USP42

Chr 7

ubiquitin specific peptidase 42

NCBI Gene: 84132 ENSG00000106346 UniProt: Q9H9J4

The protein functions as a deubiquitinating enzyme that removes ubiquitin from target proteins and may play an important role during spermatogenesis. Mutations in this gene cause neurodevelopmental disorders, though the specific phenotypes and inheritance patterns are not well-characterized in the current literature. This gene is highly constrained against loss-of-function variants (pLI ~1.0, LOEUF 0.133), suggesting that complete loss of protein function is likely incompatible with normal development.

ResearchSummary from RefSeq, UniProt

Enables cysteine-type deubiquitinase activity. Predicted to be involved in protein deubiquitination; regulation of apoptotic process; and regulation of protein stability. Predicted to be located in nucleoplasm. Predicted to be active in cytosol and nucleus. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.13

Clinical Summary— USP42

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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

308 VUS of 363 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.13LOEUF

pLI 1.000

Z-score 6.10

OE 0.04 (0.02–0.13)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

-1.63Z-score

OE missense 1.16 (1.10–1.23)

916 obs / 787.2 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.04 (0.02–0.13)

0≤0.351.4

Missense OE?1.16 (1.10–1.23)

0≤0.61.4

Synonymous OE?1.25

0≤1.21.6

LoF obs/exp: 2 / 47.2Missense obs/exp: 916 / 787.2Syn Z: -3.61

This gene — mechanism propensity

0.3395th %ile

GOF

0.4085th %ile

LOF

0.78top 5%

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

LOFprediction above median · LOEUF 0.13

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

363 submitted variants in ClinVar

ClinVar

Classification Summary

VUS308

Likely Benign29

Benign1

308

VUS

Likely Benign

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	308	0	308
Likely Benign	26	3	29
Benign	0	1	1
Total	334	4	338

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

View in ClinVar →

39 pathogenic / likely-pathogenic (of 54) ClinVar copy-number / structural variants overlap USP42 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →