LIG4

Chr 13SomaticAR

DNA ligase 4

Also known as: LIG4S

NCBI Gene: 3981 ENSG00000174405 UniProt: P49917 OMIM: 601837

DNA ligase IV catalyzes the final ligation step in non-homologous end joining DNA repair and is essential for V(D)J recombination in developing lymphocytes. Biallelic mutations cause LIG4 syndrome, an autosomal recessive disorder characterized by severe combined immunodeficiency, developmental delays, microcephaly, growth retardation, and increased cancer susceptibility. The gene is highly intolerant to loss-of-function variation (pLI near 0), reflecting its critical role in DNA repair and immune system development.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a DNA ligase that joins single-strand breaks in a double-stranded polydeoxynucleotide in an ATP-dependent reaction. This protein is essential for V(D)J recombination and DNA double-strand break (DSB) repair through nonhomologous end joining (NHEJ). This protein forms a complex with the X-ray repair cross complementing protein 4 (XRCC4), and further interacts with the DNA-dependent protein kinase (DNA-PK). Both XRCC4 and DNA-PK are known to be required for NHEJ. The crystal structure of the complex formed by this protein and XRCC4 has been resolved. Defects in this gene are the cause of LIG4 syndrome. Alternatively spliced transcript variants encoding the same protein have been observed. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

{Multiple myeloma, resistance to}MIM #254500

Somatic

LIG4 syndromeMIM #606593

UniProtSevere combined immunodeficiency autosomal recessive T-cell-negative/B-cell-negative/NK-cell-positive with sensitivity to ionizing radiation

Clinical highlights

Gene-disease validity (ClinGen)

DNA ligase IV deficiency · ARDefinitivesufficient evidence for diagnostic panels

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.80

LOEUF

LOF

Mechanism· G2P