LIG3

Chr 17AR

DNA ligase 3

Also known as: LIG2, LIG3alpha, MTDPS20

NCBI Gene: 3980ENSG00000005156UniProt: P49916

This gene is a member of the DNA ligase family. Each member of this family encodes a protein that catalyzes the joining of DNA ends but they each have a distinct role in DNA metabolism. The protein encoded by this gene is involved in excision repair and is located in both the mitochondria and nucleus, with translation initiation from the upstream start codon allowing for transport to the mitochondria and translation initiation from a downstream start codon allowing for transport to the nucleus. Additionally, alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Mitochondrial DNA depletion syndrome 20 (MNGIE type)MIM #619780
AR
211
ClinVar variants
16
Pathogenic / LP
0.00
pLI score
1
Active trials
Clinical Summary— LIG3
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
16 Pathogenic / Likely Pathogenic· 130 VUS of 211 total submissions
💊
Clinical Trials
1 active or recruiting trial — 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.
0.68LOEUF
pLI 0.000
Z-score 3.39
OE 0.49 (0.35–0.68)
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.
1.63Z-score
OE missense 0.81 (0.75–0.88)
478 obs / 589.1 exp
Tolerant

Mild missense constraint

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.0.49 (0.35–0.68)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.81 (0.75–0.88)
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.0.96
0≤1.21.6
LoF obs/exp: 25 / 51.2Missense obs/exp: 478 / 589.1Syn Z: 0.43

ClinVar Variant Classifications

211 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic12
Likely Pathogenic4
VUS130
Likely Benign27
Benign19
Conflicting4
12
Pathogenic
4
Likely Pathogenic
130
VUS
27
Likely Benign
19
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
4
8
0
12
Likely Pathogenic
2
0
2
0
4
VUS
3
114
13
0
130
Likely Benign
0
11
3
13
27
Benign
0
1
5
13
19
Conflicting
—4
Total51303126196

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

View in ClinVar →

Protein Context — Lollipop Plot

LIG3 · protein map & ClinVar variants

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Mitochondrial DNA depletion syndrome 20 (MNGIE type)

MIM #619780

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Extrachromosomal DNA biogenesis is dependent on DNA looping and religation by YY1-Lig3-PARylation complex.
Qin LN et al.·Mol Cell
2025
Loss of nuclear DNA ligase III reverts PARP inhibitor resistance in BRCA1/53BP1 double-deficient cells by exposing ssDNA gaps.
Paes Dias M et al.·Mol Cell
2021
Glutamine Supplementation as a Novel Metabolic Therapeutic Strategy for LIG3-Dependent Chronic Intestinal Pseudo-Obstruction.
Diquigiovanni C et al.·Gastroenterology
2025
Toxicity and therapy outcome associations in LIG3, SLCO1B3, ABCB1, OPRM1 and GSTP1 in high-grade serous ovarian cancer.
Deng F et al.·Basic Clin Pharmacol Toxicol
2023
Computational investigation unveils pathogenic LIG3 non-synonymous mutations and therapeutic targets in acute myeloid leukemia.
Hossen MA et al.·PLoS One
2025
Biallelic variants in LIG3 cause a novel mitochondrial neurogastrointestinal encephalomyopathy.
Bonora E et al.·Brain
2021
Mitochondrial DNA replication and repair defects: Clinical phenotypes and therapeutic interventions.
Roy A et al.·Biochim Biophys Acta Bioenerg
2022Review
Altered Mitochondrial Dynamics in Motor Neuron Disease: An Emerging Perspective.
Kodavati M et al.·Cells
2020Review
Clinical and Pathological Features of Severe Gut Dysmotility.
Bianco F et al.·Adv Exp Med Biol
2022
Autoantibody profiling to predict response to the anti-PD-1 therapy, pembrolizumab, in rare tumors.
Derbala MH et al.·ESMO Open
2025
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
Colorectal Cancer

Diet Modulation of Bacterial Sulfur and Bile Acid Metabolism and Colon Cancer Risk

ENROLLING BY INVITATION
NCT03550885Phase NAUniversity of Illinois at ChicagoStarted 2018-08-01
High taurine and saturated fat dietLow in taurine and saturated fat diet

External Resources

Links to major genomics databases and tools