UBA5

Chr 3AR

ubiquitin like modifier activating enzyme 5

Also known as: DEE44, EIEE44, SCAR24, THIFP1, UBE1DC1

NCBI Gene: 79876ENSG00000081307UniProt: Q9GZZ9

This gene encodes a member of the E1-like ubiquitin-activating enzyme family. This protein activates ubiquitin-fold modifier 1, a ubiquitin-like post-translational modifier protein, via the formation of a high-energy thioester bond. Alternative splicing results in multiple transcript variants. A pseudogene of this gene has been identified on chromosome 1. [provided by RefSeq, Feb 2016]

Primary Disease Associations & Inheritance

?Spinocerebellar ataxia, autosomal recessive 24MIM #617133
AR
Developmental and epileptic encephalopathy 44MIM #617132
AR
318
ClinVar variants
56
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— UBA5
🧬
Gene-Disease Validity (ClinGen)
genetic developmental and epileptic encephalopathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
56 Pathogenic / Likely Pathogenic· 125 VUS of 318 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
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.
0.72LOEUF
pLI 0.000
Z-score 2.58
OE 0.43 (0.26–0.72)
Tolerant

Typical tolerance to LoF variation

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.
1.29Z-score
OE missense 0.75 (0.66–0.85)
158 obs / 210.8 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.0.43 (0.26–0.72)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.75 (0.66–0.85)
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.0.77
0≤1.21.6
LoF obs/exp: 10 / 23.5Missense obs/exp: 158 / 210.8Syn Z: 1.52

ClinVar Variant Classifications

318 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic38
Likely Pathogenic18
VUS125
Likely Benign125
Benign4
Conflicting8
38
Pathogenic
18
Likely Pathogenic
125
VUS
125
Likely Benign
4
Benign
8
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
14
5
19
0
38
Likely Pathogenic
4
8
5
1
18
VUS
1
106
16
2
125
Likely Benign
0
3
57
65
125
Benign
0
1
3
0
4
Conflicting
—8
Total1912310068318

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

View in ClinVar →

Protein Context — Lollipop Plot

UBA5 · protein map & ClinVar variants

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

Gene2Phenotype Curations

UBA5-related severe infantile-onset encephalopathy

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

?Spinocerebellar ataxia, autosomal recessive 24

MIM #617133

Molecular basis of disorder known

Autosomal recessive

Developmental and epileptic encephalopathy 44

MIM #617132

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
VCP/p97 UFMylation stabilizes BECN1 and facilitates the initiation of autophagy.
Wang Z et al.·Autophagy
2024
Patient-derived models of UBA5-associated encephalopathy identify defects in neurodevelopment and highlight potential therapeutic avenues.
Chen H et al.·Sci Transl Med
2025Functional
UBA5-epileptic encephalopathy: new patient, a novel variant, and a review of epileptic phenotypes.
Cinnirella C et al.·Epileptic Disord
2025Review
Hereditary ataxias and paraparesias: clinical and genetic update.
Parodi L et al.·Curr Opin Neurol
2018Review
A homozygous UBA5 pathogenic variant causes a fatal congenital neuropathy.
Cabrera-Serrano M et al.·J Med Genet
2020
Homozygous UBA5 Variant Leads to Hypomyelination with Thalamic Involvement and Axonal Neuropathy.
Al-Saady ML et al.·Neuropediatrics
2021
Abnormal function of the UBA5 protein in a case of early developmental and epileptic encephalopathy with suppression-burst.
Mignon-Ravix C et al.·Hum Mutat
2018
Allelic strengths of encephalopathy-associated UBA5 variants correlate between in vivo and in vitro assays.
Pan X et al.·Elife
2023
E1 Enzymes as Therapeutic Targets in Cancer.
Barghout SH et al.·Pharmacol Rev
2021Review
UBA5 missense variants disrupt UFM1 activation: Structural, dynamic, and functional dissection.
Ai L et al.·Int J Biol Macromol
2026Functional
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

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools