UBA5

Chr 3AR

ubiquitin like modifier activating enzyme 5

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

NCBI Gene: 79876 ENSG00000081307 OMIM: 610552

The protein functions as an E1-like enzyme that catalyzes the first step in ufmylation by activating UFM1 through ATP-dependent adenylation and thioester bond formation, a post-translational modification pathway essential for ribosome recycling, DNA damage response, and reticulophagy. Biallelic mutations cause autosomal recessive spinocerebellar ataxia type 24 and developmental and epileptic encephalopathy 44. Disease mutations can cause pathogenicity through multiple mechanisms including loss-of-function and dominant-negative effects depending on the specific variant.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.722 OMIM phenotypes

Clinical Summary— UBA5

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Gene-Disease Validity (ClinGen)

genetic developmental and epileptic encephalopathy · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

45 unique Pathogenic / Likely Pathogenic· 116 VUS of 304 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.72LOEUF

pLI 0.000

Z-score 2.58

OE 0.43 (0.26–0.72)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.29Z-score

OE missense 0.75 (0.66–0.85)

158 obs / 210.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.43 (0.26–0.72)

0≤0.351.4

Missense OE?0.75 (0.66–0.85)

0≤0.61.4

Synonymous OE?0.77

0≤1.21.6

LoF obs/exp: 10 / 23.5Missense obs/exp: 158 / 210.8Syn Z: 1.52

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveUBA5-related severe infantile-onset encephalopathyLOFAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.7036th %ile

GOF

0.6248th %ile

LOF

0.2969th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

304 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic27

Likely Pathogenic18

VUS116

Likely Benign125

Benign4

Conflicting8

Pathogenic

Likely Pathogenic

116

VUS

125

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	17	5	5	0	27
Likely Pathogenic	8	8	1	1	18
VUS	2	107	5	2	116
Likely Benign	0	3	57	65	125
Benign	0	1	3	0	4
Conflicting	—				8
Total	27	124	71	68	298

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

View in ClinVar →

12 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap UBA5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →