neuronopathy, distal hereditary motor, type 5A

Summary

neuronopathy, distal hereditary motor, type 5A (MONDO:0015353) is a disease caused by GARS1 (GenCC Definitive), with 5 cohort genes.

At a glance

• Causal gene: GARS1 (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 129

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neuronopathy, distal hereditary motor, type 5A
Mondo ID	MONDO:0015353
OMIM	600794
DOID	DOID:0111204
GARD	0018266
Is cancer (heuristic)	no

Also known as: dHMN 5A · dHMN5 · distal hereditary motor neuropathy type V · distal HMN V · distal spinal muscular atrophy type 5 · HMN 5A · HMN5A · neuronopathy, distal hereditary motor, type 5 · neuronopathy, distal hereditary motor, type 5A · neuronopathy, distal hereditary motor, type VA · neuropathy, distal hereditary motor, type 5A · spinal muscular atrophy, distal, type 5 · spinal muscular atrophy, distal, type 5A · spinal muscular atrophy, distal, with upper limb predominance

Data availability: 129 ClinVar variants · 6 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 5A

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

129 retrieved; paginated sample, class counts are floors:

39 conflicting classifications of pathogenicity, 37 uncertain significance, 20 benign/likely benign, 19 benign, 7 pathogenic, 2 pathogenic/likely pathogenic, 2 likely benign, 2 likely pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
4543	NM_001122955.4(BSCL2):c.455A>G (p.Asn152Ser)	BSCL2	Pathogenic	criteria provided, multiple submitters, no conflicts
4544	NM_001122955.4(BSCL2):c.461C>T (p.Ser154Leu)	BSCL2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1326212	NM_002047.4(GARS1):c.1015G>A (p.Gly339Arg)	GARS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
410314	NM_002047.4(GARS1):c.1415A>G (p.His472Arg)	GARS1	Pathogenic	criteria provided, multiple submitters, no conflicts
476747	NM_002047.4(GARS1):c.1000A>T (p.Ile334Phe)	GARS1	Pathogenic	criteria provided, multiple submitters, no conflicts
661670	NM_002047.4(GARS1):c.979G>A (p.Gly327Arg)	GARS1	Pathogenic	criteria provided, multiple submitters, no conflicts
9205	NM_002047.4(GARS1):c.548T>C (p.Leu183Pro)	GARS1	Pathogenic	criteria provided, single submitter
9207	NM_002047.4(GARS1):c.1738G>C (p.Gly580Arg)	GARS1	Pathogenic	criteria provided, single submitter
223153	NM_018129.4(PNPO):c.674G>A (p.Arg225His)	PNPO	Pathogenic	criteria provided, multiple submitters, no conflicts
216930	NM_002047.4(GARS1):c.998A>T (p.Glu333Val)	GARS1	Likely pathogenic	criteria provided, single submitter
617635	NM_002047.4(GARS1):c.643G>C (p.Asp215His)	GARS1	Likely pathogenic	no assertion criteria provided
220467	NM_001122955.4(BSCL2):c.588C>T (p.Cys196=)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
246599	NM_001122955.4(BSCL2):c.448G>A (p.Val150Ile)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305177	NM_001122955.4(BSCL2):c.845C>T (p.Ala282Val)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305178	NM_001122955.4(BSCL2):c.823G>A (p.Gly275Arg)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305180	NM_001122955.4(BSCL2):c.615C>T (p.Ser205=)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305185	NM_001122955.4(BSCL2):c.124C>T (p.Arg42Cys)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305189	NM_001122955.4(BSCL2):c.88-662C>A	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305190	NM_001122955.4(BSCL2):c.88-663G>A	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
305191	NM_001122955.4(BSCL2):c.88-674G>T	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
509292	NM_001122955.4(BSCL2):c.1234+7G>A	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
515141	NM_001122955.4(BSCL2):c.810C>T (p.Arg270=)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
879418	NM_001122955.4(BSCL2):c.1200C>T (p.Ser400=)	BSCL2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
194367	NM_002047.4(GARS1):c.1716G>A (p.Pro572=)	GARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
216550	NM_002047.4(GARS1):c.1852G>A (p.Val618Ile)	GARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
245685	NM_002047.4(GARS1):c.302G>A (p.Arg101His)	GARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
360003	NM_002047.4(GARS1):c.384G>A (p.Leu128=)	GARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
360005	NM_002047.4(GARS1):c.764C>T (p.Ala255Val)	GARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
360006	NM_002047.4(GARS1):c.765G>A (p.Ala255=)	GARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
360008	NM_002047.4(GARS1):c.882-15T>G	GARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 36 · Orphanet: 9 · 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
GARS1	Definitive	Autosomal dominant	neuronopathy, distal hereditary motor, type 5A	9
BSCL2	Strong	Autosomal dominant	neuronopathy, distal hereditary motor, type 5C	16
REEP1	Strong	Autosomal dominant	neuronopathy, distal hereditary motor, type 5B	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BSCL2	Orphanet:100998	Autosomal dominant spastic paraplegia type 17
BSCL2	Orphanet:139536	Distal hereditary motor neuropathy type 5
BSCL2	Orphanet:363400	Progressive encephalopathy-severe neurodegeneration-lipodystrophy syndrome
BSCL2	Orphanet:696289	Congenital generalized lipodystrophy type 2
GARS1	Orphanet:139536	Distal hereditary motor neuropathy type 5
GARS1	Orphanet:99938	Autosomal dominant Charcot-Marie-Tooth disease type 2D
REEP1	Orphanet:101011	Autosomal dominant spastic paraplegia type 31
REEP1	Orphanet:139536	Distal hereditary motor neuropathy type 5
PNPO	Orphanet:79096	Pyridoxamine-5-phosphate deficiency-developmental and epileptic encephalopathy

