Spastic paraplegia 80, autosomal dominant

Summary

Spastic paraplegia 80, autosomal dominant (MONDO:0032737) is a disease caused by UBAP1 (GenCC Strong), with 1 cohort gene.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: UBAP1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 29

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		13	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	spastic paraplegia 80, autosomal dominant
Mondo ID	MONDO:0032737
OMIM	618418
Orphanet	631068
DOID	DOID:0112341
UMLS	C5193084
MedGen	1682111
GARD	0025732
Is cancer (heuristic)	no

Also known as: autosomal dominant spastic paraplegia type 80 · SPASTIC PARAPLEGIA 80, AUTOSOMAL DOMINANT · SPG80

Data availability: 29 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 › palsy › paraplegia › hereditary spastic paraplegia › spastic paraplegia 80, autosomal dominant

Related subtypes (44): hereditary spastic paraplegia 3A, hereditary spastic paraplegia 4, mast syndrome, hereditary spastic paraplegia 5A, hereditary spastic paraplegia 16, hereditary spastic paraplegia 2, macrocephaly-spastic paraplegia-dysmorphism syndrome, Charcot-Marie-Tooth disease type 5, hereditary spastic paraplegia 6, hereditary spastic paraplegia 10, hereditary spastic paraplegia 14, hereditary spastic paraplegia 13, hereditary spastic paraplegia 7, hereditary spastic paraplegia 33, hereditary spastic paraplegia 31, hereditary spastic paraplegia 30, hereditary spastic paraplegia 35, hereditary spastic paraplegia 50, hereditary spastic paraplegia 48, hereditary spastic paraplegia 51, hereditary spastic paraplegia 47, hereditary spastic paraplegia 52, hereditary spastic paraplegia 56, early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome, hereditary spastic paraplegia 77, pure hereditary spastic paraplegia, complex hereditary spastic paraplegia, pure or complex hereditary spastic paraplegia, spastic paraplegia 87, autosomal recessive, spastic paraplegia 81, autosomal recessive, spastic paraplegia 82, autosomal recessive, spastic paraplegia 83, autosomal recessive, spastic paraplegia 88, autosomal dominant, spastic paraplegia 79A, autosomal dominant, with ataxia, spastic paraplegia 89, autosomal recessive, spastic paraplegia 90A, autosomal dominant, spastic paraplegia 90B, autosomal recessive, spastic paraplegia 91, autosomal dominant, with or without cerebellar ataxia, spastic paraplegia 72b, autosomal recessive, spastic paraplegia 92, autosomal recessive, spastic paraplegia 93, autosomal recessive, IFIH1-related hereditary spastic paraplegia, RNASEH2B-related hereditary spastic paraplegia, ADAR-related hereditary spastic paraplegia

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

29 retrieved; paginated sample, class counts are floors:

11 pathogenic, 8 likely pathogenic, 7 uncertain significance, 2 conflicting classifications of pathogenicity, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1686288	NM_016525.5(UBAP1):c.293del (p.Gly98fs)	UBAP1	Pathogenic	criteria provided, single submitter
2500178	NM_016525.5(UBAP1):c.476_477del (p.Asp158_Phe159insTer)	UBAP1	Pathogenic	criteria provided, single submitter
627551	NM_016525.5(UBAP1):c.436_437insTGAG (p.Ser146fs)	UBAP1	Pathogenic	no assertion criteria provided
627552	NM_016525.5(UBAP1):c.426_427del (p.Lys143fs)	UBAP1	Pathogenic	criteria provided, multiple submitters, no conflicts
627553	NM_016525.5(UBAP1):c.373C>T (p.Gln125Ter)	UBAP1	Pathogenic	no assertion criteria provided
627554	NM_016525.5(UBAP1):c.286_290dup (p.Glu97fs)	UBAP1	Pathogenic	no assertion criteria provided
627555	NM_016525.5(UBAP1):c.295dup (p.Asp99fs)	UBAP1	Pathogenic	no assertion criteria provided
627556	NM_016525.5(UBAP1):c.361dup (p.Leu121fs)	UBAP1	Pathogenic	no assertion criteria provided
689455	NM_016525.5(UBAP1):c.247_248insGTGAATTC (p.Ile83fs)	UBAP1	Pathogenic	no assertion criteria provided
689456	NM_016525.5(UBAP1):c.526G>T (p.Glu176Ter)	UBAP1	Pathogenic	no assertion criteria provided
827821	NM_016525.5(UBAP1):c.316A>T (p.Lys106Ter)	UBAP1	Pathogenic	criteria provided, single submitter
932242	NM_016525.5(UBAP1):c.535G>T (p.Glu179Ter)	UBAP1	Pathogenic/Likely pathogenic	no assertion criteria provided
1679276	NM_016525.5(UBAP1):c.1265A>G (p.Gln422Arg)	UBAP1	Likely pathogenic	criteria provided, single submitter
3338070	NM_016525.5(UBAP1):c.478_482dup (p.Cys161fs)	UBAP1	Likely pathogenic	no assertion criteria provided
3362862	NM_016525.5(UBAP1):c.487G>T (p.Glu163Ter)	UBAP1	Likely pathogenic	criteria provided, single submitter
3900660	NM_016525.5(UBAP1):c.429dup (p.Val144fs)	UBAP1	Likely pathogenic	criteria provided, single submitter
4076285	NM_016525.5(UBAP1):c.768del (p.Ile257fs)	UBAP1	Likely pathogenic	criteria provided, single submitter
4077726	NM_016525.5(UBAP1):c.-20C>T	UBAP1	Likely pathogenic	criteria provided, single submitter
4077727	NM_001171201.1(UBAP1):c.19G>T (p.Gly7Ter)	UBAP1	Likely pathogenic	criteria provided, single submitter
4813691	NM_016525.5(UBAP1):c.478G>T (p.Glu160Ter)	UBAP1	Likely pathogenic	criteria provided, single submitter
1695246	NM_016525.5(UBAP1):c.1252G>A (p.Glu418Lys)	UBAP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2346184	NM_001171201.1(UBAP1):c.25A>T (p.Arg9Trp)	UBAP1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1700882	NM_016525.5(UBAP1):c.1364_1368delAAAAG (p.Glu455fs)	UBAP1	Uncertain significance	criteria provided, multiple submitters, no conflicts
2438458	NM_016525.5(UBAP1):c.1169C>T (p.Pro390Leu)	UBAP1	Uncertain significance	criteria provided, single submitter
2690406	NM_016525.5(UBAP1):c.304A>T (p.Met102Leu)	UBAP1	Uncertain significance	criteria provided, single submitter
3892804	NM_016525.5(UBAP1):c.1193C>T (p.Thr398Met)	UBAP1	Uncertain significance	criteria provided, single submitter
4076284	NM_016525.5(UBAP1):c.1027C>T (p.Leu343Phe)	UBAP1	Uncertain significance	criteria provided, single submitter
4076286	NM_016525.5(UBAP1):c.998C>T (p.Pro333Leu)	UBAP1	Uncertain significance	criteria provided, single submitter
4080959	NM_016525.5(UBAP1):c.239A>G (p.Glu80Gly)	UBAP1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · 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
UBAP1	Strong	Autosomal dominant	spastic paraplegia 80, autosomal dominant	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
UBAP1	Orphanet:100993	Autosomal dominant spastic paraplegia type 12
UBAP1	Orphanet:631068	Autosomal dominant spastic paraplegia type 80

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
UBAP1	HGNC:12461	ENSG00000165006	Q9NZ09	Ubiquitin-associated protein 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
UBAP1	Ubiquitin-associated protein 1	Component of the ESCRT-I complex, a regulator of vesicular trafficking process.

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)
UBAP1	Other/Unknown	no		UBA-like_sf, UBA, UMA

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
gastrocnemius	1
lower esophagus mucosa	1
muscle of leg	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
UBAP1	288	ubiquitous	marker	lower esophagus mucosa, gastrocnemius, muscle of leg

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
UBAP1	894

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
UBAP1	Q9NZ09	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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
Membrane binding and targetting of GAG proteins	1	815.7×	0.004	UBAP1
Budding and maturation of HIV virion	1	407.9×	0.004	UBAP1
Endosomal Sorting Complex Required For Transport (ESCRT)	1	368.4×	0.004	UBAP1
Late endosomal microautophagy	1	326.3×	0.004	UBAP1
HCMV Late Events	1	98.5×	0.010	UBAP1

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
protein transport to vacuole involved in ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	1	1053.2×	0.002	UBAP1
ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathway	1	543.6×	0.002	UBAP1
multivesicular body assembly	1	526.6×	0.002	UBAP1
membrane fission	1	411.0×	0.002	UBAP1

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
UBAP1	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	UBAP1

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)
UBAP1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.