spastic paraplegia 79A, autosomal dominant, with ataxia

Summary

spastic paraplegia 79A, autosomal dominant, with ataxia (MONDO:0859363) is a disease caused by UCHL1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: UCHL1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 15

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	spastic paraplegia 79A, autosomal dominant, with ataxia
Mondo ID	MONDO:0859363
OMIM	620221
DOID	DOID:0070455
UMLS	C5774300
MedGen	1824073
GARD	0026717
Is cancer (heuristic)	no

Data availability: 15 ClinVar variants · 3 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 79A, autosomal dominant, with ataxia

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 80, autosomal dominant, spastic paraplegia 81, autosomal recessive, spastic paraplegia 82, autosomal recessive, spastic paraplegia 83, autosomal recessive, spastic paraplegia 88, autosomal dominant, 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

15 retrieved; paginated sample, class counts are floors:

6 pathogenic, 5 pathogenic/likely pathogenic, 2 uncertain significance, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1380167	NM_004181.5(UCHL1):c.532C>T (p.Arg178Ter)	UCHL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1699069	NM_004181.5(UCHL1):c.250C>T (p.Gln84Ter)	UCHL1	Pathogenic	criteria provided, single submitter
2077519	NM_004181.5(UCHL1):c.145CTG[5] (p.Leu52_Phe53insLeu)	UCHL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2443800	NM_004181.5(UCHL1):c.73C>T (p.Gln25Ter)	UCHL1	Pathogenic	no assertion criteria provided
2443801	NM_004181.5(UCHL1):c.95_98dup (p.Leu34fs)	UCHL1	Pathogenic	no assertion criteria provided
2578416	NM_004181.5(UCHL1):c.260_261dup (p.Asn88fs)	UCHL1	Pathogenic	criteria provided, single submitter
3068443	NM_004181.5(UCHL1):c.366_367del (p.Lys123fs)	UCHL1	Pathogenic	no assertion criteria provided
3767302	NM_004181.5(UCHL1):c.30dup (p.Glu11fs)	UCHL1	Pathogenic	criteria provided, single submitter
4531939	NM_004181.5(UCHL1):c.172C>T (p.Gln58Ter)	UCHL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
986797	NM_004181.5(UCHL1):c.64dup (p.Val22fs)	UCHL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
987431	NM_004181.5(UCHL1):c.349_364del (p.Phe117fs)	UCHL1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3776083	NM_004181.5(UCHL1):c.583A>T (p.Lys195Ter)	UCHL1	Likely pathogenic	criteria provided, single submitter
3898760	NM_004181.5(UCHL1):c.44_45+2del	UCHL1	Likely pathogenic	criteria provided, single submitter
2664330	NM_004181.5(UCHL1):c.603C>G (p.Cys201Trp)	UCHL1	Uncertain significance	criteria provided, single submitter
3248551	NM_004181.5(UCHL1):c.149T>C (p.Leu50Pro)	UCHL1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · 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
UCHL1	Strong	Autosomal recessive	early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
UCHL1	Orphanet:2828	Young-onset Parkinson disease
UCHL1	Orphanet:352654	Early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndrome

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
UCHL1	HGNC:12513	ENSG00000154277	P09936	Ubiquitin carboxyl-terminal hydrolase isozyme L1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
UCHL1	Ubiquitin carboxyl-terminal hydrolase isozyme L1	Deubiquitinase that plays a role in the regulation of several processes such as maintenance of synaptic function, cardiac function, inflammatory response or osteoclastogenesis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Protease	1	36.6×	0.027

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
UCHL1	Protease	yes	3.4.19.12	Peptidase_C12_UCH, Peptidase_C12_UCH_sf, Papain-like_cys_pep_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
lateral nuclear group of thalamus	1
pons	1
right frontal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
UCHL1	248	ubiquitous	marker	pons, right frontal lobe, lateral nuclear group of thalamus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
UCHL1	4,090

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
UCHL1	P09936	14

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
UCH proteinases	1	124.1×	0.008	UCHL1

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
male germ cell proliferation	1	5617.3×	0.001	UCHL1
axon target recognition	1	5617.3×	0.001	UCHL1
axonal transport of mitochondrion	1	1404.3×	0.004	UCHL1
muscle cell development	1	936.2×	0.004	UCHL1
positive regulation of glycolytic process	1	674.1×	0.004	UCHL1
eating behavior	1	601.9×	0.004	UCHL1
neuromuscular process	1	526.6×	0.004	UCHL1
adult walking behavior	1	495.6×	0.004	UCHL1
negative regulation of MAPK cascade	1	300.9×	0.005	UCHL1
regulation of macroautophagy	1	295.6×	0.005	UCHL1
response to ischemia	1	251.5×	0.005	UCHL1
cellular response to xenobiotic stimulus	1	240.7×	0.005	UCHL1
protein catabolic process	1	237.3×	0.005	UCHL1
protein deubiquitination	1	177.4×	0.006	UCHL1
proteasome-mediated ubiquitin-dependent protein catabolic process	1	52.2×	0.019	UCHL1

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
UCHL1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
UCHL1	66	Binding:66

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
UCHL1	3.4.19.12	ubiquitinyl hydrolase 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	1	UCHL1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

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)
UCHL1	66	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.