LIG4

Chr 13SomaticAR

DNA ligase 4

Also known as: LIG4S

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.

Summary from RefSeq, OMIM, UniProt
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Primary Disease Associations & Inheritance

{Multiple myeloma, resistance to}MIM #254500
Somatic
LIG4 syndromeMIM #606593
AR
UniProtSevere combined immunodeficiency autosomal recessive T-cell-negative/B-cell-negative/NK-cell-positive with sensitivity to ionizing radiation
1
Active trials
40
Pubs (1 yr)
0
P/LP submissions
P/LP missense
0.80
LOEUF
LOF
Mechanism· G2P
Clinical SummaryLIG4
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Gene-Disease Validity (ClinGen)
DNA ligase IV deficiency · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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Clinical Trials
1 active or recruiting trial — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint
0.80LOEUF
pLI 0.000
Z-score 2.33
OE 0.50 (0.330.80)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
0.20Z-score
OE missense 0.97 (0.901.05)
461 obs / 473.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.50 (0.330.80)
00.351.4
Missense OE0.97 (0.901.05)
00.61.4
Synonymous OE1.03
01.21.6
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

0 submitted variants 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.

Clinical Literature
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