USP31

Chr 16

ubiquitin specific peptidase 31

NCBI Gene: 57478 ENSG00000103404 UniProt: Q70CQ4 OMIM: 619536

The protein is a deubiquitinase that removes ubiquitin from target proteins and may regulate NF-kappa-B signaling through TRAF2 deubiquitination. Mutations cause autosomal recessive neurodevelopmental disorders with intellectual disability and variable features including seizures, hypotonia, and behavioral abnormalities. The gene shows high constraint against loss-of-function variants, suggesting intolerance to disruption.

OMIM ResearchSummary from RefSeq, UniProt

Enables cysteine-type deubiquitinase activity. Predicted to be involved in protein deubiquitination and proteolysis. Located in nucleus. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.40

Clinical Summary— USP31

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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

214 VUS of 251 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.40LOEUF

pLI 0.062

Z-score 4.98

OE 0.25 (0.16–0.40)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.47Z-score

OE missense 0.84 (0.79–0.90)

595 obs / 704.6 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.25 (0.16–0.40)

0≤0.351.4

Missense OE?0.84 (0.79–0.90)

0≤0.61.4

Synonymous OE?1.12

0≤1.21.6

LoF obs/exp: 13 / 51.6Missense obs/exp: 595 / 704.6Syn Z: -1.56

This gene — mechanism propensity

0.6841th %ile

GOF

0.6149th %ile

LOF

0.4134th %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

251 submitted variants in ClinVar

ClinVar

Classification Summary

VUS214

Likely Benign8

214

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	214	0	214
Likely Benign	6	2	8
Benign	0	0	0
Total	220	2	222

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

View in ClinVar →

29 pathogenic / likely-pathogenic (of 35) ClinVar copy-number / structural variants overlap USP31 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →