Adult-onset proximal spinal muscular atrophy, autosomal dominant

Summary

Adult-onset proximal spinal muscular atrophy, autosomal dominant (MONDO:0008453) is a disease with 3 cohort genes.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe)
• Cohort genes: 3
• ClinVar variants: 359
• Phenotypes (HPO): 20

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.1	Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

20 HPO clinical features (Orphanet curated; top 20 by frequency):

HPO ID	Term	Frequency
HP:0001284	Areflexia	Frequent (30-79%)
HP:0002380	Fasciculations	Frequent (30-79%)
HP:0002505	Loss of ambulation	Frequent (30-79%)
HP:0003391	Gowers sign	Frequent (30-79%)
HP:0003394	Muscle spasm	Frequent (30-79%)
HP:0003445	EMG: neuropathic changes	Frequent (30-79%)
HP:0003551	Difficulty climbing stairs	Frequent (30-79%)
HP:0007126	Proximal amyotrophy	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0001337	Tremor	Occasional (5-29%)
HP:0001387	Joint stiffness	Occasional (5-29%)
HP:0001883	Talipes	Occasional (5-29%)
HP:0002362	Shuffling gait	Occasional (5-29%)
HP:0002486	Myotonia	Occasional (5-29%)
HP:0002515	Waddling gait	Occasional (5-29%)
HP:0003236	Elevated circulating creatine kinase concentration	Occasional (5-29%)
HP:0003484	Upper limb muscle weakness	Occasional (5-29%)
HP:0007340	Lower limb muscle weakness	Occasional (5-29%)
HP:0008981	Calf muscle hypertrophy	Occasional (5-29%)
HP:0002483	Bulbar signs	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	adult-onset proximal spinal muscular atrophy, autosomal dominant
Mondo ID	MONDO:0008453
OMIM	182980
Orphanet	209335
DOID	DOID:0111194
UMLS	C1854058
MedGen	340120
GARD	0017102
Is cancer (heuristic)	no

Also known as: autosomal dominant adult-onset proximal SMA · autosomal dominant late-onset spinal muscular atrophy, Finkel type · Finkel disease · SMAFK · spinal muscular atrophy, late-onset, FINKEL type

Data availability: 359 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 › spinal muscular atrophy › adult-onset proximal spinal muscular atrophy, autosomal dominant

Related subtypes (18): spinal muscular atrophy-progressive myoclonic epilepsy syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, spinal muscular atrophy, facioscapulohumeral type, 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 4, 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

359 retrieved; paginated sample, class counts are floors:

205 uncertain significance, 83 likely benign, 39 benign, 16 benign/likely benign, 15 conflicting classifications of pathogenicity, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
4806	NM_004738.5(VAPB):c.166C>T (p.Pro56Ser)	VAPB	Pathogenic	criteria provided, multiple submitters, no conflicts
543291	NM_001365951.3(KIF1B):c.1771G>A (p.Gly591Arg)	KIF1B	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
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: 4 · 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	Supportive	Autosomal dominant	adult-onset proximal spinal muscular atrophy, autosomal dominant	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
KIF1B	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
KIF1B	Orphanet:99946	Autosomal dominant Charcot-Marie-Tooth disease type 2A1

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
VAPB	HGNC:12649	ENSG00000124164	O95292	Vesicle-associated membrane protein-associated protein B/C	gencc,clinvar
KIF1B	HGNC:16636	ENSG00000054523	O60333	Kinesin-like protein KIF1B	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.
KIF1B	Kinesin-like protein KIF1B	Has a plus-end-directed microtubule motor activity and functions as a motor for transport of vesicles and organelles along microtubules.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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	9.7×	0.246
Scaffold/PPI	1	5.8×	0.246
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
VAPB	Antibody/Immunoglobulin	yes		MSP_dom, PapD-like_sf, Ig-like_fold
KIF1B	Scaffold/PPI	no		FHA_dom, Kinesin_motor_dom, PH_domain
APCDD1L	Other/Unknown	no		APCDD1_dom, APCDD1

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1
biceps brachii	1
medial globus pallidus	1
skeletal muscle tissue of rectus abdominis	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
KIF1B	287	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, biceps brachii, medial globus pallidus
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
KIF1B	2,257
APCDD1L	429

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
VAPB	O95292	2
KIF1B	O60333	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
APCDD1L	Q8NCL9	82.31

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 14. Enrichment computed across 3 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
Sphingolipid de novo biosynthesis	1	142.8×	0.030	VAPB
RHOD GTPase cycle	1	102.0×	0.030	VAPB
Kinesins	1	89.2×	0.030	KIF1B
RHOG GTPase cycle	1	74.2×	0.030	VAPB
RHOC GTPase cycle	1	73.2×	0.030	VAPB
Golgi-to-ER retrograde transport	1	66.4×	0.030	KIF1B
RAC2 GTPase cycle	1	63.4×	0.030	VAPB
COPI-dependent Golgi-to-ER retrograde traffic	1	55.4×	0.030	KIF1B
Intra-Golgi and retrograde Golgi-to-ER traffic	1	52.4×	0.030	KIF1B
RHOA GTPase cycle	1	37.3×	0.037	VAPB
Factors involved in megakaryocyte development and platelet production	1	33.2×	0.038	KIF1B
Membrane Trafficking	1	18.5×	0.057	KIF1B
Hemostasis	1	18.0×	0.057	KIF1B
Vesicle-mediated transport	1	17.4×	0.057	KIF1B

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 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	2808.7×	0.004	VAPB
COPII-coated vesicle budding	1	1872.4×	0.004	VAPB
retrograde neuronal dense core vesicle transport	1	1123.5×	0.004	KIF1B
host-mediated perturbation of viral RNA genome replication	1	936.2×	0.004	VAPB
obsolete endoplasmic reticulum-plasma membrane tethering	1	936.2×	0.004	VAPB
endoplasmic reticulum membrane organization	1	802.5×	0.004	VAPB
IRE1-mediated unfolded protein response	1	624.1×	0.004	VAPB
neuron-neuron synaptic transmission	1	561.7×	0.004	KIF1B
host-mediated activation of viral genome replication	1	561.7×	0.004	VAPB
apoptotic process involved in development	1	561.7×	0.004	KIF1B
host-mediated suppression of viral genome replication	1	510.7×	0.004	VAPB
mitochondrion transport along microtubule	1	468.1×	0.004	KIF1B
suppression of viral release by host	1	330.4×	0.005	VAPB
anterograde synaptic vesicle transport	1	330.4×	0.005	KIF1B
viral release from host cell	1	312.1×	0.005	VAPB
cholesterol transport	1	244.2×	0.006	VAPB
neuromuscular synaptic transmission	1	200.6×	0.007	KIF1B
positive regulation of viral genome replication	1	193.7×	0.007	VAPB
endoplasmic reticulum organization	1	140.4×	0.009	VAPB
negative regulation of Wnt signaling pathway	1	114.6×	0.011	APCDD1L
endoplasmic reticulum unfolded protein response	1	98.5×	0.012	VAPB
intracellular calcium ion homeostasis	1	48.4×	0.023	VAPB
endoplasmic reticulum to Golgi vesicle-mediated transport	1	45.3×	0.024	VAPB
vesicle-mediated transport	1	32.1×	0.032	KIF1B
apoptotic process	1	9.6×	0.101	KIF1B

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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
KIF1B	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
KIF1B	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	2	KIF1B, APCDD1L

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
VAPB	1	—
KIF1B	1	—
APCDD1L	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.