UFD1

Chr 22AD

ubiquitin recognition factor in ER associated degradation 1

Also known as: UFD1L

NCBI Gene: 7353 ENSG00000070010 UniProt: Q92890 OMIM: 601754

UFD1 encodes an essential component of the ubiquitin-dependent proteolytic pathway that forms a complex with VCP and NPLOC4 to degrade misfolded proteins and regulate nuclear envelope formation during mitosis. Mutations cause autosomal dominant Charcot-Marie-Tooth disease type 2Y, frontotemporal dementia and/or amyotrophic lateral sclerosis 6, and inclusion body myopathy with early-onset Paget disease and frontotemporal dementia. The gene is highly constrained against loss-of-function variants, reflecting its essential cellular functions.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

LOFmechanismADLOEUF 0.233 OMIM phenotypes

Clinical Summary— UFD1

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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.

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ClinVar Variants

24 VUS of 53 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

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?

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?

LoF OE?0.05 (0.02–0.23)

0≤0.351.4

Missense OE?0.44 (0.36–0.53)

0≤0.61.4

Synonymous OE?0.84

0≤1.21.6

LoF obs/exp: 1 / 21.0Missense obs/exp: 80 / 183.2Syn Z: 1.02

This gene — mechanism propensity

0.4487th %ile

GOF

0.2895th %ile

LOF

0.69top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.23

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

53 submitted variants in ClinVar

ClinVar

Classification Summary

VUS24

Likely Benign4

Benign15

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	24	0	0	24
Likely Benign	0	1	3	4
Benign	0	14	1	15
Total	24	15	4	43

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

View in ClinVar →

392 pathogenic / likely-pathogenic (of 411) ClinVar copy-number / structural variants overlap UFD1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →