Amyotrophic lateral sclerosis type 2, juvenile

Summary

Amyotrophic lateral sclerosis type 2, juvenile (MONDO:0008780) is a disease caused by ALS2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: ALS2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 147

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	amyotrophic lateral sclerosis type 2, juvenile
Mondo ID	MONDO:0008780
MeSH	C565957
OMIM	205100
DOID	DOID:0060194
UMLS	C1859807
MedGen	349246
GARD	0015137
Is cancer (heuristic)	no

Also known as: ALS2 · ALS2 amyotrophic lateral sclerosis · amyotrophic lateral sclerosis 2, juvenile · amyotrophic lateral sclerosis caused by mutation in ALS2

Data availability: 147 ClinVar variants · 1 GenCC gene-disease record.

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 › amyotrophic lateral sclerosis › familial amyotrophic lateral sclerosis › juvenile amyotrophic lateral sclerosis › amyotrophic lateral sclerosis type 2, juvenile

Related subtypes (3): juvenile amyotrophic lateral sclerosis with dementia, amyotrophic lateral sclerosis type 5, amyotrophic lateral sclerosis type 16

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

147 retrieved; paginated sample, class counts are floors:

61 uncertain significance, 27 conflicting classifications of pathogenicity, 19 benign, 11 likely pathogenic, 10 pathogenic, 8 benign/likely benign, 6 pathogenic/likely pathogenic, 5 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
100653	NM_020919.4(ALS2):c.2761C>T (p.Arg921Ter)	ALS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1184930	NM_020919.4(ALS2):c.4626+1G>A	ALS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1678521	NM_020919.4(ALS2):c.4223T>A (p.Leu1408Ter)	ALS2	Pathogenic	criteria provided, single submitter
1678522	NM_020919.4(ALS2):c.2707dup (p.Met903fs)	ALS2	Pathogenic	criteria provided, single submitter
1693002	NM_020919.4(ALS2):c.2580+2T>C	ALS2	Pathogenic	criteria provided, multiple submitters, no conflicts
183239	NM_020919.4(ALS2):c.2002G>T (p.Gly668Ter)	ALS2	Pathogenic	no assertion criteria provided
183240	NM_020919.4(ALS2):c.4573dup (p.Val1525fs)	ALS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3359053	NM_020919.4(ALS2):c.1250C>G (p.Ser417Ter)	ALS2	Pathogenic	criteria provided, single submitter
393199	NM_020919.4(ALS2):c.3415C>T (p.Arg1139Ter)	ALS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
425255	NM_020919.4(ALS2):c.3158G>A (p.Trp1053Ter)	ALS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4405	NM_020919.4(ALS2):c.138del (p.Ala47fs)	ALS2	Pathogenic	no assertion criteria provided
4414	NM_020919.4(ALS2):c.553del (p.Thr185fs)	ALS2	Pathogenic	criteria provided, single submitter
533743	NM_020919.4(ALS2):c.1233T>G (p.Tyr411Ter)	ALS2	Pathogenic	criteria provided, multiple submitters, no conflicts
645923	NM_020919.4(ALS2):c.3520A>T (p.Lys1174Ter)	ALS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
804392	NM_020919.4(ALS2):c.601C>T (p.Arg201Ter)	ALS2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
873268	NM_020919.4(ALS2):c.4381C>T (p.Arg1461Ter)	ALS2	Pathogenic	criteria provided, multiple submitters, no conflicts
1339519	NM_020919.4(ALS2):c.1649C>T (p.Pro550Leu)	ALS2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1895403	NM_020919.4(ALS2):c.1321_1327del (p.Ile441fs)	ALS2	Likely pathogenic	criteria provided, single submitter
242457	NM_020919.4(ALS2):c.4261C>T (p.Arg1421Ter)	ALS2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2441678	NM_020919.4(ALS2):c.4064del (p.Gln1355fs)	ALS2	Likely pathogenic	criteria provided, single submitter
2444046	NM_020919.4(ALS2):c.3893del (p.Asp1298fs)	ALS2	Likely pathogenic	criteria provided, single submitter
2444376	NM_020919.4(ALS2):c.2168dup (p.Leu723fs)	ALS2	Likely pathogenic	criteria provided, single submitter
4278025	NM_020919.4(ALS2):c.3686G>A (p.Trp1229Ter)	ALS2	Likely pathogenic	criteria provided, single submitter
694319	NM_020919.4(ALS2):c.1718C>A (p.Ala573Glu)	ALS2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
804391	NM_020919.4(ALS2):c.2104G>T (p.Glu702Ter)	ALS2	Likely pathogenic	criteria provided, single submitter
873269	NM_020919.4(ALS2):c.4808C>T (p.Pro1603Leu)	ALS2	Likely pathogenic	criteria provided, single submitter
973527	NM_020919.4(ALS2):c.4753_4754dup (p.Ser1585fs)	ALS2	Likely pathogenic	criteria provided, single submitter
241307	NM_020919.4(ALS2):c.1115C>G (p.Pro372Arg)	ALS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
241310	NM_020919.4(ALS2):c.2241C>T (p.Tyr747=)	ALS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
261366	NM_020919.4(ALS2):c.1816-8C>T	ALS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

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	Strong	Autosomal recessive	amyotrophic lateral sclerosis type 2, juvenile	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.