Neuronopathy, distal hereditary motor, type 5

Summary

Neuronopathy, distal hereditary motor, type 5 (MONDO:0100350) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 6
• Phenotypes (HPO): 16

Clinical features

Signs & symptoms

Clinical features (HPO)

16 HPO clinical features (Orphanet curated; top 16 by frequency):

HPO ID	Term	Frequency
HP:0002317	Unsteady gait	Frequent (30-79%)
HP:0002495	Impaired vibratory sensation	Frequent (30-79%)
HP:0003392	First dorsal interossei muscle weakness	Frequent (30-79%)
HP:0003393	Thenar muscle atrophy	Frequent (30-79%)
HP:0003426	First dorsal interossei muscle atrophy	Frequent (30-79%)
HP:0003427	Thenar muscle weakness	Frequent (30-79%)
HP:0003435	Cold-induced hand cramps	Frequent (30-79%)
HP:0003484	Upper limb muscle weakness	Frequent (30-79%)
HP:0003693	Distal amyotrophy	Frequent (30-79%)
HP:0007178	Motor polyneuropathy	Frequent (30-79%)
HP:0009053	Distal lower limb muscle weakness	Frequent (30-79%)
HP:0001347	Hyperreflexia	Occasional (5-29%)
HP:0001761	Pes cavus	Occasional (5-29%)
HP:0001765	Hammertoe	Occasional (5-29%)
HP:0008081	Pes valgus	Occasional (5-29%)
HP:0040131	Abnormal motor nerve conduction velocity	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	neuronopathy, distal hereditary motor, type 5
Mondo ID	MONDO:0100350
MeSH	C563443
Orphanet	139536
DOID	DOID:0111203
UMLS	C1833308
MedGen	318838
GARD	0016955
Is cancer (heuristic)	no

Also known as: dHMN5 · distal hereditary motor neuropathy type V · distal HMN V · distal spinal muscular atrophy type 5

Data availability: 6 ClinVar variants.

Disease family

An umbrella term covering 3 Mondo subtypes.

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

Related subtypes (10): neuronopathy, distal hereditary motor, autosomal dominant 1, hereditary spastic paraplegia 17, neuronopathy, distal hereditary motor, autosomal dominant 8, distal hereditary motor neuropathy type 2, distal hereditary motor neuropathy type 7, neuronopathy, distal hereditary motor, type 9, neuronopathy, distal hereditary motor, autosomal dominant 10, neuronopathy, distal hereditary motor, autosomal dominant 11, myopathy, myofibrillar, 13, with rimmed vacuoles, neuronopathy, distal hereditary motor, autosomal dominant 15

Subtypes (3): neuronopathy, distal hereditary motor, type 5B, 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

6 retrieved; paginated sample, class counts are floors:

3 uncertain significance, 2 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
476747	NM_002047.4(GARS1):c.1000A>T (p.Ile334Phe)	GARS1	Pathogenic	criteria provided, multiple submitters, no conflicts
476762	NM_002047.4(GARS1):c.794C>T (p.Ser265Phe)	GARS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
637545	NM_002047.4(GARS1):c.598G>A (p.Asp200Asn)	GARS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
637059	NM_002047.4(GARS1):c.332C>T (p.Ala111Val)	GARS1	Uncertain significance	criteria provided, single submitter
637107	NM_002047.4(GARS1):c.998A>G (p.Glu333Gly)	GARS1	Uncertain significance	no assertion criteria provided
944149	NM_002047.4(GARS1):c.2065C>T (p.Arg689Cys)	GARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 2 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GARS1	Orphanet:139536	Distal hereditary motor neuropathy type 5
GARS1	Orphanet:99938	Autosomal dominant Charcot-Marie-Tooth disease type 2D

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
GARS1	HGNC:4162	ENSG00000106105	P41250	Glycine–tRNA ligase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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).

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GARS1	Enzyme (other)	yes	6.1.1.14	WHEP-TRS_dom, aa-tRNA-synt_IIb, tRNA-synt_gly

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
cartilage tissue	1
lateral nuclear group of thalamus	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GARS1	293	ubiquitous	marker	secondary oocyte, cartilage tissue, lateral nuclear group of thalamus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GARS1	2,426

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GARS1	P41250	14

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Mitochondrial tRNA aminoacylation	1	519.1×	0.002	GARS1
Cytosolic tRNA aminoacylation	1	439.2×	0.002	GARS1

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
mitochondrial glycyl-tRNA aminoacylation	1	8426.0×	3e-04	GARS1
diadenosine tetraphosphate biosynthetic process	1	5617.3×	3e-04	GARS1
tRNA aminoacylation for protein translation	1	842.6×	0.001	GARS1

Therapeutics

Drug target analysis

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

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
GARS1	1	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CRENOLANIB	3	GARS1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
GARS1	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GARS1	6.1.1.14	glycine-tRNA ligase

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

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.