ALS2-related motor neuron disease

Summary

ALS2-related motor neuron disease (MONDO:0100227) is a disease caused by ALS2 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: ALS2 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 8

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	ALS2-related motor neuron disease
Mondo ID	MONDO:0100227
GARD	0026088
Is cancer (heuristic)	no

Also known as: Alsin-related motor neuron disease

Data availability: 8 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › neurodegenerative disease › motor neuron disorder › hereditary motor neuron disease › ALS2-related motor neuron disease

Related subtypes (8): prenatal-onset spinal muscular atrophy with congenital bone fractures, spinal muscular atrophy, familial amyotrophic lateral sclerosis, neurogenic scapuloperoneal syndrome, Kaeser type, riboflavin transporter deficiency, motor neuron disease with dementia and ophthalmoplegia, lateral sclerosis, distal hereditary motor neuropathy

Subtypes (3): amyotrophic lateral sclerosis type 2, juvenile, juvenile primary lateral sclerosis, infantile-onset ascending hereditary spastic paralysis

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

8 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 3 conflicting classifications of pathogenicity, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2690510	NM_020919.4(ALS2):c.3047dup (p.Tyr1017fs)	ALS2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
333593	NM_020919.4(ALS2):c.2909G>T (p.Gly970Val)	ALS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
533752	NM_020919.4(ALS2):c.331G>A (p.Val111Ile)	ALS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
896447	NM_020919.4(ALS2):c.3983G>A (p.Ser1328Asn)	ALS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1718405	NM_020919.4(ALS2):c.2539T>C (p.Tyr847His)	ALS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
333594	NM_020919.4(ALS2):c.2712G>A (p.Thr904=)	ALS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3779423	NM_020919.4(ALS2):c.1382G>A (p.Gly461Glu)	ALS2	Uncertain significance	criteria provided, single submitter
813696	NM_020919.4(ALS2):c.4871T>C (p.Ile1624Thr)	ALS2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 3 · 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
ALS2	Definitive	Autosomal recessive	ALS2-related motor neuron disease	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ALS2	Orphanet:247604	Juvenile primary lateral sclerosis
ALS2	Orphanet:293168	Infantile-onset ascending hereditary spastic paralysis
ALS2	Orphanet:300605	Juvenile amyotrophic lateral sclerosis

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
ALS2	HGNC:443	ENSG00000003393	Q96Q42	Alsin	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ALS2	Alsin	May act as a GTPase regulator.

Protein-family classification

Druggable: 0 · Difficult: 0 · 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
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ALS2	Other/Unknown	no		DH_dom, Reg_chr_condens, VPS9

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
cerebellar cortex	1
cerebellar hemisphere	1
cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ALS2	254	ubiquitous	marker	cerebellum, cerebellar cortex, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALS2	2,652

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ALS2	Q96Q42	74.69

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. 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
Rab regulation of trafficking	1	368.4×	0.024	ALS2
RAB GEFs exchange GTP for GDP on RABs	1	124.1×	0.034	ALS2
RAC1 GTPase cycle	1	61.1×	0.034	ALS2
RHO GTPase cycle	1	60.1×	0.034	ALS2
Membrane Trafficking	1	37.1×	0.034	ALS2
Vesicle-mediated transport	1	34.8×	0.034	ALS2
Signaling by Rho GTPases	1	34.2×	0.034	ALS2
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	33.5×	0.034	ALS2
Signal Transduction	1	10.2×	0.098	ALS2

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
regulation of endosome size	1	1532.0×	0.005	ALS2
receptor recycling	1	1296.3×	0.005	ALS2
lysosomal transport	1	702.2×	0.005	ALS2
positive regulation of protein kinase activity	1	674.1×	0.005	ALS2
positive regulation of Rac protein signal transduction	1	648.1×	0.005	ALS2
neuromuscular junction development	1	526.6×	0.005	ALS2
regulation of postsynaptic membrane neurotransmitter receptor levels	1	495.6×	0.005	ALS2
behavioral fear response	1	432.1×	0.005	ALS2
endosome organization	1	374.5×	0.005	ALS2
synaptic transmission, glutamatergic	1	358.6×	0.005	ALS2
positive regulation of GTPase activity	1	276.3×	0.005	ALS2
neuron projection morphogenesis	1	276.3×	0.005	ALS2
endosomal transport	1	244.2×	0.005	ALS2
locomotory behavior	1	179.3×	0.007	ALS2
response to oxidative stress	1	130.6×	0.009	ALS2
protein homooligomerization	1	122.1×	0.009	ALS2
intracellular protein localization	1	104.7×	0.010	ALS2

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
ALS2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ALS2

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)
ALS2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.