LIG4

Chr 13SomaticAR

DNA ligase 4

Also known as: LIG4S

NCBI Gene: 3981ENSG00000174405UniProt: P49917OMIM: 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.

OMIMResearchSummary from RefSeq, OMIM, UniProt
LOFmechanismSomatic/ARLOEUF 0.802 OMIM phenotypes
Clinical Summary— LIG4
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Gene-Disease Validity (ClinGen)
DNA ligase IV deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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ClinVar Variants
150 unique Pathogenic / Likely Pathogenic· 237 VUS of 600 total submissions
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
0.80LOEUF
pLI 0.000
Z-score 2.33
OE 0.50 (0.33–0.80)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
0.20Z-score
OE missense 0.97 (0.90–1.05)
461 obs / 473.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.50 (0.33–0.80)
0≤0.351.4
Missense OE0.97 (0.90–1.05)
0≤0.61.4
Synonymous OE1.03
0≤1.21.6
LoF obs/exp: 13 / 25.8Missense obs/exp: 461 / 473.3Syn Z: -0.31
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveLIG4-related syndromeLOFAR

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

DN
0.6452th %ile
GOF
0.5464th %ile
LOF
0.2680th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

600 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic127
Likely Pathogenic23
VUS237
Likely Benign170
Benign18
Conflicting24
127
Pathogenic
23
Likely Pathogenic
237
VUS
170
Likely Benign
18
Benign
24
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
63
4
60
0
127
Likely Pathogenic
13
10
0
0
23
VUS
0
217
20
0
237
Likely Benign
0
7
8
155
170
Benign
0
2
13
3
18
Conflicting
—24
Total76240101158599

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

View in ClinVar →

Protein Context — Lollipop Plot

LIG4 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
A Chinese Girl With LIG4 Syndrome and Hematopoietic Stem Cell Transplantation: A Rare Case Report and Review of the Literature
Jiang C et al.·Clin Case Rep
2024Review
Case Report: Wide Spectrum of Manifestations of Ligase IV Deficiency: Report of 3 Cases
Castro ACE et al.·Front Immunol
2022Cohort
Novel Compound Heterozygous Mutations of LIG4 Gene in an Indian LIG4 Syndrome Patient with Severe Microcephaly: Case Report, In-silico Analysis and Systematic Review.
Singh A et al.·Curr Pediatr Rev
2024Review
Disruption of the Schizosaccharomyces japonicus lig4 Disturbs Several Cellular Processes and Leads to a Pleiotropic Phenotype
Acs-Szabo L et al.·J Fungi (Basel)
2023
Characterization of a Cohort of Patients With LIG4 Deficiency Reveals the Founder Effect of p.R278L, Unique to the Chinese Population
Luo X et al.·Front Immunol
2021Cohort
Top 5 full-text resultsSearch PubTator3 ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
BRCA1-A and LIG4 complexes mediate ecDNA biogenesis and cancer drug resistance.
Chung OW et al.·Proc Natl Acad Sci U S A
2026
Integrated case-control and in silico analysis of DNA double-strand break repair gene variants (RAD51, XRCC2, XRCC3, XRCC4, and LIG4) for ovarian cancer susceptibility.
Sistla HC et al.·Gene
2026
Lactate Enhances Non-Homologous End Joining Repair and Chemoresistance Through Facilitating XRCC4-LIG4 Complex Assembly in Ovarian Cancer.
Lu J et al.·Biomedicines
2025Open Access
PIPKIγ promotes non-homologous end joining through LIG4 to enhance radiotherapy resistance in triple-negative breast cancer.
Dong W et al.·Cell Death Dis
2025Open Access
Lig3-dependent rescue of mouse viability and DNA double-strand break repair by catalytically inactive Lig4.
Medina-Suárez D et al.·Nucleic Acids Res
2025Open AccessFunctional
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients