Neuronopathy, distal hereditary motor, type 9

Summary

Neuronopathy, distal hereditary motor, type 9 (MONDO:0060585) is a disease caused by WARS1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: WARS1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 11

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	neuronopathy, distal hereditary motor, type 9
Mondo ID	MONDO:0060585
OMIM	617721
DOID	DOID:0111212
UMLS	C4540265
MedGen	1617571
GARD	0026000
Is cancer (heuristic)	no

Also known as: HMN9

Data availability: 11 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 9

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 5, 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

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

11 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 3 benign, 2 conflicting classifications of pathogenicity, 2 no classifications from unflagged records

ClinVar	Variant (HGVS)	Gene	Classification	Review
2592873	NM_004184.4(WARS1):c.700A>G (p.Ile234Val)	WARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
441278	NM_004184.4(WARS1):c.770A>G (p.His257Arg)	WARS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1180500	NM_004184.4(WARS1):c.964G>A (p.Asp322Asn)	WARS1	Uncertain significance	criteria provided, single submitter
1709756	NM_004184.4(WARS1):c.841C>T (p.Pro281Ser)	WARS1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3235044	NM_004184.4(WARS1):c.1248C>G (p.Ile416Met)	WARS1	Uncertain significance	criteria provided, single submitter
3775643	NM_004184.4(WARS1):c.970G>A (p.Ala324Thr)	WARS1	Uncertain significance	criteria provided, single submitter
932924	NM_004184.4(WARS1):c.413T>A (p.Phe138Tyr)	WARS1	no classifications from unflagged records	no classifications from unflagged records
975157	NM_004184.4(WARS1):c.941A>G (p.Asp314Gly)	WARS1	no classifications from unflagged records	no classifications from unflagged records
1178170	NM_004184.4(WARS1):c.826+6A>G	WARS1	Benign	criteria provided, multiple submitters, no conflicts
1252470	NM_004184.4(WARS1):c.1254+35T>C	WARS1	Benign	criteria provided, multiple submitters, no conflicts
1265241	NM_004184.4(WARS1):c.1003C>T (p.Leu335=)	WARS1	Benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 2 · 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
WARS1	Definitive	Autosomal dominant	distal hereditary motor neuropathy	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
WARS1	Orphanet:2512	Autosomal recessive primary microcephaly
WARS1	Orphanet:528084	Non-specific syndromic intellectual disability

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
WARS1	HGNC:12729	ENSG00000140105	P23381	Tryptophan–tRNA ligase, cytoplasmic	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
WARS1	Tryptophan–tRNA ligase, cytoplasmic	Catalyzes the attachment of tryptophan to tRNA(Trp) in a two-step reaction: tryptophan is first activated by ATP to form Trp-AMP and then transferred to the acceptor end of the tRNA(Trp).

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)
WARS1	Enzyme (other)	yes	6.1.1.2	WHEP-TRS_dom, aa-tRNA-synth_I_CS, aa-tRNA-synth_Ic

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
leukocyte	1
monocyte	1
mononuclear cell	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
WARS1	291	ubiquitous	marker	monocyte, mononuclear cell, leukocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
WARS1	2,543

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
WARS1	P23381	13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
Cytosolic tRNA aminoacylation	1	439.2×	0.007	WARS1
tRNA Aminoacylation	1	285.5×	0.007	WARS1
Translation	1	62.1×	0.021	WARS1
Metabolism of proteins	1	12.4×	0.081	WARS1

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
tryptophanyl-tRNA aminoacylation	1	16852.0×	4e-04	WARS1
regulation of angiogenesis	1	421.3×	0.007	WARS1
translation	1	102.8×	0.019	WARS1
angiogenesis	1	62.4×	0.024	WARS1
negative regulation of cell population proliferation	1	42.1×	0.026	WARS1
intracellular signal transduction	1	38.1×	0.026	WARS1

Therapeutics

Drug target analysis

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

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
WARS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
WARS1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
WARS1	6.1.1.2	tryptophan-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

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	1	WARS1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
WARS1	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.