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GeneE
25 sources retrieved Β· Most recent: April 2026 Β· Index updated 14 days ago
β“˜GeneE is for informational purposes only. It is not a substitute for professional medical advice, diagnosis, or treatment.
LIG4
DNA ligase 4
Chromosome 13 Β· 13q33.3
NCBI Gene: 3981Ensembl: ENSG00000174405.15HGNC: HGNC:6601UniProt: A0A0C4DGV9
215PubMed Papers
22Diseases
0Drugs
113Pathogenic Variants
FUNCTIONAL ROLE
DNA RepairHub Gene
RESEARCH IMPACT
TrendingVariant-Rich
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
V(D)J recombinationsingle strand break repairDNA bindingDNA ligase activityLIG4 syndromeDNA ligase IV deficiencysevere combined immunodeficiency due to DCLRE1C deficiencymultiple myeloma
✦AI Summary

LIG4 encodes DNA ligase IV, an essential enzyme that catalyzes the final ligation step in non-homologous end joining (NHEJ), the primary pathway for repairing DNA double-strand breaks in mammalian cells 1. LIG4 forms a functional complex with XRCC4 and operates within a flexible Ο‰-shaped framework composed of XRCC4 and XLF, where it coordinates with DNA polymerase ΞΌ to complete gap filling and end joining 1. The enzyme exhibits mechanistic flexibility, ligating nicks and compatible DNA overhangs alone, and can ligate ends with microhomology and gaps when complexed with XRCC4 1. Beyond DNA repair, LIG4 plays a crucial role in V(D)J recombination during immune system development. Mutations in LIG4 cause LIG4 syndrome, a rare autosomal recessive disorder characterized by microcephaly, growth retardation, immunodeficiency, radiosensitivity, and pancytopenia 2. The syndrome requires at least one hypomorphic allele for viability, as complete loss of LIG4 function is embryonically lethal 2. Recent studies have also implicated LIG4 in extrachromosomal circular DNA (ecDNA) biogenesis, where it mediates cancer drug resistance by enabling ecDNA-driven adaptation 3.

Sources cited
1
LIG4 catalyzes final ligation in NHEJ within Ο‰-shaped XRCC4-XLF framework and coordinates with DNA polymerase ΞΌ
PMID: 40500445
2
LIG4 mutations cause syndrome with microcephaly, immunodeficiency, and radiosensitivity; requires hypomorphic alleles for viability
PMID: 19467349
3
LIG4 mediates extrachromosomal circular DNA biogenesis and cancer drug resistance
PMID: 40027615
⚠Limited data available β€” This gene has 3 indexed publications. Summary and analysis may be incomplete.
Disease Associationsβ“˜22
LIG4 syndromeOpen Targets
0.80Strong
DNA ligase IV deficiencyOpen Targets
0.79Strong
severe combined immunodeficiency due to DCLRE1C deficiencyOpen Targets
0.69Moderate
multiple myelomaOpen Targets
0.66Moderate
T-B- severe combined immunodeficiencyOpen Targets
0.53Moderate
T-B+ severe combined immunodeficiencyOpen Targets
0.53Moderate
T+ B+ severe combined immunodeficiencyOpen Targets
0.53Moderate
genetic disorderOpen Targets
0.51Moderate
severe combined immunodeficiencyOpen Targets
0.49Moderate
lymphomaOpen Targets
0.47Moderate
acute lymphoblastic leukemiaOpen Targets
0.47Moderate
combined immunodeficiencyOpen Targets
0.46Moderate
HIV infectionOpen Targets
0.46Moderate
Dubowitz syndromeOpen Targets
0.37Weak
Down syndromeOpen Targets
0.37Weak
microcephalic primordial dwarfismOpen Targets
0.37Weak
Omenn syndromeOpen Targets
0.37Weak
papillary thyroid carcinomaOpen Targets
0.27Weak
type 2 diabetes mellitusOpen Targets
0.14Weak
StrabismusOpen Targets
0.12Weak
LIG4 syndromeUniProt
Severe combined immunodeficiency autosomal recessive T-cell-negative/B-cell-negative/NK-cell-positive with sensitivity to ionizing radiationUniProt
Pathogenic Variants113
NM_206937.2(LIG4):c.1578G>A (p.Trp526Ter)Pathogenic
DNA ligase IV deficiency
β˜…β˜…β˜†β˜†2026β†’ Residue 526
NM_206937.2(LIG4):c.1904del (p.Lys635fs)Pathogenic
not provided|DNA ligase IV deficiency|Inborn genetic diseases|LIG4-related disorder|Multiple myeloma;DNA ligase IV deficiency
β˜…β˜…β˜†β˜†2026β†’ Residue 635
NM_206937.2(LIG4):c.2440C>T (p.Arg814Ter)Pathogenic
DNA ligase IV deficiency|not provided|Inborn genetic diseases|DNA ligase IV deficiency;Multiple myeloma|prenatal LIG4 syndrome with aqueductal stenosis|LIG4-related disorder
β˜…β˜…β˜†β˜†2026β†’ Residue 814
NM_206937.2(LIG4):c.1271_1275del (p.Lys424fs)Pathogenic
LIG4-related disorder|not provided|DNA ligase IV deficiency|Multiple myeloma;DNA ligase IV deficiency
β˜…β˜…β˜†β˜†2026β†’ Residue 424
NM_206937.2(LIG4):c.833G>T (p.Arg278Leu)Pathogenic
DNA ligase IV deficiency|Severe combined immunodeficiency disease|DNA ligase IV deficiency;Multiple myeloma
β˜…β˜…β˜†β˜†2026β†’ Residue 278
NM_206937.2(LIG4):c.2592_2595del (p.Ile864fs)Pathogenic
not provided|DNA ligase IV deficiency|LIG4-related disorder|Severe combined immunodeficiency disease
β˜…β˜…β˜†β˜†2025β†’ Residue 864
NM_206937.2(LIG4):c.2585_2586del (p.His862fs)Pathogenic
DNA ligase IV deficiency|Multiple myeloma;DNA ligase IV deficiency
β˜…β˜…β˜†β˜†2025β†’ Residue 862
NM_206937.2(LIG4):c.1512_1513del (p.Arg505fs)Pathogenic
not provided|DNA ligase IV deficiency|prenatal LIG4 syndrome with aqueductal stenosis|DNA ligase IV deficiency;Multiple myeloma
β˜…β˜…β˜†β˜†2025β†’ Residue 505
NM_206937.2(LIG4):c.613del (p.Ser205fs)Pathogenic
Inborn genetic diseases|DNA ligase IV deficiency|not provided|Multiple myeloma;DNA ligase IV deficiency
β˜…β˜…β˜†β˜†2025β†’ Residue 205
NM_206937.2(LIG4):c.724_725del (p.Leu242fs)Pathogenic
DNA ligase IV deficiency|Multiple myeloma;DNA ligase IV deficiency
β˜…β˜…β˜†β˜†2025β†’ Residue 242
NM_206937.2(LIG4):c.1746_1750del (p.Glu582fs)Pathogenic
DNA ligase IV deficiency|Multiple myeloma;DNA ligase IV deficiency|not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 582
NM_206937.2(LIG4):c.845A>G (p.His282Arg)Likely pathogenic
DNA ligase IV deficiency
β˜…β˜…β˜†β˜†2025β†’ Residue 282
NM_206937.2(LIG4):c.833G>A (p.Arg278His)Pathogenic
DNA ligase IV deficiency|not provided|Severe combined immunodeficiency disease
β˜…β˜…β˜†β˜†2025β†’ Residue 278
NM_206937.2(LIG4):c.1751_1755del (p.Ile584fs)Pathogenic
not provided|DNA ligase IV deficiency
β˜…β˜…β˜†β˜†2025β†’ Residue 584
NM_206937.2(LIG4):c.597_600del (p.Gln200fs)Pathogenic
DNA ligase IV deficiency|DNA ligase IV deficiency;Multiple myeloma
β˜…β˜…β˜†β˜†2024β†’ Residue 200
NM_206937.2(LIG4):c.879_883del (p.Asn294fs)Pathogenic
DNA ligase IV deficiency|Multiple myeloma;DNA ligase IV deficiency
β˜…β˜…β˜†β˜†2024β†’ Residue 294
NM_206937.2(LIG4):c.845A>T (p.His282Leu)Pathogenic
DNA ligase IV deficiency|Severe combined immunodeficiency disease
β˜…β˜…β˜†β˜†2024β†’ Residue 282
NM_206937.2(LIG4):c.2094C>G (p.Tyr698Ter)Pathogenic
DNA ligase IV deficiency
β˜…β˜…β˜†β˜†2024β†’ Residue 698
NM_206937.2(LIG4):c.743C>T (p.Pro248Leu)Likely pathogenic
DNA ligase IV deficiency|Inborn genetic diseases|not provided
β˜…β˜…β˜†β˜†2024β†’ Residue 248
NM_206937.2(LIG4):c.1738C>T (p.Arg580Ter)Pathogenic
DNA ligase IV deficiency|not provided|DNA ligase IV deficiency;Multiple myeloma
β˜…β˜…β˜†β˜†2024β†’ Residue 580
View on ClinVar β†—
Related Genes
XPAProtein interaction100%APTXProtein interaction100%PNKPProtein interaction100%RAD23BProtein interaction100%XPCProtein interaction99%XRCC5Protein interaction98%
Tissue Expression6 tissues
Liver
100%
Brain
98%
Heart
80%
Bone Marrow
43%
Lung
42%
Ovary
34%
Gene Interaction Network
Click a node to explore
LIG4XPAAPTXPNKPRAD23BXPCXRCC5
PROTEIN STRUCTURE
Preparing viewer…
PDB4HTP Β· 2.25 Γ… Β· X-ray
View on RCSB β†—
Constraintβ“˜
LOEUFβ“˜
1.04LoF Tolerant
pLIβ“˜
0.00Tolerant
Observed/Expected LoF0.69 [0.46–1.04]
RankingsWhere LIG4 stands among ~20K protein-coding genes
  • #1,929of 20,598
    Most Researched215 Β· top 10%
  • #687of 5,498
    Most Pathogenic Variants113 Β· top quartile
  • #10,395of 17,882
    Most Constrained (LOEUF)1.04
Genes detectedLIG4
Sources retrieved25 papers
Response timeβ€”
πŸ“„ Sources
25β–Ό
1
Dynamic assemblies and coordinated reactions of non-homologous end joining.
PMID: 40500445
Nature Β· 2025
1.00
2
A landscape of germ line mutations in a cohort of inherited bone marrow failure patients.
PMID: 29146883
Blood Β· 2018
0.90
3
Chromosome end protection by RAP1-mediated inhibition of DNA-PK.
PMID: 40240611
Nature Β· 2025
0.80
4
Increasing the efficiency of homology-directed repair for CRISPR-Cas9-induced precise gene editing in mammalian cells.
PMID: 25803306
Nat Biotechnol Β· 2015
0.70
5
Ku limits RNA-induced innate immunity to allow Alu expansion in primates.
PMID: 40373806
Nature Β· 2025
0.60