UCHL1

Chr 4ADAR

ubiquitin C-terminal hydrolase L1

Also known as: HEL-117, HEL-S-53, NDGOA, PARK5, PGP 9.5, PGP9.5, PGP95, SPG79

NCBI Gene: 7345ENSG00000154277UniProt: P09936

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]

Primary Disease Associations & Inheritance

{?Parkinson disease 5, susceptibility to}MIM #613643
AD
Spastic paraplegia 79A, autosomal dominantMIM #620221
AD
Spastic paraplegia 79B, autosomal recessiveMIM #615491
AR
246
ClinVar variants
42
Pathogenic / LP
0.99
pLI score· haploinsufficient
1
Active trials
Clinical Summary— UCHL1
🧬
Gene-Disease Validity (ClinGen)
hereditary spastic paraplegia · ARModerate

Moderate evidence — consider for supplementary testing

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.99). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
42 Pathogenic / Likely Pathogenic· 84 VUS of 246 total submissions
💊
Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
LoF intolerant — likely haploinsufficient
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.21LOEUF
pLI 0.991
Z-score 3.48
OE 0.00 (0.00–0.21)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.70Z-score
OE missense 0.82 (0.70–0.97)
102 obs / 123.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.00 (0.00–0.21)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.82 (0.70–0.97)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.42
0≤1.21.6
LoF obs/exp: 0 / 14.1Missense obs/exp: 102 / 123.9Syn Z: -2.27

ClinVar Variant Classifications

246 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic30
Likely Pathogenic12
VUS84
Likely Benign92
Benign25
Conflicting3
30
Pathogenic
12
Likely Pathogenic
84
VUS
92
Likely Benign
25
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
6
2
22
0
30
Likely Pathogenic
8
0
4
0
12
VUS
4
55
25
0
84
Likely Benign
0
2
54
36
92
Benign
0
1
24
0
25
Conflicting
—3
Total186012936246

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

UCHL1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

{?Parkinson disease 5, susceptibility to}

MIM #613643

Molecular basis of disorder known

Autosomal dominant

Spastic paraplegia 79A, autosomal dominant

MIM #620221

Molecular basis of disorder known

Autosomal dominant

Spastic paraplegia 79B, autosomal recessive

MIM #615491

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Role of UCHL1 in the pathogenesis of neurodegenerative diseases and brain injury.
Mi Z et al.·Ageing Res Rev
2023Review
Deficiency of the Deubiquitinase UCHL1 Attenuates Pulmonary Arterial Hypertension.
Tang H et al.·Circulation
2024
An update on diagnostic and prognostic biomarkers for traumatic brain injury.
Wang KK et al.·Expert Rev Mol Diagn
2018Review
UCHL1 is a potential molecular indicator and therapeutic target for neuroendocrine carcinomas.
Liu S et al.·Cell Rep Med
2024
Spatial transcriptional landscape of human heart failure.
Lee SE et al.·Eur Heart J
2025
Time Course and Diagnostic Accuracy of Glial and Neuronal Blood Biomarkers GFAP and UCH-L1 in a Large Cohort of Trauma Patients With and Without Mild Traumatic Brain Injury.
Papa L et al.·JAMA Neurol
2016Cohort
Serum GFAP and UCH-L1 for prediction of absence of intracranial injuries on head CT (ALERT-TBI): a multicentre observational study.
Bazarian JJ et al.·Lancet Neurol
2018
CX3CR1(+)/UCHL1(+) microglial extracellular vesicles in blood: a potential biomarker for multiple sclerosis.
Duan J et al.·J Neuroinflammation
2024
Prognostic value of day-of-injury plasma GFAP and UCH-L1 concentrations for predicting functional recovery after traumatic brain injury in patients from the US TRACK-TBI cohort: an observational cohort study.
Korley FK et al.·Lancet Neurol
2022Cohort
Variants in mitochondrial disease genes are common causes of inherited peripheral neuropathies.
Ferreira T et al.·J Neurol
2024
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Amyotrophic Lateral Sclerosis (ALS)

A Patient-tailored Genetic/Biomarker/iPSC Combined Approach in ALS - PERMEALS

RECRUITING
NCT06917924A.O.U. Città della Salute e della ScienzaStarted 2023-05-20
lumbar puncture

External Resources

Links to major genomics databases and tools