UBL4A

Chr X

ubiquitin like 4A

Also known as: DX254E, DXS254E, GDX, GET5, MDY2, TMA24, UBL4

NCBI Gene: 8266 ENSG00000102178 UniProt: P11441 OMIM: 312070

UBL4A encodes a component of the BAG6/BAT3 cytosolic protein quality control complex that maintains misfolded proteins in a soluble state and mediates proper delivery of tail-anchored proteins to the endoplasmic reticulum or directs them to proteasomal degradation. Mutations cause autosomal dominant intellectual disability through a dominant-negative mechanism. The protein is relatively tolerant to loss-of-function variants based on constraint metrics.

OMIM ResearchSummary from RefSeq, UniProt, Mechanism

Enables protein-folding chaperone binding activity. Involved in establishment of protein localization to membrane; regulation of protein stability; and ubiquitin-dependent protein catabolic process. Located in cytosol; membrane; and nucleoplasm. Part of BAT3 complex. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.18

Clinical Summary— UBL4A

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.25) despite low pLI — interpret in context.

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ClinVar Variants

12 VUS of 34 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?

1.18LOEUF

pLI 0.299

Z-score 1.38

OE 0.25 (0.09–1.18)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.70Z-score

OE missense 0.73 (0.57–0.95)

40 obs / 54.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.25 (0.09–1.18)

0≤0.351.4

Missense OE?0.73 (0.57–0.95)

0≤0.61.4

Synonymous OE?1.26

0≤1.21.6

LoF obs/exp: 1 / 4.0Missense obs/exp: 40 / 54.6Syn Z: -1.07

This gene — mechanism propensity

0.7034th %ile

GOF

0.5856th %ile

LOF

0.3940th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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

ClinVar Variant Classifications

34 submitted variants in ClinVar

ClinVar

Classification Summary

VUS12

Likely Benign2

VUS

Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	12	0	12
Likely Benign	1	1	2
Benign	0	0	0
Total	13	1	14

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

View in ClinVar →

55 pathogenic / likely-pathogenic (of 66) ClinVar copy-number / structural variants overlap UBL4A — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →