Amyotrophic lateral sclerosis type 15

disease

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Also known as ALS15amyotrophic lateral sclerosis 15 with or without frontotemporal dementiaamyotrophic lateral sclerosis 15, with or without frontotemporal dementia, X-linked dominantamyotrophic lateral sclerosis caused by mutation in UBQLN2UBQLN2 amyotrophic lateral sclerosis

Summary

Amyotrophic lateral sclerosis type 15 (MONDO:0010459) is a disease caused by UBQLN2 (GenCC Definitive), with 1 cohort gene.

At a glance

Causal gene: UBQLN2 (GenCC Definitive)
Cohort genes: 1
ClinVar variants: 195

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	amyotrophic lateral sclerosis type 15
Mondo ID	MONDO:0010459
OMIM	300857
DOID	DOID:0060206
UMLS	C3275459
MedGen	477090
GARD	0015269
Is cancer (heuristic)	no

Also known as: ALS15 · amyotrophic lateral sclerosis 15 with or without frontotemporal dementia · amyotrophic lateral sclerosis 15, with or without frontotemporal dementia, X-linked dominant · amyotrophic lateral sclerosis caused by mutation in UBQLN2 · amyotrophic lateral sclerosis type 15 · UBQLN2 amyotrophic lateral sclerosis

Data availability: 195 ClinVar variants · 4 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 › amyotrophic lateral sclerosis › familial amyotrophic lateral sclerosis › amyotrophic lateral sclerosis type 15

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

195 retrieved; paginated sample, class counts are floors:

125 uncertain significance, 38 likely benign, 14 conflicting classifications of pathogenicity, 8 benign, 5 benign/likely benign, 3 pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
29950	NM_013444.4(UBQLN2):c.1490C>A (p.Pro497His)	UBQLN2	Pathogenic	criteria provided, multiple submitters, no conflicts
29951	NM_013444.4(UBQLN2):c.1489C>T (p.Pro497Ser)	UBQLN2	Pathogenic	criteria provided, single submitter
29952	NM_013444.4(UBQLN2):c.1516C>A (p.Pro506Thr)	UBQLN2	Pathogenic	criteria provided, single submitter
157594	NM_013444.4(UBQLN2):c.1490C>T (p.Pro497Leu)	UBQLN2	Likely pathogenic	criteria provided, single submitter
3336842	NM_013444.4(UBQLN2):c.1663C>T (p.Pro555Ser)	UBQLN2	Likely pathogenic	criteria provided, single submitter
1178345	NM_013444.4(UBQLN2):c.724G>A (p.Ala242Thr)	LOC130068340	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1607950	NM_013444.4(UBQLN2):c.1019G>T (p.Ser340Ile)	UBQLN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1940920	NM_013444.4(UBQLN2):c.359G>C (p.Gly120Ala)	UBQLN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2152427	NM_013444.4(UBQLN2):c.327G>C (p.Gln109His)	UBQLN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2286700	NM_013444.4(UBQLN2):c.1043A>G (p.Asn348Ser)	UBQLN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
260311	NM_013444.4(UBQLN2):c.1461C>A (p.Thr487=)	UBQLN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2660710	NM_013444.4(UBQLN2):c.1596C>T (p.Gly532=)	UBQLN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2914332	NM_013444.4(UBQLN2):c.1318C>T (p.Pro440Ser)	UBQLN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
29954	NM_013444.4(UBQLN2):c.1573C>T (p.Pro525Ser)	UBQLN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3046320	NM_013444.4(UBQLN2):c.141G>A (p.Ala47=)	UBQLN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3647648	NM_013444.4(UBQLN2):c.1640C>T (p.Thr547Met)	UBQLN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
368607	NM_013444.4(UBQLN2):c.243A>G (p.Leu81=)	UBQLN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
752102	NM_013444.4(UBQLN2):c.1715C>T (p.Ala572Val)	UBQLN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
873224	NM_013444.4(UBQLN2):c.1516C>T (p.Pro506Ser)	UBQLN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2170914	NM_013444.4(UBQLN2):c.648G>T (p.Gln216His)	LOC130068339	Uncertain significance	criteria provided, single submitter
2828655	NM_013444.4(UBQLN2):c.645T>G (p.Ile215Met)	LOC130068339	Uncertain significance	criteria provided, single submitter
3658475	NM_013444.4(UBQLN2):c.519G>C (p.Gln173His)	LOC130068339	Uncertain significance	criteria provided, single submitter
4682331	NM_013444.4(UBQLN2):c.492C>T (p.Phe164=)	LOC130068339	Uncertain significance	criteria provided, multiple submitters, no conflicts
4753367	NM_013444.4(UBQLN2):c.705C>T (p.Leu235=)	LOC130068340	Uncertain significance	criteria provided, single submitter
1016959	NM_013444.4(UBQLN2):c.1727C>A (p.Pro576Gln)	UBQLN2	Uncertain significance	criteria provided, single submitter
1303196	NM_013444.4(UBQLN2):c.1037C>G (p.Ser346Cys)	UBQLN2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1310943	NM_013444.4(UBQLN2):c.278A>G (p.His93Arg)	UBQLN2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1357319	NM_013444.4(UBQLN2):c.1279C>G (p.Arg427Gly)	UBQLN2	Uncertain significance	criteria provided, single submitter
1368686	NM_013444.4(UBQLN2):c.1013C>T (p.Thr338Ile)	UBQLN2	Uncertain significance	criteria provided, single submitter
1385910	NM_013444.4(UBQLN2):c.857A>G (p.Gln286Arg)	UBQLN2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
UBQLN2	Definitive	X-linked	amyotrophic lateral sclerosis type 15	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
UBQLN2	Orphanet:803	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
UBQLN2	HGNC:12509	ENSG00000188021	Q9UHD9	Ubiquilin-2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
UBQLN2	Ubiquilin-2	Plays an important role in the regulation of different protein degradation mechanisms and pathways including ubiquitin-proteasome system (UPS), autophagy and the endoplasmic reticulum-associated protein degradation (ERAD) pathway.

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)
UBQLN2	Other/Unknown	no		Ubiquitin-like_dom, STI1_HS-bd, UBA-like_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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar vermis	1
pons	1
postcentral gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
UBQLN2	295	ubiquitous	marker	cerebellar vermis, pons, postcentral gyrus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
UBQLN2	6,872

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
UBQLN2	Q9UHD9	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Cargo recognition for clathrin-mediated endocytosis	1	104.8×	0.010	UBQLN2

GO biological processes by enrichment

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of G protein-coupled receptor internalization	1	8426.0×	9e-04	UBQLN2
negative regulation of clathrin-dependent endocytosis	1	4213.0×	9e-04	UBQLN2
regulation of autophagosome assembly	1	1123.5×	0.002	UBQLN2
positive regulation of ERAD pathway	1	887.0×	0.002	UBQLN2
regulation of macroautophagy	1	295.6×	0.005	UBQLN2
autophagosome assembly	1	224.7×	0.006	UBQLN2
ERAD pathway	1	181.2×	0.006	UBQLN2
ubiquitin-dependent protein catabolic process	1	74.2×	0.013	UBQLN2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
UBQLN2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
UBQLN2	1	Binding:1

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	UBQLN2

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)
UBQLN2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: UBQLN2