Polyneuropathy

Summary

Polyneuropathy (MONDO:0001824) is a disease (an umbrella term covering 10 Mondo subtypes) with 14 cohort genes (2 GWAS associations across 15 studies) and 59 clinical trials. Top therapeutic interventions include acoramidis, imipramine, and cilostazol.

At a glance

• Umbrella term: 10 Mondo subtypes
• Cohort genes: 14
• GWAS associations: 2
• ClinVar variants: 16
• Clinical trials: 59

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	polyneuropathy
Mondo ID	MONDO:0001824
EFO	EFO:0009562
MeSH	D011115
DOID	DOID:1389
ICD-11	58868923
NCIT	C26951
SNOMED CT	42345000
UMLS	C0152025
MedGen	57502
Is cancer (heuristic)	no

Also known as: polyneuropathy

Data availability: 16 ClinVar variants · 2 GWAS associations (15 studies) · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 10 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › polyneuropathy

Related subtypes (29): autoimmune neuropathy, autonomic neuropathy, mononeuropathy, ischemic neuropathy, neuritis, motor peripheral neuropathy, sensory peripheral neuropathy, uremic neuropathy, nerve compression syndrome, axonal neuropathy, diabetic neuropathy, acquired peripheral neuropathy, hereditary peripheral neuropathy, neuralgia, peripheral nerve lesion, nerve plexus disorder, traumatic neuropathy, radiation-induced neuropathy, vasculitic neuropathy, chronic idiopathic neuropathy, chemotherapy-induced neuropathy, infectious neuropathy, vitamin deficiency related neuropathy, paraproteinemia-associated neuropathy, neuropathy in cryoglobulinemia, neuropathy in endocrine disorder, sarcoid neuropathy, neuropathy, small fiber, idiopathic small fibers neuropathy

Subtypes (10): idiopathic progressive polyneuropathy, polyneuropathy in collagen vascular disease, critical illness polyneuropathy, demyelinating polyneuropathy, chronic polyneuropathy, paraneoplastic polyneuropathy, polyradiculoneuropathy, polyneuritis, toxic polyneuropathy, organophosphate-induced delayed polyneuropathy

Genetics & variants

GWAS landscape

2 GWAS associations across 15 studies. Top hits map to 1 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs7294354	5e-08	B4GALNT3	T	1.19
rs147738081	5e-08	LINC02789 - RNU6-778P	T	1.68

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90473352	UK Biobank Whole-Genome Sequencing Consortium	2025	5,338	453,102	Whole-genome sequencing of 490,640 UK Biobank participants.
GCST90079850	Backman JD	2021	1,972	384,992	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90083836	Backman JD	2021	1,972	384,992	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90079849	Backman JD	2021	1,543	385,937	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90083835	Backman JD	2021	1,543	385,937	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90473353	UK Biobank Whole-Genome Sequencing Consortium	2025	1,513	456,927	Whole-genome sequencing of 490,640 UK Biobank participants.
GCST90094686	Winsvold BS	2021	1,147	62,204	Genome-Wide Association Study of 2,093 Cases With Idiopathic Polyneuropathy and 445,256 Controls Identifies First Susceptibility Loci.
GCST90473351	UK Biobank Whole-Genome Sequencing Consortium	2025	683	457,757	Whole-genome sequencing of 490,640 UK Biobank participants.
GCST90079852	Backman JD	2021	586	387,338	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90083838	Backman JD	2021	586	387,338	Exome sequencing and analysis of 454,787 UK Biobank participants.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	0
Tier 2: splice/UTR	0
Tier 3: regulatory	0
Tier 4: intronic/intergenic	2

MAF distribution

Bucket	Variants
common (>=0.05)	1
low_freq (0.01-0.05)	1
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	1
intergenic_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs7294354	12	479778	T>A,G	0.428	intron_variant	B4GALNT3	5e-08	Tier 4: intronic/intergenic
rs147738081	1	199885545	C>T	0.031	intergenic_variant	LINC02789 - RNU6-778P	5e-08	Tier 4: intronic/intergenic

ClinVar germline variants

16 retrieved; paginated sample, class counts are floors:

8 uncertain significance, 3 likely benign, 1 benign/likely benign, 1 likely pathogenic, 1 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4200	NM_018972.4(GDAP1):c.715C>T (p.Leu239Phe)	GDAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
689557	NM_003119.4(SPG7):c.87G>A (p.Trp29Ter)	LOC130059818	Pathogenic	criteria provided, multiple submitters, no conflicts
373982	NM_000123.4(ERCC5):c.2929_2930del (p.Leu977fs)	BIVM-ERCC5	Likely pathogenic	criteria provided, single submitter
437001	NM_198994.3(TGM6):c.691C>T (p.Arg231Ter)	TGM6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
982987	NM_001761.3(CCNF):c.290A>G (p.Lys97Arg)	CCNF	Uncertain significance	criteria provided, single submitter
973831	NM_020944.3(GBA2):c.1807T>A (p.Trp603Arg)	GBA2	Uncertain significance	criteria provided, single submitter
973832	NM_020944.3(GBA2):c.1444A>C (p.Asn482His)	GBA2	Uncertain significance	criteria provided, single submitter
1343403	NM_000158.4(GBE1):c.2102C>T (p.Pro701Leu)	GBE1	Uncertain significance	criteria provided, multiple submitters, no conflicts
689547	NM_170707.4(LMNA):c.1270A>C (p.Thr424Pro)	LMNA	Uncertain significance	criteria provided, single submitter
689545	NM_002693.3(POLG):c.2982G>C (p.Trp994Cys)	POLG	Uncertain significance	criteria provided, single submitter
694650	NM_001371279.1(REEP1):c.789G>A (p.Pro263=)	REEP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
373969	NM_006306.4(SMC1A):c.2981A>G (p.Gln994Arg)	SMC1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
689550	NM_001376.5(DYNC1H1):c.2539-10C>A	DYNC1H1	Likely benign	criteria provided, single submitter
221058	NM_030973.4(MED25):c.2088G>A (p.Leu696=)	MED25	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
689543	NM_030973.4(MED25):c.1086C>T (p.Pro362=)	MED25	Likely benign	criteria provided, single submitter
689579	NM_030973.4(MED25):c.305+14C>G	MED25	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 58 · 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
NDC1	Limited	Autosomal recessive	polyneuropathy	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SMC1A	Orphanet:199	Cornelia de Lange syndrome
SMC1A	Orphanet:220386	Semilobar holoprosencephaly
SMC1A	Orphanet:3095	Atypical Rett syndrome
SMC1A	Orphanet:708203	Intellectual disability-small hands and feet-drug-resistant epilepsy syndrome
CCNF	Orphanet:803	Amyotrophic lateral sclerosis
GDAP1	Orphanet:101097	Autosomal recessive Charcot-Marie-Tooth disease with hoarseness
GDAP1	Orphanet:101102	Charcot-Marie-Tooth disease type 2H
GDAP1	Orphanet:217055	Autosomal recessive intermediate Charcot-Marie-Tooth disease type A
GDAP1	Orphanet:99944	Autosomal dominant Charcot-Marie-Tooth disease type 2K
GDAP1	Orphanet:99948	Charcot-Marie-Tooth disease type 4A
TGM6	Orphanet:276193	Spinocerebellar ataxia type 35
TGM6	Orphanet:319465	Inherited acute myeloid leukemia
GBA2	Orphanet:320391	Autosomal recessive spastic paraplegia type 46
GBA2	Orphanet:352641	Autosomal recessive cerebellar ataxia with late-onset spasticity
REEP1	Orphanet:101011	Autosomal dominant spastic paraplegia type 31
REEP1	Orphanet:139536	Distal hereditary motor neuropathy type 5
MED25	Orphanet:464738	Basel-Vanagaite-Smirin-Yosef syndrome
MED25	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
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
GBE1	Orphanet:206583	Adult polyglucosan body disease
GBE1	Orphanet:308621	Glycogen storage disease due to glycogen branching enzyme deficiency, progressive hepatic form
GBE1	Orphanet:308638	Glycogen storage disease due to glycogen branching enzyme deficiency, non progressive hepatic form
GBE1	Orphanet:308655	Glycogen storage disease due to glycogen branching enzyme deficiency, fatal perinatal neuromuscular form
GBE1	Orphanet:308670	Glycogen storage disease due to glycogen branching enzyme deficiency, congenital neuromuscular form
GBE1	Orphanet:308684	Glycogen storage disease due to glycogen branching enzyme deficiency, childhood combined hepatic and myopathic form
GBE1	Orphanet:308698	Glycogen storage disease due to glycogen branching enzyme deficiency, childhood neuromuscular form
GBE1	Orphanet:308712	Glycogen storage disease due to glycogen branching enzyme deficiency, adult neuromuscular form
LMNA	Orphanet:154	Familial isolated dilated cardiomyopathy
LMNA	Orphanet:157973	Congenital muscular dystrophy due to LMNA mutation
LMNA	Orphanet:1662	Restrictive dermopathy
LMNA	Orphanet:168796	Heart-hand syndrome, Slovenian type
LMNA	Orphanet:2229	Dilated cardiomyopathy-hypergonadotropic hypogonadism syndrome
LMNA	Orphanet:2348	Familial partial lipodystrophy, Dunnigan type
LMNA	Orphanet:280365	Autosomal semi-dominant severe lipodystrophic laminopathy
LMNA	Orphanet:293888	Inherited isolated arrhythmogenic cardiomyopathy, dominant-left variant
LMNA	Orphanet:293899	Inherited isolated arrhythmogenic ventricular dysplasia, biventricular variant
LMNA	Orphanet:293910	Inherited isolated arrhythmogenic cardiomyopathy, dominant-right variant
LMNA	Orphanet:300751	Familial dilated cardiomyopathy with conduction defect due to LMNA mutation
LMNA	Orphanet:363618	LMNA-related cardiocutaneous progeria syndrome
LMNA	Orphanet:54260	Left ventricular noncompaction
LMNA	Orphanet:675396	Epithelioid hemangioma
LMNA	Orphanet:740	Hutchinson-Gilford progeria syndrome
LMNA	Orphanet:79084	Familial partial lipodystrophy, Köbberling type
LMNA	Orphanet:79474	Atypical Werner syndrome
LMNA	Orphanet:90153	Mandibuloacral dysplasia with type A lipodystrophy
LMNA	Orphanet:98853	Autosomal dominant Emery-Dreifuss muscular dystrophy
LMNA	Orphanet:98855	Autosomal recessive Emery-Dreifuss muscular dystrophy
LMNA	Orphanet:98856	Charcot-Marie-Tooth disease type 2B1

Cohort genes → proteins

14 cohort genes, 13 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	14

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NDC1	HGNC:25525	ENSG00000058804	Q9BTX1	Nucleoporin NDC1	gencc
SMC1A	HGNC:11111	ENSG00000072501	Q14683	Structural maintenance of chromosomes protein 1A	clinvar
CCNF	HGNC:1591	ENSG00000162063	P41002	Cyclin-F	clinvar
GDAP1	HGNC:15968	ENSG00000104381	Q8TB36	Ganglioside-induced differentiation-associated protein 1	clinvar
TGM6	HGNC:16255	ENSG00000166948	O95932	Protein-glutamine gamma-glutamyltransferase 6	clinvar
GBA2	HGNC:18986	ENSG00000070610	Q9HCG7	Non-lysosomal glucosylceramidase	clinvar
MED9	HGNC:25487	ENSG00000141026	Q9NWA0	Mediator of RNA polymerase II transcription subunit 9	clinvar
REEP1	HGNC:25786	ENSG00000068615	Q9H902	Receptor expression-enhancing protein 1	clinvar
MED25	HGNC:28845	ENSG00000104973	Q71SY5	Mediator of RNA polymerase II transcription subunit 25	clinvar
DYNC1H1	HGNC:2961	ENSG00000197102	Q14204	Cytoplasmic dynein 1 heavy chain 1	clinvar
GBE1	HGNC:4180	ENSG00000114480	Q04446	1,4-alpha-glucan-branching enzyme	clinvar
BIVM-ERCC5	HGNC:43690	ENSG00000270181		BIVM-ERCC5 readthrough	clinvar
LMNA	HGNC:6636	ENSG00000160789	P02545	Prelamin-A/C	clinvar
POLG	HGNC:9179	ENSG00000140521	P54098	DNA polymerase subunit gamma-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NDC1	Nucleoporin NDC1	Component of the nuclear pore complex (NPC), which plays a key role in de novo assembly and insertion of NPC in the nuclear envelope.
SMC1A	Structural maintenance of chromosomes protein 1A	Involved in chromosome cohesion during cell cycle and in DNA repair.
CCNF	Cyclin-F	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 target proteins.
GDAP1	Ganglioside-induced differentiation-associated protein 1	Regulates the mitochondrial network by promoting mitochondrial fission.
TGM6	Protein-glutamine gamma-glutamyltransferase 6	Catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins.
GBA2	Non-lysosomal glucosylceramidase	Non-lysosomal glucosylceramidase that catalyzes the hydrolysis of glucosylceramides/GlcCers (such as beta-D-glucosyl-(1<->1’)-N-acylsphing-4-enine) to free glucose and ceramides (such as N-acylsphing-4-enine).
MED9	Mediator of RNA polymerase II transcription subunit 9	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
REEP1	Receptor expression-enhancing protein 1	Required for endoplasmic reticulum (ER) network formation, shaping and remodeling; it links ER tubules to the cytoskeleton.
MED25	Mediator of RNA polymerase II transcription subunit 25	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
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.
GBE1	1,4-alpha-glucan-branching enzyme	Glycogen-branching enzyme participates in the glycogen biosynthetic process along with glycogenin and glycogen synthase.
LMNA	Prelamin-A/C	Lamins are intermediate filament proteins that assemble into a filamentous meshwork, and which constitute the major components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane.
POLG	DNA polymerase subunit gamma-1	Catalytic subunit of DNA polymerase gamma solely responsible for replication of mitochondrial DNA (mtDNA).

