MUS81

Chr 11

MUS81 structure-specific endonuclease subunit

Also known as: SLX3

NCBI Gene: 80198ENSG00000172732UniProt: Q96NY9

This gene encodes a structure-specific endonuclease which belongs to the XPF/MUS81 endonuclease family and plays a critical role in the resolution of recombination intermediates during DNA repair after inter-strand cross-links, replication fork collapse, and DNA double-strand breaks. The encoded protein associates with one of two closely related essential meiotic endonuclease proteins (EME1 or EME2) to form a complex that processes DNA secondary structures. It contains an N-terminal DEAH helicase domain, an excision repair cross complementation group 4 (ERCC4) endonuclease domain, and two tandem C-terminal helix-hairpin-helix domains. Mice with a homozygous knockout of the orthologous gene have significant meiotic defects including the failure to repair a subset of DNA double strand breaks. [provided by RefSeq, Jun 2017]

223
ClinVar variants
13
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— MUS81
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
13 Pathogenic / Likely Pathogenic· 137 VUS of 223 total submissions
Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.99LOEUF
pLI 0.000
Z-score 1.62
OE 0.70 (0.51–0.99)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.06Z-score
OE missense 0.99 (0.91–1.09)
331 obs / 333.9 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.70 (0.51–0.99)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.99 (0.91–1.09)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.95
0≤1.21.6
LoF obs/exp: 24 / 34.2Missense obs/exp: 331 / 333.9Syn Z: 0.43

ClinVar Variant Classifications

223 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic10
Likely Pathogenic3
VUS137
Likely Benign35
Benign10
Conflicting3
10
Pathogenic
3
Likely Pathogenic
137
VUS
35
Likely Benign
10
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
1
8
0
10
Likely Pathogenic
1
0
2
0
3
VUS
2
124
11
0
137
Likely Benign
0
3
7
25
35
Benign
0
2
6
2
10
Conflicting
—3
Total41303427198

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

View in ClinVar →

Protein Context — Lollipop Plot

MUS81 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype

OMIM

No OMIM entries found.

Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
BLM and BRCA1-BARD1 coordinate complementary mechanisms of joint DNA molecule resolution.
Tsukada K et al.·Mol Cell
2024Functional
Ubiquitination of the histone variant mH2A1.2 prevents toxic RAD18 accumulation at a subset of genomic loci upon replication stress.
Galloy M et al.·Mol Cell
2025
TDP1 phosphorylation by CDK1 in mitosis promotes MUS81-dependent repair of trapped Top1-DNA covalent complexes.
Paul Chowdhuri S et al.·EMBO J
2024
Synergistic inhibition of CHK1 and MUS81 to combat replication stress resistance in high-risk neuroblastoma.
Hilgert E et al.·Sci Rep
2025
Senataxin RNA/DNA helicase promotes replication restart at co-transcriptional R-loops to prevent MUS81-dependent fork degradation.
Rao S et al.·Nucleic Acids Res
2024
Deep structure-function analysis of the endonuclease Mus81 with dominant mutational scanning.
Oppedisano A et al.·Proc Natl Acad Sci U S A
2025
Phosphorylation by CK2 regulates MUS81/EME1 in mitosis and after replication stress.
Palma A et al.·Nucleic Acids Res
2018
Expression of MUS81 Mediates the Sensitivity of Castration-Resistant Prostate Cancer to Olaparib.
Gong L et al.·J Immunol Res
2022
Targeting Replication Stress Response Pathways to Enhance Genotoxic Chemo- and Radiotherapy.
Nickoloff JA·Molecules
2022Review
Coordinated roles of SLX4 and MutSβ in DNA repair and the maintenance of genome stability.
Young SJ et al.·Crit Rev Biochem Mol Biol
2021Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools