UFD1

Chr 22AD

ubiquitin recognition factor in ER associated degradation 1

Also known as: UFD1L

NCBI Gene: 7353ENSG00000070010UniProt: Q92890

The protein encoded by this gene forms a complex with two other proteins, nuclear protein localization-4 and valosin-containing protein, and this complex is necessary for the degradation of ubiquitinated proteins. In addition, this complex controls the disassembly of the mitotic spindle and the formation of a closed nuclear envelope after mitosis. Mutations in this gene have been associated with Catch 22 syndrome as well as cardiac and craniofacial defects. Alternative splicing results in multiple transcript variants encoding different isoforms. A related pseudogene has been identified on chromosome 18. [provided by RefSeq, Jun 2009]

Primary Disease Associations & Inheritance

Charcot-Marie-Tooth disease, type 2YMIM #616687
AD
Frontotemporal dementia and/or amyotrophic lateral sclerosis 6MIM #613954
AD
Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1MIM #167320
AD
438
ClinVar variants
378
Pathogenic / LP
1.00
pLI score· haploinsufficient
0
Active trials
Clinical Summary— UFD1
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
378 Pathogenic / Likely Pathogenic· 40 VUS of 438 total submissions

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.
0.23LOEUF
pLI 0.996
Z-score 4.04
OE 0.05 (0.02–0.23)
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.
2.71Z-score
OE missense 0.44 (0.36–0.53)
80 obs / 183.2 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

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.0.05 (0.02–0.23)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.44 (0.36–0.53)
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.0.84
0≤1.21.6
LoF obs/exp: 1 / 21.0Missense obs/exp: 80 / 183.2Syn Z: 1.02

ClinVar Variant Classifications

438 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic370
Likely Pathogenic8
VUS40
Likely Benign4
Benign16
370
Pathogenic
8
Likely Pathogenic
40
VUS
4
Likely Benign
16
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories· variant type breakdown unavailable

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
————370
Likely Pathogenic
————8
VUS
————40
Likely Benign
————4
Benign
————16
Total—438

Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

UFD1 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

3 OMIM entries

OMIM

Charcot-Marie-Tooth disease, type 2Y

MIM #616687

Molecular basis of disorder known

Autosomal dominant

Frontotemporal dementia and/or amyotrophic lateral sclerosis 6

MIM #613954

Molecular basis of disorder known

Autosomal dominant

Inclusion body myopathy with early-onset Paget disease and frontotemporal dementia 1

MIM #167320

Molecular basis of disorder known

Autosomal dominant
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
A UFD1 variant encoding a microprotein modulates UFD1f and IPMK ubiquitination to play pivotal roles in anti-stress responses.
Li X et al.·Nat Commun
2025
Aberrant nuclear pore complex degradation contributes to neurodegeneration in VCP disease.
Dubey SK et al.·Neuron
2026
Control of p97 function by cofactor binding.
Buchberger A et al.·FEBS Lett
2015Review
PCBP2 Posttranscriptional Modifications Induce Breast Cancer Progression via Upregulation of UFD1 and NT5E.
Wang X et al.·Mol Cancer Res
2021
Cdc48Ufd1/Npl4 segregase removes mislocalized centromeric histone H3 variant CENP-A from non-centromeric chromatin.
Ohkuni K et al.·Nucleic Acids Res
2022
Different dynamic movements of wild-type and pathogenic VCPs and their cofactors to damaged mitochondria in a Parkin-mediated mitochondrial quality control system.
Kimura Y et al.·Genes Cells
2013
A multiparameter panel method for outcome prediction following aneurysmal subarachnoid hemorrhage.
Turck N et al.·Intensive Care Med
2010
Different p97/VCP complexes function in retrotranslocation step of mammalian ER-associated degradation (ERAD).
Ballar P et al.·Int J Biochem Cell Biol
2011
Ataxin-3 binds VCP/p97 and regulates retrotranslocation of ERAD substrates.
Zhong X et al.·Hum Mol Genet
2006
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