UFSP2

Chr 4ADAR

UFM1 specific peptidase 2

Also known as: BHD, C4orf20, DEE106, SEMDDR

NCBI Gene: 55325 ENSG00000109775 UniProt: Q9NUQ7 OMIM: 611482

The protein is a thiol-dependent isopeptidase that cleaves UFM1 (ubiquitin-fold modifier 1) from conjugated target proteins and processes UFM1 precursors, playing a critical role in cellular protein modification and ribosome recycling. Mutations cause developmental and epileptic encephalopathy, spondyloepimetaphyseal dysplasia, and Beukes hip dysplasia, affecting both neurological development and skeletal systems. The gene shows extreme intolerance to loss-of-function variants (pLI near 1.0) and follows both autosomal dominant and autosomal recessive inheritance patterns.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a highly conserved cysteine protease. The protein cleaves two C-terminal residues from ubiquitin-fold modifier 1, a ubiquitin-like post-translational modifier protein. Activation of ubiquitin-fold modifier 1 by the encoded protein exposes a C-terminal glycine residue that allows interaction with other proteins and transfer to its target protein. An allelic variant of this gene has been associated with Beukes hip dysplasia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2016]

GeneReviews OMIM ResearchGenerating clinical summary…

AD/ARLOEUF 0.833 OMIM phenotypes

Clinical Summary— UFSP2

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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

9 unique Pathogenic / Likely Pathogenic· 81 VUS of 132 total submissions

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GeneReview available — UFSP2

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.83LOEUF

pLI 0.000

Z-score 2.22

OE 0.52 (0.34–0.83)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.48Z-score

OE missense 0.92 (0.82–1.02)

235 obs / 256.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.52 (0.34–0.83)

0≤0.351.4

Missense OE?0.92 (0.82–1.02)

0≤0.61.4

Synonymous OE?1.02

0≤1.21.6

LoF obs/exp: 13 / 25.0Missense obs/exp: 235 / 256.5Syn Z: -0.12

ClinVar Variant Classifications

132 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic5

VUS81

Likely Benign14

Benign6

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	1	3	0	0	4
Likely Pathogenic	1	4	0	0	5
VUS	2	79	0	0	81
Likely Benign	0	7	0	7	14
Benign	0	0	2	4	6
Conflicting	—				1
Total	4	93	2	11	111

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

View in ClinVar →

116 pathogenic / likely-pathogenic (of 142) ClinVar copy-number / structural variants overlap UFSP2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →