Distal hereditary motor neuropathy

Summary

Distal hereditary motor neuropathy (MONDO:0018894) is a disease caused by WARS1 (GenCC Definitive), with 27 cohort genes. The dominant Reactome pathway is Cytosolic tRNA aminoacylation (4 cohort genes).

At a glance

• Causal gene: WARS1 (GenCC Definitive)
• Cohort genes: 27
• ClinVar variants: 158

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	distal hereditary motor neuropathy
Mondo ID	MONDO:0018894
Orphanet	53739
SNOMED CT	230247001
UMLS	C0393541
MedGen	98274
GARD	0012683
Is cancer (heuristic)	no

Also known as: dHMN · distal spinal muscular atrophy · dSMA · neuronopathy, distal hereditary motor

Data availability: 158 ClinVar variants · 3 GenCC gene-disease records · 1 cell line.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › hereditary peripheral neuropathy › distal hereditary motor neuropathy

Related subtypes (64): giant axonal neuropathy, Finnish type amyloidosis, familial amyloid neuropathy, carpal tunnel syndrome, congenital trigeminal anesthesia, familial recurrent peripheral facial palsy, meralgia paraesthetica, familial, amyotrophic neuralgia, hereditary neuropathy with liability to pressure palsies, abetalipoproteinemia, VPS13A-related neurodegenerative disease, mitochondrial DNA depletion syndrome 4a, oxoglutaricaciduria, cerebrotendinous xanthomatosis, Chediak-Higashi syndrome, homocystinuria due to methylene tetrahydrofolate reductase deficiency, Krabbe disease, beta-mannosidosis, biotinidase deficiency, Leigh syndrome, hereditary sensory and autonomic neuropathy with spastic paraplegia, ornithine aminotransferase deficiency, adult polyglucosan body disease, Sandhoff disease, Tay-Sachs disease, methylmalonic aciduria and homocystinuria type cblC, familial isolated deficiency of vitamin E, Kearns-Sayre syndrome, NARP syndrome, Charcot-Marie-Tooth disease type 5, hereditary motor and sensory neuropathy, Okinawa type, fumaric aciduria, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, Niemann-Pick disease type B, long chain 3-hydroxyacyl-CoA dehydrogenase deficiency, primary CD59 deficiency, PHARC syndrome, progressive demyelinating neuropathy with bilateral striatal necrosis, cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome, ataxia - oculomotor apraxia type 4, adrenomyeloneuropathy, neuropathy with hearing impairment, hereditary motor and sensory neuropathy, hereditary sensory and autonomic neuropathy, Charcot-Marie-Tooth disease, infantile axonal neuropathy, mitochondrial neurogastrointestinal encephalomyopathy, attenuated Chédiak-Higashi syndrome, coenzyme Q10 deficiency, familial episodic pain syndrome, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, metachromatic leukodystrophy, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2, proximal spinal muscular atrophy, pyruvate dehydrogenase deficiency, peroxisome biogenesis disorder, neurodegeneration with brain iron accumulation 2A, neuropathy, congenital hypomelinating, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, EMILIN-1-related connective tissue disease, PRPS1 deficiency disorder, neuropathy, hereditary sensory and autonomic, type IId, peripheral motor neuropathy, childhood-onset, biotin-responsive

Subtypes (3): X-linked distal spinal muscular atrophy type 3, neuronopathy, distal hereditary motor, autosomal dominant, neuronopathy, distal hereditary motor, autosomal recessive

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

158 retrieved; paginated sample, class counts are floors:

65 uncertain significance, 30 conflicting classifications of pathogenicity, 17 benign/likely benign, 15 benign, 14 pathogenic, 11 pathogenic/likely pathogenic, 5 likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
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
9207	NM_002047.4(GARS1):c.1738G>C (p.Gly580Arg)	GARS1	Pathogenic	criteria provided, single submitter
220419	NM_001540.5(HSPB1):c.250G>C (p.Gly84Arg)	HSPB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
162194	NM_002180.3(IGHMBP2):c.138T>A (p.Cys46Ter)	IGHMBP2	Pathogenic	criteria provided, multiple submitters, no conflicts
162195	NM_002180.3(IGHMBP2):c.2911_2912del (p.Arg971fs)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
228355	NM_002180.3(IGHMBP2):c.127C>T (p.Arg43Ter)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
235774	NM_002180.3(IGHMBP2):c.1808G>A (p.Arg603His)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
245627	NM_002180.3(IGHMBP2):c.1082T>C (p.Leu361Pro)	IGHMBP2	Pathogenic	criteria provided, multiple submitters, no conflicts
488694	NM_002180.3(IGHMBP2):c.1813C>T (p.Arg605Ter)	IGHMBP2	Pathogenic	criteria provided, multiple submitters, no conflicts
522258	NM_002180.3(IGHMBP2):c.904C>T (p.Gln302Ter)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
561032	NM_002180.3(IGHMBP2):c.1708C>T (p.Arg570Ter)	IGHMBP2	Pathogenic	criteria provided, multiple submitters, no conflicts
573815	NM_002180.3(IGHMBP2):c.1156T>C (p.Trp386Arg)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
581680	NM_002180.3(IGHMBP2):c.1693G>A (p.Asp565Asn)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
620136	NM_002180.3(IGHMBP2):c.1336C>T (p.Gln446Ter)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
637456	NM_002180.3(IGHMBP2):c.1144G>A (p.Glu382Lys)	IGHMBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
637465	NM_002180.3(IGHMBP2):c.661del (p.Thr221fs)	IGHMBP2	Pathogenic	criteria provided, single submitter
637901	NM_002180.3(IGHMBP2):c.121del (p.Gln41fs)	IGHMBP2	Pathogenic	criteria provided, single submitter
637906	NM_002180.3(IGHMBP2):c.163C>T (p.Gln55Ter)	IGHMBP2	Pathogenic	criteria provided, single submitter
637908	NM_002180.3(IGHMBP2):c.2356del (p.Ala786fs)	IGHMBP2	Pathogenic	criteria provided, multiple submitters, no conflicts
218307	NM_001303256.3(MORC2):c.754C>T (p.Arg252Trp)	MORC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2289	NM_015046.7(SETX):c.1166T>C (p.Leu389Ser)	SETX	Pathogenic	criteria provided, multiple submitters, no conflicts
694977	NM_024577.4(SH3TC2):c.386-2A>C	SH3TC2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
411680	NM_003119.4(SPG7):c.1450-1_1457del	SPG7	Pathogenic	criteria provided, multiple submitters, no conflicts
5002	NM_021625.5(TRPV4):c.805C>T (p.Arg269Cys)	TRPV4	Pathogenic	criteria provided, multiple submitters, no conflicts
664361	NM_001374736.1(DST):c.3061-2A>T	DST	Likely pathogenic	criteria provided, single submitter
637899	NM_002180.3(IGHMBP2):c.1060+1G>T	IGHMBP2	Likely pathogenic	criteria provided, single submitter
2290	NM_015046.7(SETX):c.8C>T (p.Thr3Ile)	SETX	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2291	NM_015046.7(SETX):c.6407G>A (p.Arg2136His)	SETX	Likely pathogenic	criteria provided, single submitter
1679203	NM_003384.3(VRK1):c.197C>G (p.Ala66Gly)	VRK1	Likely pathogenic	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 24 · Orphanet: 63 · 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
FBXO38	Strong	Autosomal dominant	neuronopathy, distal hereditary motor, type 2D	5
BAG3	Moderate	Autosomal dominant	neuronopathy, distal hereditary motor, autosomal dominant	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FBXO38	Orphanet:139525	Distal hereditary motor neuropathy type 2
WARS1	Orphanet:2512	Autosomal recessive primary microcephaly
WARS1	Orphanet:528084	Non-specific syndromic intellectual disability
BAG3	Orphanet:154	Familial isolated dilated cardiomyopathy
BAG3	Orphanet:199340	BAG3-related myofibrillar myopathy
DST	Orphanet:314381	Hereditary sensory and autonomic neuropathy type 6
DST	Orphanet:412181	Epidermolysis bullosa simplex due to BP230 deficiency
SPG7	Orphanet:35689	Primary lateral sclerosis
SPG7	Orphanet:99013	Spastic paraplegia type 7
SPTAN1	Orphanet:697160	Infantile epileptic spasms syndrome
VRK1	Orphanet:2254	Pontocerebellar hypoplasia type 1
VRK1	Orphanet:423894	Microcephaly-complex motor and sensory axonal neuropathy syndrome
PRX	Orphanet:64748	Dejerine-Sottas syndrome
PRX	Orphanet:99952	Charcot-Marie-Tooth disease type 4F
SLC5A7	Orphanet:139589	Distal hereditary motor neuropathy type 7
SLC5A7	Orphanet:98914	Presynaptic congenital myasthenic syndromes
LITAF	Orphanet:101083	Charcot-Marie-Tooth disease type 1C
TRPV4	Orphanet:1216	Autosomal dominant congenital benign spinal muscular atrophy
TRPV4	Orphanet:263482	Spondyloepimetaphyseal dysplasia, Maroteaux type
TRPV4	Orphanet:2635	Metatropic dysplasia
TRPV4	Orphanet:431255	Scapuloperoneal spinal muscular atrophy
TRPV4	Orphanet:85169	Familial digital arthropathy-brachydactyly
TRPV4	Orphanet:86820	Familial avascular necrosis of femoral head
TRPV4	Orphanet:93304	Autosomal dominant brachyolmia
TRPV4	Orphanet:93314	Spondylometaphyseal dysplasia, Kozlowski type
TRPV4	Orphanet:99937	Autosomal dominant Charcot-Marie-Tooth disease type 2C
AARS1	Orphanet:228174	Autosomal dominant Charcot-Marie-Tooth disease type 2N
AARS1	Orphanet:33364	Trichothiodystrophy
AARS1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
MORC2	Orphanet:466768	Autosomal dominant Charcot-Marie-Tooth disease type 2Z
PLEKHG5	Orphanet:206580	Autosomal recessive lower motor neuron disease with childhood onset
PLEKHG5	Orphanet:369867	Autosomal recessive intermediate Charcot-Marie-Tooth disease type C
SH3TC2	Orphanet:99949	Charcot-Marie-Tooth disease type 4C
DYNC1H1	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
DYNC1H1	Orphanet:209341	DYNC1H1-related autosomal dominant childhood-onset proximal spinal muscular atrophy
DYNC1H1	Orphanet:284232	Autosomal dominant Charcot-Marie-Tooth disease type 2O
ETFDH	Orphanet:394529	Multiple acyl-CoA dehydrogenase deficiency, severe neonatal type
ETFDH	Orphanet:394532	Multiple acyl-CoA dehydrogenase deficiency, mild type
FUS	Orphanet:275872	Frontotemporal dementia with motor neuron disease
FUS	Orphanet:300605	Juvenile amyotrophic lateral sclerosis
FUS	Orphanet:79105	Myxofibrosarcoma
FUS	Orphanet:803	Amyotrophic lateral sclerosis
FUS	Orphanet:99967	Myxoid/round cell liposarcoma
GARS1	Orphanet:139536	Distal hereditary motor neuropathy type 5
GARS1	Orphanet:99938	Autosomal dominant Charcot-Marie-Tooth disease type 2D
SETX	Orphanet:357043	Amyotrophic lateral sclerosis type 4
SETX	Orphanet:64753	Spinocerebellar ataxia with axonal neuropathy type 2
HSPB1	Orphanet:139525	Distal hereditary motor neuropathy type 2
HSPB1	Orphanet:99940	Autosomal dominant Charcot-Marie-Tooth disease type 2F
IGHMBP2	Orphanet:443073	Charcot-Marie-Tooth disease type 2S

Cohort genes → proteins

27 cohort genes, 27 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	27

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FBXO38	HGNC:28844	ENSG00000145868	Q6PIJ6	F-box only protein 38	gencc,clinvar
WARS1	HGNC:12729	ENSG00000140105	P23381	Tryptophan–tRNA ligase, cytoplasmic	gencc
BAG3	HGNC:939	ENSG00000151929	O95817	BAG family molecular chaperone regulator 3	gencc
DST	HGNC:1090	ENSG00000151914	Q03001	Dystonin	clinvar
SPG7	HGNC:11237	ENSG00000197912	Q9UQ90	Mitochondrial inner membrane m-AAA protease component paraplegin	clinvar
SPTAN1	HGNC:11273	ENSG00000197694	Q13813	Spectrin alpha chain, non-erythrocytic 1	clinvar
TDRKH	HGNC:11713	ENSG00000182134	Q9Y2W6	Tudor and KH domain-containing protein	clinvar
VRK1	HGNC:12718	ENSG00000100749	Q99986	Serine/threonine-protein kinase VRK1	clinvar
PRX	HGNC:13797	ENSG00000105227	Q9BXM0	Periaxin	clinvar
SLC5A7	HGNC:14025	ENSG00000115665	Q9GZV3	High affinity choline transporter 1	clinvar
PRDX6	HGNC:16753	ENSG00000117592	P30041	Peroxiredoxin-6	clinvar
LITAF	HGNC:16841	ENSG00000189067	Q99732	Lipopolysaccharide-induced tumor necrosis factor-alpha factor	clinvar
TRPV4	HGNC:18083	ENSG00000111199	Q9HBA0	Transient receptor potential cation channel subfamily V member 4	clinvar
AARS1	HGNC:20	ENSG00000090861	P49588	Alanine–tRNA ligase, cytoplasmic	clinvar
MORC2	HGNC:23573	ENSG00000133422	Q9Y6X9	ATPase MORC2	clinvar
PLEKHG5	HGNC:29105	ENSG00000171680	O94827	Pleckstrin homology domain-containing family G member 5	clinvar
SH3TC2	HGNC:29427	ENSG00000169247	Q8TF17	SH3 domain and tetratricopeptide repeat-containing protein 2	clinvar
DYNC1H1	HGNC:2961	ENSG00000197102	Q14204	Cytoplasmic dynein 1 heavy chain 1	clinvar
ETFDH	HGNC:3483	ENSG00000171503	Q16134	Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial	clinvar
FUS	HGNC:4010	ENSG00000089280	P35637	RNA-binding protein FUS	clinvar
GARS1	HGNC:4162	ENSG00000106105	P41250	Glycine–tRNA ligase	clinvar
SETX	HGNC:445	ENSG00000107290	Q7Z333	Helicase senataxin	clinvar
HSPB1	HGNC:5246	ENSG00000106211	P04792	Heat shock protein beta-1	clinvar
IGHMBP2	HGNC:5542	ENSG00000132740	P38935	DNA-binding protein SMUBP-2	clinvar
MARS1	HGNC:6898	ENSG00000166986	P56192	Methionine–tRNA ligase, cytoplasmic	clinvar
NEFL	HGNC:7739	ENSG00000277586	P07196	Neurofilament light polypeptide	clinvar
PMP22	HGNC:9118	ENSG00000109099	Q01453	Peripheral myelin protein 22	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FBXO38	F-box only protein 38	Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of PDCD1/PD-1, thereby regulating T-cells-mediated immunity.
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).
BAG3	BAG family molecular chaperone regulator 3	Co-chaperone and adapter protein that connects different classes of molecular chaperones including heat shock proteins 70 (HSP70s), e.g.
DST	Dystonin	Cytoskeletal linker protein.
SPG7	Mitochondrial inner membrane m-AAA protease component paraplegin	Catalytic component of the m-AAA protease, a protease that plays a key role in proteostasis of inner mitochondrial membrane proteins, and which is essential for axonal and neuron development.
SPTAN1	Spectrin alpha chain, non-erythrocytic 1	Fodrin, which seems to be involved in secretion, interacts with calmodulin in a calcium-dependent manner and is thus candidate for the calcium-dependent movement of the cytoskeleton at the membrane.
TDRKH	Tudor and KH domain-containing protein	Participates in the primary piRNA biogenesis pathway and is required during spermatogenesis to repress transposable elements and prevent their mobilization, which is essential for the germline integrity.
VRK1	Serine/threonine-protein kinase VRK1	Serine/threonine kinase involved in the regulation of key cellular processes including the cell cycle, nuclear condensation, transcription regulation, and DNA damage response.
PRX	Periaxin	Scaffolding protein that functions as part of a dystroglycan complex in Schwann cells, and as part of EZR and AHNAK-containing complexes in eye lens fiber cells.
SLC5A7	High affinity choline transporter 1	High-affinity Na(+)-coupled choline transmembrane symporter.
PRDX6	Peroxiredoxin-6	Thiol-specific peroxidase that catalyzes the reduction of hydrogen peroxide and organic hydroperoxides to water and alcohols, respectively.
LITAF	Lipopolysaccharide-induced tumor necrosis factor-alpha factor	Plays a role in endosomal protein trafficking and in targeting proteins for lysosomal degradation.
TRPV4	Transient receptor potential cation channel subfamily V member 4	Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity.
AARS1	Alanine–tRNA ligase, cytoplasmic	Catalyzes the attachment of alanine to tRNA(Ala) in a two-step reaction: alanine is first activated by ATP to form Ala-AMP and then transferred to the acceptor end of tRNA(Ala).
MORC2	ATPase MORC2	ATP-dependent chromatin remodeler essential for epigenetic silencing by the HUSH (human silencing hub) complex.
PLEKHG5	Pleckstrin homology domain-containing family G member 5	Functions as a guanine exchange factor (GEF) for RAB26 and thus regulates autophagy of synaptic vesicles in axon terminal of motoneurons.
SH3TC2	SH3 domain and tetratricopeptide repeat-containing protein 2	Is involved in nerve myelination and is required for the integrity of nodes of Ranvier.
DYNC1H1	Cytoplasmic dynein 1 heavy chain 1	Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules.
ETFDH	Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial	Accepts electrons from ETF and reduces ubiquinone.
FUS	RNA-binding protein FUS	DNA/RNA-binding protein that plays a role in various cellular processes such as transcription regulation, RNA splicing, RNA transport, DNA repair and damage response.
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).
SETX	Helicase senataxin	ATP-dependent 5’->3’ DNA/RNA helicase that preferentially unwinds RNA substrates over DNA, playing a crucial role in resolving R-loops and promoting transcription termination.
HSPB1	Heat shock protein beta-1	Small heat shock protein which functions as a molecular chaperone probably maintaining denatured proteins in a folding-competent state.
IGHMBP2	DNA-binding protein SMUBP-2	5’ to 3’ helicase that unwinds RNA and DNA duplexes in an ATP-dependent reaction.
MARS1	Methionine–tRNA ligase, cytoplasmic	Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA.
NEFL	Neurofilament light polypeptide	Neurofilaments usually contain three intermediate filament proteins: NEFL, NEFM, and NEFH which are involved in the maintenance of neuronal caliber.
PMP22	Peripheral myelin protein 22	Might be involved in growth regulation, and in myelinization in the peripheral nervous system.

Protein-family classification

Druggable: 9 · Difficult: 9 · Unknown: 9 · Druggable fraction: 0.33

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	6	3.8×	0.031
Enzyme (other)	5	2.2×	0.277
Ion channel	1	4.1×	0.576
Transporter	1	2.9×	0.590
Protease	1	1.4×	0.744
Kinase	1	1.0×	0.744
Transcription factor	3	0.9×	0.744
Other/Unknown	9	0.6×	0.995

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FBXO38	Other/Unknown	no		F-box_dom, LRR_dom_sf, F-box-like_dom_sf
WARS1	Enzyme (other)	yes	6.1.1.2	WHEP-TRS_dom, aa-tRNA-synth_I_CS, aa-tRNA-synth_Ic
BAG3	Scaffold/PPI	no		WW_dom, BAG_domain, WW_dom_sf
DST	Scaffold/PPI	no		Plectin_repeat, SH3_domain, Actinin_actin-bd_CS
SPG7	Protease	yes	3.4.24.B18	Peptidase_M41, AAA+_ATPase, ATPase_AAA_core
SPTAN1	Scaffold/PPI	no		SH3_domain, Spectrin_repeat, EF_hand_dom
TDRKH	Other/Unknown	no		Tudor, KH_dom, KH_dom_type_1
VRK1	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
PRX	Scaffold/PPI	no		PDZ, PDZ_sf, Myelin_sheath_structural
SLC5A7	Transporter	yes		Na/solute_symporter, Na/Glc_symporter_sf, Choline_transporter
PRDX6	Enzyme (other)	yes	1.11.1.27	AhpC/TSA, Thioredoxin_domain, Peroxiredoxin_C
LITAF	Other/Unknown	no		LITAF, LITAF_fam
TRPV4	Ion channel	yes		Ankyrin_rpt, Ion_trans_dom, TrpV1-4
AARS1	Other/Unknown	no		Ala-tRNA-lgiase_IIc, DHHA1_dom, Transl_B-barrel_sf
MORC2	Transcription factor	no		Znf_CW, HATPase_C_sf, Morc_S5
PLEKHG5	Scaffold/PPI	no		DH_dom, PH_domain, PH-like_dom_sf
SH3TC2	Scaffold/PPI	no		SH3_domain, TPR-like_helical_dom_sf, TPR_rpt
DYNC1H1	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
ETFDH	Enzyme (other)	yes	1.5.5.1	ETF-QO/FixX_C, 4Fe4S_Fe-S-bd, FAD/NAD-bd_sf
FUS	Transcription factor	no		RRM_dom, Znf_RanBP2, Nucleotide-bd_a/b_plait_sf
GARS1	Enzyme (other)	yes	6.1.1.14	WHEP-TRS_dom, aa-tRNA-synt_IIb, tRNA-synt_gly
SETX	Other/Unknown	no		P-loop_NTPase, DNA2/NAM7_AAA_11, DNA2/NAM7-like_C
HSPB1	Other/Unknown	no		Alpha-crystallin/sHSP_animal, A-crystallin/Hsp20_dom, HSP20-like_chaperone
IGHMBP2	Transcription factor	no	3.6.4.12	Znf_AN1, R3H_dom, AAA+_ATPase
MARS1	Enzyme (other)	yes	6.1.1.10	WHEP-TRS_dom, aa-tRNA-synth_I_CS, GST_C
NEFL	Other/Unknown	no		Intermed_filament_DNA-bd, IF_conserved, IF_rod_dom
PMP22	Other/Unknown	no		PMP22, PMP22/EMP/MP20/Claudin, PMP22_EMP_MP20

Expression context

Cohort genes with no expression data: 0.

24 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)	27
unknown	0

Top tissues across cohort

Tissue	Cohort genes
sural nerve	4
right hemisphere of cerebellum	4
calcaneal tendon	3
primordial germ cell in gonad	3
cerebellar hemisphere	3
right testis	3
gastrocnemius	2
corpus callosum	2
cerebellar cortex	2
left testis	2
secondary oocyte	2
olfactory bulb	2
trigeminal ganglion	2
mucosa of stomach	2
cartilage tissue	2
lower esophagus mucosa	2
ventricular zone	2
lateral nuclear group of thalamus	2
dorsal root ganglion	2
adrenal tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FBXO38	287	ubiquitous	marker	calcaneal tendon, adrenal tissue, endothelial cell
WARS1	291	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
BAG3	286	ubiquitous	marker	gastrocnemius, skeletal muscle tissue of rectus abdominis, body of tongue
DST	305	ubiquitous	marker	corpus callosum, calcaneal tendon, medial globus pallidus
SPG7	302	ubiquitous	marker	primordial germ cell in gonad, sural nerve, left lobe of thyroid gland
SPTAN1	293	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
TDRKH	194	ubiquitous	marker	primordial germ cell in gonad, right testis, left testis
VRK1	286	ubiquitous	marker	oocyte, bone marrow, secondary oocyte
PRX	258	ubiquitous	marker	olfactory bulb, trigeminal ganglion, sural nerve
SLC5A7	101	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, pancreatic ductal cell, primordial germ cell in gonad
PRDX6	295	ubiquitous	marker	corpus epididymis, gastrocnemius, mucosa of stomach
LITAF	294	ubiquitous	marker	blood, palpebral conjunctiva, periodontal ligament
TRPV4	171	ubiquitous	marker	cartilage tissue, lower esophagus mucosa, olfactory segment of nasal mucosa
AARS1	301	ubiquitous	marker	endometrium epithelium, type B pancreatic cell, frontal pole
MORC2	292	ubiquitous	yes	cervix squamous epithelium, sperm, male germ cell
PLEKHG5	175	ubiquitous	yes	sural nerve, right hemisphere of cerebellum, cerebellar hemisphere
SH3TC2	168	broad	marker	corpus callosum, sural nerve, C1 segment of cervical spinal cord
DYNC1H1	290	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone
ETFDH	285	ubiquitous	marker	apex of heart, heart left ventricle, hindlimb stylopod muscle
FUS	304	ubiquitous	marker	right testis, ventricular zone, right hemisphere of cerebellum
GARS1	293	ubiquitous	marker	secondary oocyte, cartilage tissue, lateral nuclear group of thalamus
SETX	281	ubiquitous	marker	right testis, calcaneal tendon, left testis
HSPB1	299	ubiquitous	marker	lower esophagus mucosa, ascending aorta, thoracic aorta
IGHMBP2	189	ubiquitous	yes	mucosa of stomach, esophagogastric junction muscularis propria, lower esophagus muscularis layer
MARS1	301	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
NEFL	214	broad	marker	dorsal root ganglion, pons, lateral nuclear group of thalamus
PMP22	294	ubiquitous	marker	olfactory bulb, trigeminal ganglion, dorsal root ganglion

Protein interactions among cohort

Intra-cohort edges: 20.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MARS1	5,727
HSPB1	5,491
FUS	5,250
BAG3	4,957
NEFL	4,644
DYNC1H1	4,215
PRDX6	4,106
SPG7	3,970
SETX	3,127
SPTAN1	3,083

Intra-cohort edges

A	B	Sources
AARS1	GARS1	string_interaction
AARS1	WARS1	string_interaction
BAG3	DYNC1H1	intact
BAG3	HSPB1	string_interaction
BAG3	LITAF	biogrid_interaction, intact
DYNC1H1	IGHMBP2	string_interaction
FUS	SETX	string_interaction
GARS1	IGHMBP2	string_interaction
GARS1	MARS1	string_interaction
IGHMBP2	MORC2	string_interaction
IGHMBP2	PLEKHG5	string_interaction
IGHMBP2	SETX	string_interaction
IGHMBP2	SH3TC2	string_interaction
LITAF	SH3TC2	string_interaction
MARS1	WARS1	string_interaction
MORC2	SH3TC2	string_interaction
NEFL	PMP22	string_interaction
PLEKHG5	SH3TC2	string_interaction
PMP22	PRX	string_interaction
PMP22	SH3TC2	string_interaction

Structural data

PDB: 18 · AlphaFold-only: 9 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DYNC1H1	Q14204	97
VRK1	Q99986	26
FUS	P35637	23
TRPV4	Q9HBA0	19
GARS1	P41250	14
WARS1	P23381	13
SLC5A7	Q9GZV3	12
MORC2	Q9Y6X9	9
SPTAN1	Q13813	7
MARS1	P56192	7
AARS1	P49588	6
HSPB1	P04792	6
TDRKH	Q9Y2W6	5
IGHMBP2	P38935	4
PRDX6	P30041	3
DST	Q03001	2
SPG7	Q9UQ90	1
PRX	Q9BXM0	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ETFDH	Q16134	93.60
PMP22	Q01453	89.87
SH3TC2	Q8TF17	78.63
NEFL	P07196	73.66
LITAF	Q99732	70.60
FBXO38	Q6PIJ6	67.97
PLEKHG5	O94827	64.94
BAG3	O95817	57.98
SETX	Q7Z333	52.93

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 124. Enrichment computed across 27 evidence-associated genes (22 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 22 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	4	79.9×	2e-05	WARS1, AARS1, GARS1, MARS1
tRNA Aminoacylation	3	38.9×	0.004	WARS1, AARS1, MARS1
Defective SLC5A7 in the neurotransmitter release cycle causes distal hereditary motor neuronopathy 7A (HMN7A)	1	519.1×	0.044	SLC5A7
Defective transport by SLC5A7 causes distal hereditary motor neuronopathy 7A (HMN7A)	1	519.1×	0.044	SLC5A7
EGR2 and SOX10-mediated initiation of Schwann cell myelination	2	33.5×	0.044	PRX, PMP22
RHOV GTPase cycle	2	25.9×	0.044	DST, SPTAN1
RHOU GTPase cycle	2	25.3×	0.044	DST, SPTAN1
RND1 GTPase cycle	2	24.1×	0.044	DST, PLEKHG5
RND3 GTPase cycle	2	23.6×	0.044	DST, PLEKHG5
Translation	3	8.5×	0.063	WARS1, AARS1, MARS1
Regulation of HSF1-mediated heat shock response	2	12.7×	0.121	HSPB1, BAG3
SLC-mediated bile acid transport	1	74.2×	0.139	SLC5A7
COPI-mediated anterograde transport	2	10.0×	0.161	SPTAN1, DYNC1H1
Type I hemidesmosome assembly	1	47.2×	0.185	DST
Caspase-mediated cleavage of cytoskeletal proteins	1	43.3×	0.185	SPTAN1
Acetylcholine Neurotransmitter Release Cycle	1	30.5×	0.185	SLC5A7
Processing of SMDT1	1	28.8×	0.185	SPG7
Initiation of Nuclear Envelope (NE) Reformation	1	27.3×	0.185	VRK1
Ras activation upon Ca2+ influx through NMDA receptor	1	25.9×	0.185	NEFL
Unblocking of NMDA receptors, glutamate binding and activation	1	24.7×	0.185	NEFL
Mitochondrial calcium ion transport	1	24.7×	0.185	SPG7
Negative regulation of NMDA receptor-mediated neuronal transmission	1	24.7×	0.185	NEFL
Mitochondrial tRNA aminoacylation	1	23.6×	0.185	GARS1
Apoptotic cleavage of cellular proteins	1	21.6×	0.185	SPTAN1
Nephrin family interactions	1	21.6×	0.185	SPTAN1
Apoptotic execution phase	1	21.6×	0.185	SPTAN1
Long-term potentiation	1	21.6×	0.185	NEFL
Nuclear Envelope Breakdown	1	20.8×	0.185	VRK1
Neurotransmitter release cycle	1	20.0×	0.185	SLC5A7
Fatty acyl-CoA biosynthesis	1	20.0×	0.185	MORC2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 26 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
retrograde axonal transport	3	176.8×	1e-04	DST, DYNC1H1, NEFL
tRNA aminoacylation for protein translation	3	97.2×	4e-04	AARS1, GARS1, MARS1
peripheral nervous system myelin maintenance	2	117.8×	0.010	PRX, SH3TC2
tryptophanyl-tRNA aminoacylation	1	648.1×	0.027	WARS1
striated muscle cell apoptotic process	1	648.1×	0.027	BAG3
hyperosmotic salinity response	1	648.1×	0.027	TRPV4
intermediate filament polymerization or depolymerization	1	648.1×	0.027	NEFL
positive regulation of termination of DNA-templated transcription	1	648.1×	0.027	SETX
negative regulation of protein kinase C signaling	1	648.1×	0.027	HSPB1
blood vessel endothelial cell delamination	1	648.1×	0.027	TRPV4
regulation of cytoplasmic translational fidelity	1	648.1×	0.027	AARS1
regulation of ERBB signaling pathway	1	648.1×	0.027	SH3TC2
anterograde axonal transport	2	44.7×	0.027	SPG7, NEFL
spinal cord development	2	39.3×	0.027	NEFL, BAG3
alanyl-tRNA aminoacylation	1	324.1×	0.028	AARS1
methionyl-tRNA aminoacylation	1	324.1×	0.028	MARS1
regulation of macrophage cytokine production	1	324.1×	0.028	LITAF
vasopressin secretion	1	324.1×	0.028	TRPV4
positive regulation of striated muscle contraction	1	324.1×	0.028	TRPV4
regulation of response to osmotic stress	1	324.1×	0.028	TRPV4
mitochondrial glycyl-tRNA aminoacylation	1	324.1×	0.028	GARS1
calcium ion import into cytosol	1	324.1×	0.028	TRPV4
mitochondrial outer membrane permeabilization involved in programmed cell death	1	324.1×	0.028	SPG7
response to sodium arsenite	1	324.1×	0.028	NEFL
response to acrylamide	1	324.1×	0.028	NEFL
cellular response to heat	2	26.5×	0.028	TRPV4, BAG3
neuromuscular process controlling balance	2	25.4×	0.028	AARS1, NEFL
acetylcholine biosynthetic process	1	216.1×	0.031	SLC5A7
negative regulation of striated muscle cell apoptotic process	1	216.1×	0.031	BAG3
diadenosine tetraphosphate biosynthetic process	1	216.1×	0.031	GARS1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 4 · Phased (≥1): 7 · Undrugged: 20

Druggability breadth: 15 of 27 evidence-associated genes (56%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PMP22	PROGESTERONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PMP22	213	4
TRPV4	6	3
SPTAN1	1	2
SLC5A7	1	3
DYNC1H1	1	2
GARS1	1	3
HSPB1	1	2
FBXO38	0	0
WARS1	0	0
BAG3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PROGESTERONE	4	PMP22
CLOTRIMAZOLE	4	PMP22
OXAPROZIN	4	PMP22
SALMETEROL XINAFOATE	4	PMP22
AMIODARONE HYDROCHLORIDE	4	PMP22
TRIHEXYPHENIDYL HYDROCHLORIDE	4	PMP22
AMOXAPINE	4	PMP22
RALOXIFENE HYDROCHLORIDE	4	PMP22
IDARUBICIN	4	PMP22
OXYBUTYNIN CHLORIDE	4	PMP22
PINACIDIL ANHYDROUS	4	PMP22
NICARDIPINE HYDROCHLORIDE	4	PMP22
PILOCARPINE HYDROCHLORIDE	4	PMP22
PROTRIPTYLINE HYDROCHLORIDE	4	PMP22
BENZTROPINE MESYLATE	4	PMP22
BUSPIRONE HYDROCHLORIDE	4	PMP22
DOBUTAMINE HYDROCHLORIDE	4	PMP22
PROMAZINE HYDROCHLORIDE	4	PMP22
DICYCLOMINE HYDROCHLORIDE	4	PMP22
GUANFACINE HYDROCHLORIDE	4	PMP22
HYDROCORTISONE SODIUM SUCCINATE	4	PMP22
BROMOCRIPTINE MESYLATE	4	PMP22
DIHYDROERGOTAMINE MESYLATE	4	PMP22
DOXAZOSIN MESYLATE	4	PMP22
CYCLOBENZAPRINE HYDROCHLORIDE	4	PMP22
DEXBROMPHENIRAMINE MALEATE	4	PMP22
CLOMIPRAMINE HYDROCHLORIDE	4	PMP22
CHLORMEZANONE	4	PMP22
PROMETHAZINE HYDROCHLORIDE	4	PMP22
CITALOPRAM HYDROBROMIDE	4	PMP22

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 7.

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

Symbol	Assays	Type breakdown
TRPV4	99	Binding:94, Functional:5
VRK1	74	Binding:74
HSPB1	70	Binding:70
SLC5A7	34	Binding:24, Functional:10
MARS1	26	Binding:26
PRDX6	15	Binding:15
BAG3	8	Binding:8
GARS1	8	Binding:8
SPTAN1	7	Binding:7
DYNC1H1	7	Binding:7
FUS	7	Binding:7
AARS1	2	Binding:2
WARS1	1	Binding:1
LITAF	1	Binding:1
PMP22	1	Functional:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
WARS1	6.1.1.2	tryptophan-tRNA ligase
SPG7	3.4.24.B18
PRDX6	1.11.1.27, 2.3.1.23, 3.1.1.4	glutathione-dependent peroxiredoxin, 1-acylglycerophosphocholine O-acyltransferase, phospholipase A2
ETFDH	1.5.5.1	electron-transferring-flavoprotein dehydrogenase
GARS1	6.1.1.14	glycine-tRNA ligase
IGHMBP2	3.6.4.12	DNA helicase
MARS1	6.1.1.10	methionine-tRNA ligase

Pharmacogenomics

Cohort genes with a PharmGKB record: 27; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
PROGESTERONE	4	PMP22
CLOTRIMAZOLE	4	PMP22
OXAPROZIN	4	PMP22
SALMETEROL XINAFOATE	4	PMP22
AMIODARONE HYDROCHLORIDE	4	PMP22
TRIHEXYPHENIDYL HYDROCHLORIDE	4	PMP22
AMOXAPINE	4	PMP22
RALOXIFENE HYDROCHLORIDE	4	PMP22
IDARUBICIN	4	PMP22
OXYBUTYNIN CHLORIDE	4	PMP22
PINACIDIL ANHYDROUS	4	PMP22
NICARDIPINE HYDROCHLORIDE	4	PMP22
PILOCARPINE HYDROCHLORIDE	4	PMP22
PROTRIPTYLINE HYDROCHLORIDE	4	PMP22
BENZTROPINE MESYLATE	4	PMP22
BUSPIRONE HYDROCHLORIDE	4	PMP22
DOBUTAMINE HYDROCHLORIDE	4	PMP22
PROMAZINE HYDROCHLORIDE	4	PMP22
DICYCLOMINE HYDROCHLORIDE	4	PMP22
GUANFACINE HYDROCHLORIDE	4	PMP22
HYDROCORTISONE SODIUM SUCCINATE	4	PMP22
BROMOCRIPTINE MESYLATE	4	PMP22
DIHYDROERGOTAMINE MESYLATE	4	PMP22
DOXAZOSIN MESYLATE	4	PMP22
CYCLOBENZAPRINE HYDROCHLORIDE	4	PMP22
DEXBROMPHENIRAMINE MALEATE	4	PMP22
CLOMIPRAMINE HYDROCHLORIDE	4	PMP22
CHLORMEZANONE	4	PMP22
PROMETHAZINE HYDROCHLORIDE	4	PMP22
CITALOPRAM HYDROBROMIDE	4	PMP22

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PMP22
B	Phased (≥1) drug, not yet approved	6	SPTAN1, SLC5A7, TRPV4, DYNC1H1, GARS1, HSPB1
C	Druggable family + PDB, no drug	5	WARS1, SPG7, VRK1, PRDX6, MARS1
D	Druggable family + AlphaFold only, no drug	1	ETFDH
E	Difficult family or no structure, no drug	14	FBXO38, BAG3, DST, TDRKH, PRX, LITAF, AARS1, MORC2, PLEKHG5, SH3TC2 (+4 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FBXO38	0	—
WARS1	1	—
BAG3	8	—
DST	0	—
SPG7	0	—
TDRKH	0	—
VRK1	74	—
PRX	0	—
PRDX6	15	—
LITAF	1	—
AARS1	2	—
MORC2	0	—
PLEKHG5	0	—
SH3TC2	0	—
ETFDH	0	—
FUS	7	—
SETX	0	—
IGHMBP2	0	—
MARS1	26	—
NEFL	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.