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 11 · Druggable fraction: 0.21

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
Antibody/Immunoglobulin	2	4.2×	0.122
Other/Unknown	11	1.4×	0.122
Enzyme (other)	1	0.9×	0.705

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NDC1	Other/Unknown	no		Nucleoporin_prot_Ndc1/Nup
SMC1A	Other/Unknown	no		RecF/RecN/SMC_N, SMC_hinge, SMC
CCNF	Other/Unknown	no		F-box_dom, Cyclin_C-dom, Cyclin_N
GDAP1	Other/Unknown	no		Glutathione_S-Trfase_N, Glutathione-S-Trfase_C-like, GST_C_GDAP1
TGM6	Antibody/Immunoglobulin	yes	2.3.2.13	Transglutaminase_N, Transglutaminase-like, Transglutaminase_C
GBA2	Enzyme (other)	yes	3.2.1.45	GH116_catalytic, 6-hairpin_glycosidase_sf, 6hp_glycosidase-like_sf
MED9	Other/Unknown	no		Med9, Med7/Med21-like, MED9_metazoa
REEP1	Other/Unknown	no		TB2_DP1_HVA22
MED25	Other/Unknown	no		Med25_PTOV, Mediator_Med25_SD1, Mediator_Med25_VWA
DYNC1H1	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
GBE1	Antibody/Immunoglobulin	yes		Glyco_hydro_13_N, GH13_cat_dom, A-amylase/branching_C
BIVM-ERCC5	Other/Unknown	no
LMNA	Other/Unknown	no		Lamin_tail_dom, IF_conserved, Lamin_tail_dom_sf
POLG	Other/Unknown	no		DNA-dir_DNA_pol_A_palm_dom, DNA-dir_DNA_pol_A_mt, RNaseH-like_sf

Expression context

Cohort genes with no expression data: 0.

12 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)	14
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	3
secondary oocyte	3
small intestine Peyer’s patch	2
cortical plate	2
ventricular zone	2
primordial germ cell in gonad	1
embryo	1
sural nerve	1
trabecular bone tissue	1
hair follicle	1
olfactory bulb	1
type B pancreatic cell	1
endothelial cell	1
bone marrow cell	1
colonic epithelium	1
kidney epithelium	1
metanephros cortex	1
right hemisphere of cerebellum	1
apex of heart	1
cardiac ventricle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NDC1	262	ubiquitous	marker	secondary oocyte, oocyte, primordial germ cell in gonad
SMC1A	289	ubiquitous	marker	sural nerve, trabecular bone tissue, embryo
CCNF	213	ubiquitous	marker	type B pancreatic cell, olfactory bulb, hair follicle
GDAP1	244	ubiquitous	yes	endothelial cell, secondary oocyte, oocyte
TGM6	39	tissue_specific	marker	colonic epithelium, bone marrow cell, kidney epithelium
GBA2	248	ubiquitous	marker	metanephros cortex, right hemisphere of cerebellum, small intestine Peyer’s patch
MED9	195	ubiquitous	marker	apex of heart, heart left ventricle, cardiac ventricle
REEP1	284	broad	marker	dorsal root ganglion, middle temporal gyrus, cortical plate
MED25	269	ubiquitous	marker	oocyte, secondary oocyte, right testis
DYNC1H1	290	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone
GBE1	293	ubiquitous	marker	gluteal muscle, tibialis anterior, biceps brachii
BIVM-ERCC5	108	ubiquitous	yes	male germ line stem cell (sensu Vertebrata) in testis, tonsil, ventricular zone
LMNA	295	ubiquitous	marker	nipple, mucosa of stomach, skin of abdomen
POLG	295	ubiquitous	marker	granulocyte, small intestine Peyer’s patch, tibial nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
LMNA	7,173
CCNF	6,626
SMC1A	5,246
DYNC1H1	4,215
GBE1	3,402
POLG	3,400
MED25	1,883
NDC1	1,815
GBA2	1,709
REEP1	1,295

Structural data

PDB: 10 · AlphaFold-only: 3 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DYNC1H1	Q14204	97
POLG	P54098	36
LMNA	P02545	28
SMC1A	Q14683	18
MED9	Q9NWA0	11
MED25	Q71SY5	10
GDAP1	Q8TB36	8
GBE1	Q04446	3
NDC1	Q9BTX1	2
CCNF	P41002	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TGM6	O95932	90.95
GBA2	Q9HCG7	89.77
REEP1	Q9H902	67.91

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 141. Enrichment computed across 14 evidence-associated genes (12 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 12 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Export of Viral Ribonucleoproteins from Nucleus	1	317.2×	0.037	NDC1
Breakdown of the nuclear lamina	1	317.2×	0.037	LMNA
Glycogen storage disease type IV (GBE1)	1	317.2×	0.037	GBE1
Nuclear Envelope Breakdown	2	76.1×	0.037	NDC1, LMNA
Respiratory Syncytial Virus Infection Pathway	2	32.8×	0.037	MED9, MED25
SUMO E3 ligases SUMOylate target proteins	2	29.7×	0.037	SMC1A, NDC1
SUMOylation	2	27.2×	0.037	SMC1A, NDC1
RSV-host interactions	2	26.1×	0.037	MED9, MED25
Adipogenesis	2	26.1×	0.037	MED9, MED25
SUMOylation of DNA damage response and repair proteins	2	24.4×	0.037	SMC1A, NDC1
Meiotic synapsis	2	23.5×	0.037	SMC1A, LMNA
Regulation of lipid metabolism by PPARalpha	2	23.5×	0.037	MED9, MED25
Transcriptional regulation of white adipocyte differentiation	2	21.6×	0.040	MED9, MED25
Interactions of Rev with host cellular proteins	1	237.9×	0.042	NDC1
Transport of Mature mRNAs Derived from Intronless Transcripts	1	135.9×	0.054	NDC1
Interactions of Vpr with host cellular proteins	1	119.0×	0.054	NDC1
Mitotic Telophase/Cytokinesis	1	119.0×	0.054	SMC1A
Mitotic Metaphase and Anaphase	2	16.1×	0.054	SMC1A, NDC1
Mitotic Anaphase	2	16.1×	0.054	SMC1A, NDC1
PPARA activates gene expression	2	15.7×	0.054	MED9, MED25
Resolution of Sister Chromatid Cohesion	2	14.4×	0.054	SMC1A, DYNC1H1
Viral Infection Pathways	3	7.7×	0.054	MED9, NDC1, MED25
HCMV Early Events	2	13.5×	0.056	NDC1, DYNC1H1
Cohesin Loading onto Chromatin	1	95.2×	0.057	SMC1A
Strand-asynchronous mitochondrial DNA replication	1	95.2×	0.057	POLG
Disease	4	4.4×	0.057	MED9, NDC1, MED25, LMNA
Infectious disease	3	6.2×	0.057	MED9, NDC1, MED25
Establishment of Sister Chromatid Cohesion	1	86.5×	0.058	SMC1A
Mitotic Prometaphase	2	11.5×	0.061	SMC1A, DYNC1H1
Glucose metabolism	1	73.2×	0.062	NDC1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 12 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
nuclear pore localization	2	561.7×	5e-04	NDC1, LMNA
nuclear migration	2	122.1×	0.006	DYNC1H1, LMNA
positive regulation of mediator complex assembly	1	1404.3×	0.014	MED25
positive regulation of transcription elongation by RNA polymerase II	2	50.1×	0.014	MED9, MED25
RNA polymerase II preinitiation complex assembly	2	45.3×	0.014	MED9, MED25
positive regulation of transcription initiation by RNA polymerase II	2	45.3×	0.014	MED9, MED25
response to DNA damage checkpoint signaling	1	702.2×	0.018	SMC1A
re-entry into mitotic cell cycle	1	468.1×	0.018	CCNF
glucosylceramide catabolic process	1	468.1×	0.018	GBA2
DNA replication proofreading	1	468.1×	0.018	POLG
DNA double-strand break attachment to nuclear envelope	1	468.1×	0.018	LMNA
cell division	3	11.5×	0.018	SMC1A, CCNF, DYNC1H1
establishment or maintenance of microtubule cytoskeleton polarity	1	351.1×	0.020	LMNA
establishment of meiotic sister chromatid cohesion	1	351.1×	0.020	SMC1A
negative regulation of centrosome duplication	1	280.9×	0.020	CCNF
regulation of metaphase plate congression	1	280.9×	0.020	DYNC1H1
glycoside catabolic process	1	234.1×	0.020	GBA2
positive regulation of chromatin binding	1	234.1×	0.020	MED25
establishment of spindle localization	1	234.1×	0.020	DYNC1H1
negative regulation of mesenchymal cell proliferation	1	234.1×	0.020	LMNA
regulation of membrane lipid distribution	1	234.1×	0.020	GBA2
establishment of mitotic sister chromatid cohesion	1	200.6×	0.021	SMC1A
nuclear pore organization	1	175.5×	0.021	NDC1
protein insertion into membrane	1	175.5×	0.021	REEP1
protein localization to nuclear envelope	1	175.5×	0.021	LMNA
regulation of protein localization to nucleus	1	175.5×	0.021	LMNA
positive regulation of spindle assembly	1	175.5×	0.021	DYNC1H1
negative regulation of cardiac muscle hypertrophy in response to stress	1	156.0×	0.022	LMNA
positive regulation of intracellular transport	1	140.4×	0.022	DYNC1H1
nuclear pore complex assembly	1	140.4×	0.022	NDC1

Therapeutics

Drugs indicated for this disease

4 approved, 2 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Eplontersen Sodium	Approved (phase 4)
Patisiran Sodium	Approved (phase 4)
Vutrisiran	Approved (phase 4)
Vutrisiran Sodium	Approved (phase 4)
Oxybutynin	Phase 3 (in late-stage trials)
Rituximab	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Levetiracetam, Phenytoin, Ranirestat.

Drug target analysis

Approved (phase 4): 4 · Phase ≥3: 4 · Phased (≥1): 5 · Undrugged: 9

Druggability breadth: 8 of 14 evidence-associated genes (57%) 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
SMC1A	SELUMETINIB
GBA2	MIGLUSTAT
LMNA	BEPRIDIL
POLG	ADEFOVIR DIPIVOXIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
LMNA	823	4
GBA2	6	4
SMC1A	2	4
DYNC1H1	1	2
POLG	1	4
NDC1	0	0
CCNF	0	0
GDAP1	0	0
TGM6	0	0
MED9	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SELUMETINIB	4	SMC1A
MIGLUSTAT	4	GBA2
MIGALASTAT	4	GBA2
BEPRIDIL	4	LMNA
PHENYLBUTAZONE	4	LMNA
CEFOTAXIME SODIUM	4	LMNA
DIENESTROL	4	LMNA
IFOSFAMIDE	4	LMNA
PROGESTERONE	4	LMNA
CLOTRIMAZOLE	4	LMNA
DAPSONE	4	LMNA
AMINOCAPROIC ACID	4	LMNA
FLUCONAZOLE	4	LMNA
COLCHICINE	4	LMNA
NABUMETONE	4	LMNA
OXAPROZIN	4	LMNA
BUMETANIDE	4	LMNA
GLIPIZIDE	4	LMNA
BROMFENAC	4	LMNA
ROPIVACAINE	4	LMNA
TIZANIDINE	4	LMNA
METAXALONE	4	LMNA
CARBAMAZEPINE	4	LMNA
SALMETEROL XINAFOATE	4	LMNA
AMIODARONE HYDROCHLORIDE	4	LMNA
METHYL SALICYLATE	4	LMNA
DIBUCAINE	4	LMNA
PHENELZINE	4	LMNA
HYDROCORTISONE ACETATE	4	LMNA
BRETYLIUM TOSYLATE	4	LMNA

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
GBA2	38	Binding:38
POLG	33	Binding:30, ADMET:2, Functional:1
LMNA	12	Binding:9, Functional:3
SMC1A	10	Binding:10
TGM6	8	Binding:8
DYNC1H1	7	Binding:7
MED25	3	Binding:3
NDC1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TGM6	2.3.2.13	protein-glutamine gamma-glutamyltransferase
GBA2	3.2.1.45	glucosylceramidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 13; 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)
SELUMETINIB	4	SMC1A
MIGLUSTAT	4	GBA2
MIGALASTAT	4	GBA2
BEPRIDIL	4	LMNA
PHENYLBUTAZONE	4	LMNA
CEFOTAXIME SODIUM	4	LMNA
DIENESTROL	4	LMNA
IFOSFAMIDE	4	LMNA
PROGESTERONE	4	LMNA
CLOTRIMAZOLE	4	LMNA
DAPSONE	4	LMNA
AMINOCAPROIC ACID	4	LMNA
FLUCONAZOLE	4	LMNA
COLCHICINE	4	LMNA
NABUMETONE	4	LMNA
OXAPROZIN	4	LMNA
BUMETANIDE	4	LMNA
GLIPIZIDE	4	LMNA
BROMFENAC	4	LMNA
ROPIVACAINE	4	LMNA
TIZANIDINE	4	LMNA
METAXALONE	4	LMNA
CARBAMAZEPINE	4	LMNA
SALMETEROL XINAFOATE	4	LMNA
AMIODARONE HYDROCHLORIDE	4	LMNA
METHYL SALICYLATE	4	LMNA
DIBUCAINE	4	LMNA
PHENELZINE	4	LMNA
HYDROCORTISONE ACETATE	4	LMNA
BRETYLIUM TOSYLATE	4	LMNA

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	SMC1A, GBA2, LMNA, POLG
B	Phased (≥1) drug, not yet approved	1	DYNC1H1
C	Druggable family + PDB, no drug	1	GBE1
D	Druggable family + AlphaFold only, no drug	1	TGM6
E	Difficult family or no structure, no drug	7	NDC1, CCNF, GDAP1, MED9, REEP1, MED25, BIVM-ERCC5

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NDC1	1	—
CCNF	0	—
GDAP1	0	—
TGM6	8	—
MED9	0	—
REEP1	0	—
MED25	3	—
GBE1	0	—
BIVM-ERCC5	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 59.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	38
PHASE4	6
PHASE3	6
PHASE2	6
PHASE1	2
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00162968	PHASE4	COMPLETED	Escitalopram as a Treatment for Pain in Polyneuropathy
NCT00832572	PHASE4	TERMINATED	Study of Ranexa in Patients With Coronary Artery Disease and Painful Polyneuropathy
NCT01047488	PHASE4	UNKNOWN	Imipramine and Pregabalin Combination in Painful Polyneuropathy
NCT01076478	PHASE4	COMPLETED	Asian Study on Cilostazol Effectivity in Neuropathies of Diabetes Mellitus Type 2-A Pilot Study in the Philippines
NCT01302275	PHASE4	COMPLETED	Oxcarbazepine for the Treatment of Chronic Peripheral Neuropathic Pain
NCT02033057	PHASE4	UNKNOWN	Muscular Electrostimulation of the Sedated and Mechanically Ventilated Critically Ill Patient. Analysis of the Effect on Acquired Muscular Weakness and Its Clinical Consequences.
NCT06563895	PHASE3	RECRUITING	Acoramidis Transthyretin Amyloidosis Prevention Trial in the Young (ACT-EARLY) Study in Asymptomatic Carriers of a Pathogenic TTR Variant
NCT06672237	PHASE3	RECRUITING	A Phase 3 Study of NTLA-2001 in ATTRv-PN
NCT07116473	PHASE3	NOT_YET_RECRUITING	To Evaluate the Long-term Safety and Tolerability of Acoramidis in Participants With Newly Diagnosed ATTR-CM (ACT-EARLY OLE)
NCT00259974	PHASE3	COMPLETED	RIMAG Study: Trial of Rituximab Versus Placebo in Polyneuropathy Associated With Anti-MAG IgM Monoclonal Gammopathy
NCT01263132	PHASE3	COMPLETED	Neuropathic Pain Management
NCT01450163	PHASE3	COMPLETED	Evaluate The Efficacy and Safety Of Pregabalin In Prevention, Reduction of Oxaliplatin-Induced Painful Neuropathy
NCT00050245	PHASE2	COMPLETED	Rituximab to Treat Neuropathy With Anti-MAG Antibodies
NCT00082316	PHASE2	COMPLETED	Tolerability of Three Local Anesthetic Formulations in Conjunction With NGX-4010 for the Treatment of Neuropathic Pain
NCT00089557	PHASE2	TERMINATED	An Open-Label Extension Study of NGX-4010 for the Treatment of Neuropathic Pain
NCT00231673	PHASE2	COMPLETED	A Study To Evaluate The Effect Of Topiramate On Clinical And Electrophysiological Parameters In Subjects With Diabetic Peripheral Polyneuropathy
NCT00723918	PHASE2	WITHDRAWN	Combination of an Investigational Cannabinoid and Methadone for HIV-associated Neuropathy
NCT01088256	PHASE2	TERMINATED	Efficacy of Etoricoxib on Peripheral Hyperalgesia
NCT00614562	PHASE1	COMPLETED	Neurally Adjusted Ventilatory Assist (NAVA) in Patients With Critical Illness Associated Polyneuropathy / or Polymyopathy (CIP/M)
NCT01867645	PHASE1	TERMINATED	The Impact of IVIG Treatment on Critical Illness Polyneuropathy and/or Myopathy in Patients With MOF and SIRS/Sepsis
NCT05023889	EARLY_PHASE1	COMPLETED	Spectrum of Peripheral and Autonomic Neuropathies in Patients With aTTRwt Amyloidosis and Response to Patisiran Therapy
NCT03862365	Not specified	RECRUITING	Exploring the Genetics of Neuropathic Pain
NCT05040373	Not specified	RECRUITING	Patisiran-Lipid Nanoparticle (LNP) Pregnancy Surveillance Program
NCT05950867	Not specified	RECRUITING	Prevalence of Wild-type TTR Cardiac Amyloidosis in Patients With Polyneuropathy of Unknown Cause.
NCT06040567	Not specified	RECRUITING	Polyneuropathy, Impairments and Physical Activity - The PolyImPAct Study
NCT06044662	Not specified	RECRUITING	Prognostic Value of Biomarkers in Polyneuropathy.
NCT06377033	Not specified	RECRUITING	Using the EHR to Advance Genomic Medicine Across a Diverse Health System
NCT06390527	Not specified	NOT_YET_RECRUITING	Ultrasonography in Diagnosis of Polyneuropathy
NCT06745011	Not specified	ENROLLING_BY_INVITATION	Prodromal Model of Parkinson’s Disease Confined to The Peripheral Nervous System
NCT06754995	Not specified	RECRUITING	Diagnostic Feasibility of 100 Hz Tetanic Stimulation
NCT06904989	Not specified	RECRUITING	A New Cancer Rehabilitation Process for Chemotherapy-Induced Foot Neuropathy Using Orthopedic Devices
NCT07152197	Not specified	RECRUITING	Effects of Resistance Exercises in Hereditary Sensory-Motor Neuropathy (Charcot-Marie-Tooth Disease)
NCT07166302	Not specified	RECRUITING	Ultrasound Evaluation of Hematoma Risk After Needle EMG in Patient on DOAC Therapy
NCT07515989	Not specified	RECRUITING	Accuracy of the Polymerase Chain Reaction of Ulnar Perineural Subcutaneous Aspirate Guided by Ultrasound for the Diagnosis and Monitoring of Leprosy Cure
NCT01370837	Not specified	COMPLETED	Neurogenic Inflammation in Diabetes
NCT01718015	Not specified	UNKNOWN	Neurotrophic Factors in Cerebrospinal Fluid in Diabetic Patients With Polyneuropathy
NCT02061059	Not specified	UNKNOWN	Cost-effectiveness of In-shoe Pressure Measurement for Therapeutic Shoes
NCT02124616	Not specified	UNKNOWN	National Registry for Egyptian Pediatric Neuromuscular Diseases
NCT02442986	Not specified	COMPLETED	Neurological Outcome in Surgical and Non-surgical Septic Patients
NCT02566941	Not specified	WITHDRAWN	Neuromuscular Electrical Stimulation in the Critically Ill

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ACORAMIDIS	4	2
IMIPRAMINE	4	2
CILOSTAZOL	4	1
ESCITALOPRAM	4	1
ETORICOXIB	4	1
OXALIPLATIN	4	1
OXCARBAZEPINE	4	1
PREGABALIN	4	1
RANOLAZINE	4	1
TAFAMIDIS	4	1
PATISIRAN	3	2
NEXIGURAN	2	1
ZICLUMERAN	2	1
CHEMBL454299	0	1