Cohort genes → proteins

5 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BSCL2	HGNC:15832	ENSG00000168000	Q96G97	Seipin	gencc,clinvar
GARS1	HGNC:4162	ENSG00000106105	P41250	Glycine–tRNA ligase	gencc,clinvar
REEP1	HGNC:25786	ENSG00000068615	Q9H902	Receptor expression-enhancing protein 1	gencc
PNPO	HGNC:30260	ENSG00000108439	Q9NVS9	Pyridoxine-5’-phosphate oxidase	clinvar
HNRNPUL2-BSCL2	HGNC:49189	ENSG00000234857		HNRNPUL2-BSCL2 readthrough (NMD candidate)	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BSCL2	Seipin	Plays a crucial role in the formation of lipid droplets (LDs) which are storage organelles at the center of lipid and energy homeostasis.
GARS1	Glycine–tRNA ligase	Catalyzes the ATP-dependent ligation of glycine to the 3’-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (Gly-AMP).
REEP1	Receptor expression-enhancing protein 1	Required for endoplasmic reticulum (ER) network formation, shaping and remodeling; it links ER tubules to the cytoskeleton.
PNPO	Pyridoxine-5’-phosphate oxidase	Catalyzes the oxidation of either pyridoxine 5’-phosphate (PNP) or pyridoxamine 5’-phosphate (PMP) into pyridoxal 5’-phosphate (PLP).

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.4

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
Enzyme (other)	2	4.8×	0.117
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BSCL2	Other/Unknown	no		Seipin
GARS1	Enzyme (other)	yes	6.1.1.14	WHEP-TRS_dom, aa-tRNA-synt_IIb, tRNA-synt_gly
REEP1	Other/Unknown	no		TB2_DP1_HVA22
PNPO	Enzyme (other)	yes	1.4.3.5	Pyridox_Oxase, Pyridox_Oxase_N, Split_barrel_FMN-bd
HNRNPUL2-BSCL2	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

4 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
pituitary gland	1
primary visual cortex	1
superior frontal gyrus	1
cartilage tissue	1
lateral nuclear group of thalamus	1
secondary oocyte	1
cortical plate	1
dorsal root ganglion	1
middle temporal gyrus	1
kidney epithelium	1
liver	1
right lobe of liver	1
islet of Langerhans	1
stromal cell of endometrium	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BSCL2	149	ubiquitous	marker	superior frontal gyrus, primary visual cortex, pituitary gland
GARS1	293	ubiquitous	marker	secondary oocyte, cartilage tissue, lateral nuclear group of thalamus
REEP1	284	broad	marker	dorsal root ganglion, middle temporal gyrus, cortical plate
PNPO	230	ubiquitous	marker	right lobe of liver, liver, kidney epithelium
HNRNPUL2-BSCL2	134		yes	stromal cell of endometrium, ventricular zone, islet of Langerhans

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GARS1	2,426
PNPO	1,710
BSCL2	1,503
REEP1	1,295
HNRNPUL2-BSCL2	0

Intra-cohort edges

A	B	Sources
BSCL2	GARS1	string_interaction
BSCL2	REEP1	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GARS1	P41250	14
PNPO	Q9NVS9	6
BSCL2	Q96G97	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
REEP1	Q9H902	67.91

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 5 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Vitamin B6 activation to pyridoxal phosphate	1	1268.9×	0.003	PNPO
Mitochondrial tRNA aminoacylation	1	173.0×	0.009	GARS1
Cytosolic tRNA aminoacylation	1	146.4×	0.009	GARS1
Expression and translocation of olfactory receptors	1	9.4×	0.103	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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
pyridoxal 5’-phosphate biosynthetic process	1	4213.0×	0.002	PNPO
pyridoxine biosynthetic process	1	2106.5×	0.002	PNPO
pyridoxamine metabolic process	1	2106.5×	0.002	PNPO
mitochondrial glycyl-tRNA aminoacylation	1	2106.5×	0.002	GARS1
diadenosine tetraphosphate biosynthetic process	1	1404.3×	0.002	GARS1
protein insertion into membrane	1	526.6×	0.005	REEP1
endoplasmic reticulum tubular network organization	1	280.9×	0.006	REEP1
lipid droplet formation	1	247.8×	0.006	BSCL2
lipid droplet organization	1	234.1×	0.006	BSCL2
tRNA aminoacylation for protein translation	1	210.7×	0.006	GARS1
negative regulation of lipid catabolic process	1	210.7×	0.006	BSCL2
lipid storage	1	135.9×	0.009	BSCL2
lipid catabolic process	1	61.1×	0.019	BSCL2
fat cell differentiation	1	45.3×	0.023	BSCL2
positive regulation of cold-induced thermogenesis	1	40.9×	0.024	BSCL2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 5 evidence-associated genes (40%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GARS1	1	3
BSCL2	0	0
REEP1	0	0
PNPO	0	0
HNRNPUL2-BSCL2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CRENOLANIB	3	GARS1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
GARS1	8	Binding:8
PNPO	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GARS1	6.1.1.14	glycine-tRNA ligase
PNPO	1.4.3.5	pyridoxal 5’-phosphate synthase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
CRENOLANIB	3	GARS1

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	1	GARS1
C	Druggable family + PDB, no drug	1	PNPO
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	BSCL2, REEP1, HNRNPUL2-BSCL2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BSCL2	0	—
REEP1	0	—
PNPO	2	—
HNRNPUL2-BSCL2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.