Neuronopathy, distal hereditary motor, autosomal recessive 4

Summary

Neuronopathy, distal hereditary motor, autosomal recessive 4 (MONDO:0012608) is a disease caused by PLEKHG5 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PLEKHG5 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 1,271

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		5	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	neuronopathy, distal hereditary motor, autosomal recessive 4
Mondo ID	MONDO:0012608
MeSH	C567023
OMIM	611067
Orphanet	206580
DOID	DOID:0111213
UMLS	C1970211
MedGen	369682
GARD	0017101
Is cancer (heuristic)	no

Also known as: autosomal recessive distal spinal muscular atrophy type 4 · autosomal recessive lower motor neuron disease with childhood onset · distal spinal muscular atrophy type 4 · DSMA4 · dSMA4 · neuronopathy, distal hereditary motor, autosomal recessive 4 · spinal muscular atrophy, distal, autosomal recessive, 4 · spinal muscular atrophy, distal, autosomal recessive, type 4

Data availability: 1,271 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › spinal cord disorder › anterior horn disorder › spinal muscular atrophy › neuronopathy, distal hereditary motor, autosomal recessive 4

Related subtypes (18): spinal muscular atrophy-progressive myoclonic epilepsy syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, spinal muscular atrophy, facioscapulohumeral type, adult-onset proximal spinal muscular atrophy, autosomal dominant, spinal muscular atrophy, segmental, spinal muscular atrophy, Ryukyuan type, scapuloperoneal spinal muscular atrophy, autosomal recessive, X-linked distal spinal muscular atrophy type 3, infantile-onset X-linked spinal muscular atrophy, autosomal recessive distal spinal muscular atrophy 1, autosomal recessive distal spinal muscular atrophy 2, neuronopathy, distal hereditary motor, autosomal recessive 3, neuronopathy, distal hereditary motor, autosomal recessive 5, neuronopathy, distal hereditary motor, autosomal dominant, bulbospinal muscular atrophy, spinal muscular atrophy with respiratory distress type 2, proximal spinal muscular atrophy, spinal muscular atrophy type 0

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

600 retrieved; paginated sample, class counts are floors:

317 likely benign, 211 uncertain significance, 23 conflicting classifications of pathogenicity, 20 benign, 14 pathogenic, 6 benign/likely benign, 5 pathogenic/likely pathogenic, 4 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1069212	NM_020631.6(PLEKHG5):c.909C>A (p.Tyr303Ter)	PLEKHG5	Pathogenic	criteria provided, single submitter
1073676	NM_020631.6(PLEKHG5):c.2149G>T (p.Glu717Ter)	PLEKHG5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1146824	NM_020631.6(PLEKHG5):c.2162_2163insTGAGCAGGAGGAGGAAGAGGAGGAGGAGGAGGAG (p.Glu721fs)	PLEKHG5	Pathogenic	criteria provided, single submitter
1163123	NM_020631.6(PLEKHG5):c.1738G>T (p.Glu580Ter)	PLEKHG5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1416561	NM_020631.6(PLEKHG5):c.386del (p.Leu129fs)	PLEKHG5	Pathogenic	criteria provided, single submitter
1424950	NM_020631.6(PLEKHG5):c.1457_1482del (p.Gln486fs)	PLEKHG5	Pathogenic	criteria provided, single submitter
1453868	NM_020631.6(PLEKHG5):c.2074_2075del (p.Gln692fs)	PLEKHG5	Pathogenic	criteria provided, single submitter
1454196	NM_020631.6(PLEKHG5):c.1289C>A (p.Ser430Ter)	PLEKHG5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1788740	NM_020631.6(PLEKHG5):c.2269G>T (p.Glu757Ter)	PLEKHG5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1796001	NM_020631.6(PLEKHG5):c.2788C>T (p.Arg930Ter)	PLEKHG5	Pathogenic	criteria provided, multiple submitters, no conflicts
1909611	NM_020631.6(PLEKHG5):c.2902del (p.Val968fs)	PLEKHG5	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1999132	NM_020631.6(PLEKHG5):c.1128T>A (p.Cys376Ter)	PLEKHG5	Pathogenic	criteria provided, single submitter
2033307	NM_020631.6(PLEKHG5):c.363C>A (p.Tyr121Ter)	PLEKHG5	Pathogenic	criteria provided, single submitter
2035800	NM_020631.6(PLEKHG5):c.365_378del (p.Leu122fs)	PLEKHG5	Pathogenic	criteria provided, single submitter
2065924	NM_020631.6(PLEKHG5):c.2540del (p.Pro847fs)	PLEKHG5	Pathogenic	criteria provided, single submitter
2135331	NM_020631.6(PLEKHG5):c.1258del (p.Asp420fs)	PLEKHG5	Pathogenic	criteria provided, single submitter
2921807	NM_020631.6(PLEKHG5):c.2665del (p.Ala889fs)	PLEKHG5	Pathogenic	criteria provided, single submitter
2925088	NM_020631.6(PLEKHG5):c.2158G>T (p.Glu720Ter)	PLEKHG5	Pathogenic	criteria provided, single submitter
2932016	NM_020631.6(PLEKHG5):c.2945del (p.Lys982fs)	PLEKHG5	Pathogenic	criteria provided, single submitter
1490708	NM_020631.6(PLEKHG5):c.1132-1G>T	PLEKHG5	Likely pathogenic	criteria provided, single submitter
1691304	NM_001042663.3(PLEKHG5):c.22_23insGGCC (p.Lys8fs)	PLEKHG5	Likely pathogenic	criteria provided, single submitter
1722449	NM_020631.6(PLEKHG5):c.2503_2510del (p.Pro835fs)	PLEKHG5	Likely pathogenic	criteria provided, single submitter
1967038	NM_020631.6(PLEKHG5):c.1934-2A>C	PLEKHG5	Likely pathogenic	criteria provided, single submitter
1019	NM_020631.6(PLEKHG5):c.1940T>C (p.Phe647Ser)	PLEKHG5	Conflicting classifications of pathogenicity	no assertion criteria provided
1028662	NM_020631.6(PLEKHG5):c.1393-16C>G	PLEKHG5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1080853	NM_020631.6(PLEKHG5):c.1393-5C>T	PLEKHG5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1160373	NM_020631.6(PLEKHG5):c.1543-5C>T	PLEKHG5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1308498	NM_020631.6(PLEKHG5):c.1393-10C>A	PLEKHG5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1398214	NM_020631.6(PLEKHG5):c.1874G>A (p.Arg625Lys)	PLEKHG5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1403245	NM_020631.6(PLEKHG5):c.784G>A (p.Ala262Thr)	PLEKHG5	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
PLEKHG5	Strong	Autosomal recessive	neuronopathy, distal hereditary motor, autosomal recessive 4	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PLEKHG5	Orphanet:206580	Autosomal recessive lower motor neuron disease with childhood onset
PLEKHG5	Orphanet:369867	Autosomal recessive intermediate Charcot-Marie-Tooth disease type C

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PLEKHG5	HGNC:29105	ENSG00000171680	O94827	Pleckstrin homology domain-containing family G member 5	gencc,clinvar
TNFRSF25	HGNC:11910	ENSG00000215788	Q93038	Tumor necrosis factor receptor superfamily member 25	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
TNFRSF25	Tumor necrosis factor receptor superfamily member 25	Receptor for TNFSF12/APO3L/TWEAK.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.0

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
Scaffold/PPI	1	8.6×	0.225
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PLEKHG5	Scaffold/PPI	no		DH_dom, PH_domain, PH-like_dom_sf
TNFRSF25	Other/Unknown	no		Death_dom, TNFR/NGFR_Cys_rich_reg, DEATH-like_dom_sf

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar hemisphere	2
right hemisphere of cerebellum	2
sural nerve	1
cerebellar cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PLEKHG5	175	ubiquitous	yes	sural nerve, right hemisphere of cerebellum, cerebellar hemisphere
TNFRSF25	205	broad	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PLEKHG5	966
TNFRSF25	21

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TNFRSF25	Q93038	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PLEKHG5	O94827	64.94

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TNFs bind their physiological receptors	1	196.9×	0.015	TNFRSF25
RND1 GTPase cycle	1	132.8×	0.015	PLEKHG5
RND3 GTPase cycle	1	129.8×	0.015	PLEKHG5
NRAGE signals death through JNK	1	92.1×	0.016	PLEKHG5
G alpha (12/13) signalling events	1	68.8×	0.017	PLEKHG5
RHOA GTPase cycle	1	37.3×	0.027	PLEKHG5

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
endothelial cell chemotaxis	1	842.6×	0.012	PLEKHG5
endothelial cell migration	1	205.5×	0.022	PLEKHG5
Rho protein signal transduction	1	123.9×	0.022	PLEKHG5
apoptotic signaling pathway	1	112.3×	0.022	TNFRSF25
regulation of small GTPase mediated signal transduction	1	72.0×	0.028	PLEKHG5
regulation of apoptotic process	1	41.7×	0.039	TNFRSF25
positive regulation of canonical NF-kappaB signal transduction	1	36.3×	0.039	PLEKHG5
cell surface receptor signaling pathway	1	32.0×	0.039	TNFRSF25
apoptotic process	1	14.3×	0.076	TNFRSF25
signal transduction	1	8.0×	0.121	TNFRSF25

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PLEKHG5	0	0
TNFRSF25	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	PLEKHG5, TNFRSF25

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PLEKHG5	0	—
TNFRSF25	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.