Amyotrophic lateral sclerosis type 8

Summary

Amyotrophic lateral sclerosis type 8 (MONDO:0012077) is a disease caused by VAPB (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: VAPB (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 359

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	amyotrophic lateral sclerosis type 8
Mondo ID	MONDO:0012077
MeSH	C563895
OMIM	608627
DOID	DOID:0050752
UMLS	C1837728
MedGen	325237
GARD	0010499
Is cancer (heuristic)	no

Also known as: ALS8 · amyotrophic lateral sclerosis 8 · amyotrophic lateral sclerosis caused by mutation in VAPB · amyotrophic lateral sclerosis type 8 · VAPB amyotrophic lateral sclerosis

Data availability: 359 ClinVar variants · 2 GenCC gene-disease records · 7 cell lines.

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 8

Related subtypes (29): amyotrophic lateral sclerosis type 1, frontotemporal dementia and/or amyotrophic lateral sclerosis 1, spinocerebellar ataxia type 2, amyotrophic lateral sclerosis type 15, frontotemporal dementia and/or amyotrophic lateral sclerosis 7, amyotrophic lateral sclerosis type 4, amyotrophic lateral sclerosis type 21, amyotrophic lateral sclerosis type 3, amyotrophic lateral sclerosis type 6, amyotrophic lateral sclerosis type 7, amyotrophic lateral sclerosis type 9, amyotrophic lateral sclerosis type 10, amyotrophic lateral sclerosis type 11, amyotrophic lateral sclerosis type 12, frontotemporal dementia and/or amyotrophic lateral sclerosis 6, amyotrophic lateral sclerosis type 18, amyotrophic lateral sclerosis type 20, amyotrophic lateral sclerosis type 19, frontotemporal dementia and/or amyotrophic lateral sclerosis 2, amyotrophic lateral sclerosis type 22, frontotemporal dementia and/or amyotrophic lateral sclerosis 3, frontotemporal dementia and/or amyotrophic lateral sclerosis 4, juvenile amyotrophic lateral sclerosis, amyotrophic lateral sclerosis type 23, frontotemporal dementia and/or amyotrophic lateral sclerosis 8, frontotemporal dementia and/or amyotrophic lateral sclerosis 5, amyotrophic lateral sclerosis 26 with or without frontotemporal dementia, amyotrophic lateral sclerosis 27, juvenile, amyotrophic lateral sclerosis 28

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

359 retrieved; paginated sample, class counts are floors:

205 uncertain significance, 83 likely benign, 39 benign, 16 benign/likely benign, 14 conflicting classifications of pathogenicity, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
30510	NM_004738.5(VAPB):c.137C>T (p.Thr46Ile)	VAPB	Pathogenic	no assertion criteria provided
4806	NM_004738.5(VAPB):c.166C>T (p.Pro56Ser)	VAPB	Pathogenic	criteria provided, multiple submitters, no conflicts
1143372	NM_004738.5(VAPB):c.486T>A (p.Asp162Glu)	VAPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1386746	NM_004738.5(VAPB):c.550C>T (p.Arg184Trp)	VAPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1756676	NM_004738.5(VAPB):c.700G>A (p.Val234Ile)	VAPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
191163	NM_004738.5(VAPB):c.656G>T (p.Gly219Val)	VAPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338929	NM_004738.5(VAPB):c.30C>T (p.Leu10=)	VAPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338930	NM_004738.5(VAPB):c.332C>T (p.Pro111Leu)	VAPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338931	NM_004738.5(VAPB):c.476CTT[1] (p.Ser160del)	VAPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338932	NM_004738.5(VAPB):c.574-4G>A	VAPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
338933	NM_004738.5(VAPB):c.618C>T (p.Ser206=)	VAPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
339001	NM_004738.5(VAPB):c.*5095T>G	VAPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
448852	NM_004738.5(VAPB):c.551G>A (p.Arg184Gln)	VAPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
448853	NM_004738.5(VAPB):c.667C>T (p.Arg223Trp)	VAPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
574276	NM_004738.5(VAPB):c.58+5G>A	VAPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
951278	NM_004738.5(VAPB):c.315A>G (p.Val105=)	VAPB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3248275	NC_000020.10:g.(?56993257)(57967907_?)dup	APCDD1L	Uncertain significance	criteria provided, single submitter
338919	NM_004738.4(VAPB):c.-283A>C	LOC130066253	Uncertain significance	criteria provided, single submitter
338922	NM_004738.5(VAPB):c.-189C>T	LOC130066253	Uncertain significance	criteria provided, single submitter
338926	NM_004738.5(VAPB):c.-152C>A	LOC130066253	Uncertain significance	criteria provided, single submitter
897764	NM_004738.4(VAPB):c.-349G>T	LOC130066253	Uncertain significance	criteria provided, single submitter
1009230	NM_004738.5(VAPB):c.421A>G (p.Ile141Val)	VAPB	Uncertain significance	criteria provided, single submitter
1015007	NM_004738.5(VAPB):c.35C>T (p.Pro12Leu)	VAPB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1042871	NM_004738.5(VAPB):c.635C>A (p.Ala212Asp)	VAPB	Uncertain significance	criteria provided, single submitter
1044550	NM_004738.5(VAPB):c.518G>A (p.Cys173Tyr)	VAPB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1047783	NM_004738.5(VAPB):c.622A>G (p.Ile208Val)	VAPB	Uncertain significance	criteria provided, single submitter
1050243	NM_004738.5(VAPB):c.535G>A (p.Glu179Lys)	VAPB	Uncertain significance	criteria provided, multiple submitters, no conflicts
1051716	NM_004738.5(VAPB):c.677C>T (p.Ala226Val)	VAPB	Uncertain significance	criteria provided, single submitter
1055705	NM_004738.5(VAPB):c.246G>C (p.Glu82Asp)	VAPB	Uncertain significance	criteria provided, single submitter
1062695	NM_004738.5(VAPB):c.38A>C (p.Gln13Pro)	VAPB	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
VAPB	Strong	Autosomal dominant	amyotrophic lateral sclerosis type 8	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
VAPB	Orphanet:209335	Autosomal dominant adult-onset proximal spinal muscular atrophy
VAPB	Orphanet:803	Amyotrophic lateral sclerosis

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
VAPB	HGNC:12649	ENSG00000124164	O95292	Vesicle-associated membrane protein-associated protein B/C	gencc,clinvar
APCDD1L	HGNC:26892	ENSG00000198768	Q8NCL9	Protein APCDD1-like	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
VAPB	Vesicle-associated membrane protein-associated protein B/C	Endoplasmic reticulum (ER)-anchored protein that mediates the formation of contact sites between the ER and endosomes via interaction with FFAT motif-containing proteins such as STARD3 or WDR44.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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	1	14.6×	0.135
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VAPB	Antibody/Immunoglobulin	yes		MSP_dom, PapD-like_sf, Ig-like_fold
APCDD1L	Other/Unknown	no		APCDD1_dom, APCDD1

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1
kidney epithelium	1
stromal cell of endometrium	1
vena cava	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
VAPB	299	ubiquitous	marker	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus
APCDD1L	125	broad	marker	kidney epithelium, vena cava, stromal cell of endometrium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
VAPB	3,807
APCDD1L	429

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VAPB	O95292	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
APCDD1L	Q8NCL9	82.31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 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
Sphingolipid de novo biosynthesis	1	285.5×	0.009	VAPB
RHOD GTPase cycle	1	203.9×	0.009	VAPB
RHOG GTPase cycle	1	148.3×	0.009	VAPB
RHOC GTPase cycle	1	146.4×	0.009	VAPB
RAC2 GTPase cycle	1	126.9×	0.009	VAPB
RHOA GTPase cycle	1	74.6×	0.013	VAPB

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
negative regulation by virus of viral protein levels in host cell	1	4213.0×	0.003	VAPB
COPII-coated vesicle budding	1	2808.7×	0.003	VAPB
host-mediated perturbation of viral RNA genome replication	1	1404.3×	0.003	VAPB
obsolete endoplasmic reticulum-plasma membrane tethering	1	1404.3×	0.003	VAPB
endoplasmic reticulum membrane organization	1	1203.7×	0.003	VAPB
IRE1-mediated unfolded protein response	1	936.2×	0.003	VAPB
host-mediated activation of viral genome replication	1	842.6×	0.003	VAPB
host-mediated suppression of viral genome replication	1	766.0×	0.003	VAPB
suppression of viral release by host	1	495.6×	0.004	VAPB
viral release from host cell	1	468.1×	0.004	VAPB
cholesterol transport	1	366.4×	0.004	VAPB
positive regulation of viral genome replication	1	290.6×	0.005	VAPB
endoplasmic reticulum organization	1	210.7×	0.006	VAPB
negative regulation of Wnt signaling pathway	1	172.0×	0.007	APCDD1L
endoplasmic reticulum unfolded protein response	1	147.8×	0.008	VAPB
intracellular calcium ion homeostasis	1	72.6×	0.015	VAPB
endoplasmic reticulum to Golgi vesicle-mediated transport	1	68.0×	0.015	VAPB

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
VAPB	0	0
APCDD1L	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
VAPB	1	Binding:1

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	1	VAPB
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	APCDD1L

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)
VAPB	1	—
APCDD1L	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.