SLX4

Chr 16AR

SLX4 structure-specific endonuclease subunit

NCBI Gene: 84464ENSG00000188827UniProt: Q8IY92

Regulatory subunit that interacts with and increases the activity of different structure-specific endonucleases. Has several distinct roles in protecting genome stability by resolving diverse forms of deleterious DNA structures originating from replication and recombination intermediates and from DNA damage. Component of the SLX1-SLX4 structure-specific endonuclease that resolves DNA secondary structures generated during DNA repair and recombination. Has endonuclease activity towards branched DNA substrates, introducing single-strand cuts in duplex DNA close to junctions with ss-DNA. Has a preference for 5'-flap structures, and promotes symmetrical cleavage of static and migrating Holliday junctions (HJs). Resolves HJs by generating two pairs of ligatable, nicked duplex products. Interacts with the structure-specific ERCC4-ERCC1 endonuclease and promotes the cleavage of bubble structures. Interacts with the structure-specific MUS81-EME1 endonuclease and promotes the cleavage of 3'-flap and replication fork-like structures. SLX4 is required for recovery from alkylation-induced DNA damage and is involved in the resolution of DNA double-strand breaks

Primary Disease Associations & Inheritance

Fanconi anemia, complementation group PMIM #613951
AR
UniProtFanconi anemia complementation group P
582
ClinVar variants
51
Pathogenic / LP
0.00
pLI score
2
Active trials
Clinical Summary— SLX4
🧬
Gene-Disease Validity (ClinGen)
hereditary breast carcinoma · ADRefuted

Refuted — evidence has disproved this relationship

3 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
51 Pathogenic / Likely Pathogenic· 355 VUS of 582 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

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.
0.87LOEUF
pLI 0.000
Z-score 2.41
OE 0.68 (0.54–0.87)
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.
-1.88Z-score
OE missense 1.16 (1.11–1.22)
1224 obs / 1052.2 exp
Tolerant

Tolerant to missense variation

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.0.68 (0.54–0.87)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.16 (1.11–1.22)
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.1.24
0≤1.21.6
LoF obs/exp: 45 / 66.2Missense obs/exp: 1224 / 1052.2Syn Z: -4.09

ClinVar Variant Classifications

582 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic29
Likely Pathogenic22
VUS355
Likely Benign173
Conflicting3
29
Pathogenic
22
Likely Pathogenic
355
VUS
173
Likely Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
12
0
17
0
29
Likely Pathogenic
13
0
9
0
22
VUS
2
328
21
4
355
Likely Benign
0
5
30
138
173
Benign
0
0
0
0
0
Conflicting
—3
Total2733377142582

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

View in ClinVar →

Protein Context — Lollipop Plot

SLX4 · protein map & ClinVar variants

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

Gene2Phenotype Curations

SLX4-related Fanconi anemia

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Fanconi anemia, complementation group P

MIM #613951

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — SLX4
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Landscape of pathogenic mutations in premature ovarian insufficiency.
Ke H et al.·Nat Med
2023
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
Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer.
Song H et al.·J Med Genet
2021
Multigene panel testing beyond BRCA1/2 in breast/ovarian cancer Spanish families and clinical actionability of findings.
Bonache S et al.·J Cancer Res Clin Oncol
2018
BLM and BRCA1-BARD1 coordinate complementary mechanisms of joint DNA molecule resolution.
Tsukada K et al.·Mol Cell
2024Functional
Germline Sequencing Analysis to Inform Clinical Gene Panel Testing for Aggressive Prostate Cancer.
Darst BF et al.·JAMA Oncol
2023
SenExo-cCCT2 Reprograms Senescence Response and Anti-Tumor Immunity Following FOLFIRINOX Chemotherapy in Pancreatic Ductal Adenocarcinoma.
Zhu S et al.·Adv Sci (Weinh)
2025
Physical interaction between SLX4 (FANCP) and XPF (FANCQ) proteins and biological consequences of interaction-defective missense mutations.
Hashimoto K et al.·DNA Repair (Amst)
2015
Germline variants of homology-directed repair or mismatch repair genes in cervical cancer.
Kokemüller L et al.·Int J Cancer
2025
Germline pathogenic variants in patients with early-onset neuroendocrine neoplasms.
Riechelmann RP et al.·Endocr Relat Cancer
2023Cohort
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
Gastric CancerGastroEsophageal Cancer

Study of SBRT/Olaparib Followed by Pembrolizumab/Olaparib in Gastric Cancers

ACTIVE NOT RECRUITING
NCT05379972Phase PHASE2University of Colorado, DenverStarted 2023-01-12
PembrolizumabOlaparibStereotactic Body Radiation Therapy
Malignant Neoplasm of BreastBreast Cancer

Comprehensive Analysis of Predictors of the Treatment With Pembrolizumab and Olaparib in Patients With Unresectable or Metastatic HER2 Negative Breast Cancer and a Deleterious Germline Mutation or a Homologous Recombination Deficiency (COMPRENDO

ACTIVE NOT RECRUITING
NCT05033756Phase PHASE2Institut fuer FrauengesundheitStarted 2022-07-30
Pembrolizumab Injection [Keytruda]Olaparib Oral Tablet [Lynparza]

External Resources

Links to major genomics databases and tools