UCHL1

protein-coding

ubiquitin C-terminal hydrolase L1, the group of Ubiquitin C-terminal hydrolases

Gene summary

The protein encoded by this gene belongs to the peptidase C12 family. This enzyme is a thiol protease that hydrolyzes a peptide bond at the C-terminal glycine of ubiquitin. This gene is specifically expressed in the neurons and in cells of the diffuse neuroendocrine system. Mutations in this gene may be associated with Parkinson disease.[provided by RefSeq, Sep 2009]

Previous symbols:

PARK5

MANE transcript

NM_004181.5

Inheritance

AD, AR

ClinVar variants

P:25U:62B:40

Top phenotype

Parkinson disease 5, autosomal dominant

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr4:41,256,413-41,268,455

External References & Databases

Ensembl (ENSG00000154277)

Transcript & Mutation Effects

hg38 • Region Span ~12.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

spastic paraplegia 79A, autosomal dominant, with ataxiaMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0859363

Submitter: Ambry Genetics

spastic paraplegia 79A, autosomal dominant, with ataxiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859363

Submitter: Labcorp Genetics (formerly Invitae)

early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014209

Submitter: Orphanet

early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014209

Submitter: PanelApp Australia

hereditary spastic paraplegiaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0019064

Submitter: ClinGen

*UCHL1* was first reported in relation to autosomal recessive spastic paraplegia in 2013 (Bilguvar et al., PMID: 23359680). This condition is characterized by spastic paraplegia, vision issues, ataxia, brain atrophy, neuropathy, and abnormal reflexes. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found key differences in inheritance pattern, molecular mechanism, and phenotypic variability. Therefore, the following disease entities have been split into two: autosomal recessive spastic paraplegia (OMIM:615491) and autosomal dominant spastic paraplegia (OMIM:620221). The split curation for autosomal dominant spastic paraplegia has been evaluated separately. Five variants (missense, in-frame deletion, splicing) that have been reported in ten probands in four publications (PMIDs: 23359680, 28007905, 29735986, 32656641) are included in this curation. This gene-disease relationship is also supported by experimental evidence (expression-level evidence, functional alteration evidence, and mouse models). Expression-level data shows that the gene is strongly expressed in the brain and spinal cord (PMID: 11555633). Functional alteration evidence demonstrated that *UCHL1* is key for synaptic function in the brain (PMID: 16923396). Two mouse models demonstrated that *UCHL1* mutants have low body weight, neurodegeneration, abnormal brain and spinal cord morphology, dysphagia, and early lethality (PMIDs: 11555633, 3340629) . In summary, there is moderate evidence supporting the relationship between *UCHL1* and autosomal recessive spastic paraplegia. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Cerebral Palsy GCEP on the meeting date May 19, 2025 (SOP Version 11).

early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndromeSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014209

Submitter: Labcorp Genetics (formerly Invitae)

early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014209

Submitter: Ambry Genetics

Parkinson disease 5, autosomal dominant, susceptibility toLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0013340

Submitter: Labcorp Genetics (formerly Invitae)

hereditary spastic paraplegiaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019064

Submitter: ClinGen

*UCHL1* was first reported in relation to autosomal dominant spastic paraplegia in 2022 (Park et al., PMID: 35986737). This condition is characterized by gait ataxia, spasticity, developmental delay, abnormal limb reflexes, muscle weakness, ocular complications, and brain structural anomalies. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found key differences in inheritance pattern, molecular mechanism, and phenotypic variability. Therefore, the following disease entities have been split into two: autosomal dominant spastic paraplegia (OMIM:620221) and autosomal recessive spastic paraplegia (OMIM:615491). The split curation for autosomal recessive spastic paraplegia has been evaluated separately. Eleven variants (nonsense, frameshift, and splicing) that have been reported in over twenty probands in two publications (PMIDs: 35986737, 39030458) are included in this curation. The maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss-of-function. This gene-disease relationship is also supported by experimental evidence (expression-level data and functional alteration evidence). Data shows that *UCHL1* has strong expression in the cerebrum, medulla, and spinal cord (PMID: 11555633). Functional alteration evidence shows that the gene is necessary for synaptic function (PMID: 16923396). In summary, there is definitive evidence supporting the relationship between *UCHL1* and autosomal recessive spastic paraplegia. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Cerebral Palsy GCEP on the meeting date May 19, 2025 (SOP Version 11).

spastic paraplegia 79A, autosomal dominant, with ataxiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859363

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Parkinson disease 5, autosomal dominantAD

Manifestation: Neurologic; Ophthalmologic

Intervention: Neurologic

Rationale: Levodopa response has been reported

Comments: For Parkinson disease 5, autosomal dominant, findings have not been replicated, and gene association has been described as uncertain

Refs: 9774100; 16450370; 23359680; 28007905; 35986737

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to UCHL1 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 151

Inborn genetic diseasesTotal: 22

Parkinson disease 5, autosomal dominant, susceptibility toTotal: 19

Spastic paraplegia 79A, autosomal dominant, with ataxiaTotal: 15

Early-onset progressive neurodegeneration-blindness-ataxia-spasticity syndromeTotal: 9

UCHL1-related disorderTotal: 8

not specifiedTotal: 5

Optic neuropathyTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004181.5. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous				36 clinvar		36
missense	2 clinvar		56 clinvar	4 clinvar		62
nonsense	4 clinvar	3 clinvar	2 clinvar			9
start loss						0
frameshift	7 clinvar	5 clinvar	2 clinvar			14
splice donor/acceptor (+/-2bp)		4 clinvar	2 clinvar			6
Total	13	12	62	40	0	127

Highest pathogenic variant AF is 0.000004789954

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 36 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004181.5	RefSeq	NP_004172.2	9	MANE Select
ENST00000284440.9	Ensembl	ENSP00000284440.4	9	MANE Select
ENST00000503431.5	Ensembl	ENSP00000422542.1	9	Standard
ENST00000503431.6	Ensembl	ENSP00000422542.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Parkinson,s disease - Homo sapiens (human)
Proteasome Degradation
Parkinsons Disease Pathway
Hepatitis C and Hepatocellular Carcinoma
Post-translational protein modification

Biological Process

response to ischemia
axon target recognition
adult walking behavior
cell population proliferation
regulation of macroautophagy

Molecular Function

cysteine-type endopeptidase activity
thiol-dependent ubiquitin-specific protease activity
protein binding
omega peptidase activity
ligase activity

Cellular Component

nucleoplasm
cytoplasm
endoplasmic reticulum membrane
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000284440
Coding exons: 9
Length: 12043
Individuals with no LoFs: 125504
Homozygous LoFs: 0
Heterozygous LoFs: 1
Defined: 125505
p: 0.00000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.699	102	124	0.823	0.00000676	1460
Missense (PolyPhen)		24	44.714	0.53674		546
Synonymous	-2.27	68	48.0	1.42	0.00000268	421
Loss of Function	3.48	0	14.1	0.00	7.08e-7	164

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.0000088	0.0000088	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Ubiquitin-protein hydrolase involved both in the processing of ubiquitin precursors and of ubiquitinated proteins. This enzyme is a thiol protease that recognizes and hydrolyzes a peptide bond at the C-terminal glycine of ubiquitin. Also binds to free monoubiquitin and may prevent its degradation in lysosomes. The homodimer may have ATP-independent ubiquitin ligase activity. {ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:9790970}.;
Disease: DISEASE: Parkinson disease 5 (PARK5) [MIM:613643]: A complex neurodegenerative disorder with manifestations ranging from typical Parkinson disease to dementia with Lewy bodies. Clinical features include parkinsonian symptoms (resting tremor, rigidity, postural instability and bradykinesia), dementia, diffuse Lewy body pathology, autonomic dysfunction, hallucinations and paranoia. {ECO:0000269|PubMed:12408865, ECO:0000269|PubMed:12705903, ECO:0000269|PubMed:9774100}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Spastic paraplegia 79, autosomal recessive (SPG79) [MIM:615491]: A form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG79 is characterized by childhood onset blindness, cerebellar ataxia, nystagmus, dorsal column dysfunction, and spasticity with upper motor neuron dysfunction. {ECO:0000269|PubMed:23359680, ECO:0000269|PubMed:28007905}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.107

Intolerance Scores

LoFtool: 0.221
RVIS EVS: -0.14
RVIS percentile EVS: 42.88

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.908

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium