USP43

Chr 17

ubiquitin specific peptidase 43

NCBI Gene: 124739 ENSG00000154914 UniProt: Q70EL4

The USP43 protein is a deubiquitinating enzyme that cleaves ubiquitin from target proteins and processes polyubiquitin precursors, and may also have ISG15-specific peptidase activity involved in DNA repair processes. This gene is highly constrained against loss-of-function variants (LOEUF 0.398), but no definitive human disease associations have been established for USP43 mutations. Further research is needed to determine the clinical significance of variants in this gene.

ResearchSummary from RefSeq, UniProt

Predicted to enable ISG15-specific peptidase activity. Predicted to be involved in translesion synthesis. Predicted to be located in nucleoplasm. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.40

Clinical Summary— USP43

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.24) despite low pLI — interpret in context.

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ClinVar Variants

144 VUS of 173 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 0.164

Z-score 4.76

OE 0.24 (0.15–0.40)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.58Z-score

OE missense 0.81 (0.75–0.88)

468 obs / 574.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.24 (0.15–0.40)

0≤0.351.4

Missense OE?0.81 (0.75–0.88)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 11 / 45.7Missense obs/exp: 468 / 574.8Syn Z: 1.65

This gene — mechanism propensity

0.7230th %ile

GOF

0.6735th %ile

LOF

0.3940th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median

GOFprediction 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

173 submitted variants in ClinVar

ClinVar

Classification Summary

VUS144

Likely Benign16

Benign3

144

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	143	1	0	144
Likely Benign	15	0	1	16
Benign	1	0	2	3
Total	159	1	3	163

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

View in ClinVar →

10 pathogenic / likely-pathogenic (of 16) ClinVar copy-number / structural variants overlap USP43 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →