UBE4A

Chr 11AR

ubiquitination factor E4A

Also known as: E4, NEDHMS, UBOX2, UFD2

NCBI Gene: 9354 ENSG00000110344 OMIM: 603753

This protein functions as a ubiquitin ligase that mediates polyubiquitin chain assembly and plays a critical role in chromosome condensation and separation through polyubiquitination of substrates. Biallelic mutations cause autosomal recessive neurodevelopmental disorder with hypotonia and gross motor and speech delay. The gene shows significant constraint against loss-of-function variants (LOEUF 0.388), indicating that such variants are likely pathogenic when present in homozygous or compound heterozygous state.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the U-box ubiquitin ligase family. The encoded protein is involved in multiubiquitin chain assembly and plays a critical role in chromosome condensation and separation through the polyubiquitination of securin. Autoantibodies against the encoded protein may be markers for scleroderma and Crohn's disease. A pseudogene of this gene is located on the long arm of chromosome 3. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Feb 2011]

OMIM ResearchGenerating clinical summary…

LOFmechanismARLOEUF 0.391 OMIM phenotype

Clinical Summary— UBE4A

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.

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ClinVar Variants

9 unique Pathogenic / Likely Pathogenic· 128 VUS of 180 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.39LOEUF

pLI 0.109

Z-score 5.11

OE 0.24 (0.16–0.39)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.21Z-score

OE missense 0.74 (0.69–0.81)

436 obs / 586.6 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.24 (0.16–0.39)

0≤0.351.4

Missense OE?0.74 (0.69–0.81)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 13 / 53.3Missense obs/exp: 436 / 586.6Syn Z: 1.35

ClinVar Variant Classifications

180 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic6

VUS128

Likely Benign13

Benign3

Conflicting1

Pathogenic

Likely Pathogenic

128

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	0	0	0	3
Likely Pathogenic	6	0	0	0	6
VUS	1	125	2	0	128
Likely Benign	0	5	0	8	13
Benign	0	0	2	1	3
Conflicting	—				1
Total	10	130	4	9	154

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

View in ClinVar →

28 pathogenic / likely-pathogenic (of 34) ClinVar copy-number / structural variants overlap UBE4A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →