1	18.5×	0.068	BICD2
Vesicle-mediated transport	1	17.4×	0.068	BICD2
Expression and translocation of olfactory receptors	1	14.1×	0.070	REEP1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
microtubule anchoring at microtubule organizing center	1	4213.0×	0.003	BICD2
minus-end-directed organelle transport along microtubule	1	2106.5×	0.003	BICD2
protein insertion into membrane	1	1053.2×	0.003	REEP1
endoplasmic reticulum tubular network organization	1	561.7×	0.005	REEP1
centrosome localization	1	443.5×	0.005	BICD2
protein localization to Golgi apparatus	1	401.2×	0.005	BICD2
regulation of microtubule cytoskeleton organization	1	271.8×	0.006	BICD2
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum	1	168.5×	0.008	BICD2
microtubule-based movement	1	147.8×	0.008	BICD2
mRNA transport	1	131.7×	0.008	BICD2
protein transport	1	21.9×	0.045	BICD2

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 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
REEP1	0	0
BICD2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	2	REEP1, BICD2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
REEP1	0	—
BICD2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.