LIG3

protein-coding

DNA ligase 3, the group of DNA ligases|Zinc fingers PARP-type

Gene summary

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]

Previous symbols:

LIG2

MANE transcript

NM_013975.4

Inheritance

ClinVar variants

P:17U:132B:42

Top phenotype

Mitochondrial DNA depletion syndrome 20 (MNGIE type)

gnomAD constraint

pLI —, LoF o/e 0.49

Max pathogenic AF

—

Genomic locus

chr17:34,980,512-35,009,743

External References & Databases

Ensembl (ENSG00000005156)

Transcript & Mutation Effects

hg38 • Region Span ~29.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

mitochondrial diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0044970

Submitter: ClinGen

The relationship between *LIG3* and *LIG3*-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of August 11, 2025. The *LIG3* gene encodes DNA ligase 3, an enzyme with several functions. This enzyme is involved in the crucial joining of the 5’ and 3’ termini of the nascent strands as a conclusive event of mitochondrial DNA (mtDNA) replication and base-excision repair. It is the only ligase responsible for mtDNA replication and maintenance, working alongside DNA polymerase gamma and other mtDNA replisome factors. DNA ligase 3 also interacts with X-ray repair cross-complementing protein 1 (XRCC1) for DNA maintenance by base excision repair, however other nuclear ligases can compensate for defects in this enzyme. The *LIG3* gene was first reported in relation to autosomal recessive *LIG3*-related primary mitochondrial disease in 2021 (PMIDs: 3385532, 34165507). *LIG3* has been associated with a single disease entity to date; mtDNA depletion syndrome 20 (MNGIE type) [OMIM# 619780]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as *LIG3*-related primary mitochondrial disease. Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included eight unique variants (four missense including one predicted to alter splice-site recognition, three nonsense, one intronic resulting in aberrant splicing) identified in four unrelated cases from two publications (PMIDs: 3385532, 34165507). Clinical features in affected individuals resembled mitochondrial neurogastrointestinal encephalomyopathy (MNGIE) and included gastrointestinal dysmotility, epilepsy, stroke-like episodes, migraines, developmental delay, myopathy, leukoencephalopathy, and progressive cortical and/or cerebellar atrophy. Muscle biopsy showed ragged red fibers and reduced COX staining, as well as variable respiratory chain enzyme deficiencies and mtDNA depletion. The mechanism of disease is loss of function. This gene-disease relationship is also supported by a biochemical function shared with other genes associated with primary mitochondrial disease (PMID: 33340416), functional alteration studies in patient cells (PMID: 33855352), a zebrafish model (PMID: 33855352), and a mouse model (PMID: 21390131). In summary, there is definitive evidence to support the relationship between *LIG3* and autosomal recessive *LIG3*-related primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on August 11, 2025 (SOP Version 11).

mitochondrial DNA depletion syndrome 20 (mngie type)STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030696

Submitter: Labcorp Genetics (formerly Invitae)

mitochondrial DNA depletion syndrome 20 (mngie type)STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0030696

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Mitochondrial DNA depletion syndrome 20 (MNGIE type)AR

Manifestation: Biochemical; Gastrointestinal; Neurologic; Ophthalmologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 33855352; 34165507

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LIG3 variants in ClinVar

6 Conditions Cataloged

Inborn genetic diseasesTotal: 106

not specifiedTotal: 56

not providedTotal: 30

Mitochondrial DNA depletion syndrome 20 (mngie type)Total: 22

LIG3-related disorderTotal: 6

Cardiac arrhythmiaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_013975.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	13 clinvar	13 clinvar	28
missense	4 clinvar		125 clinvar	15 clinvar	1 clinvar	145
nonsense	2 clinvar	5 clinvar	2 clinvar			9
start loss						0
frameshift		5 clinvar	1 clinvar			6
splice donor/acceptor (+/-2bp)		1 clinvar	2 clinvar			3
Total	6	11	132	28	14	191

Highest pathogenic variant AF is 0.000048328813

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 49 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_013975.4	RefSeq	NP_039269.2	19	MANE Select
ENST00000378526.9	Ensembl	ENSP00000367787.3	19	MANE Select
NM_002311.5	RefSeq	NP_002302.2	19	Standard
ENST00000262327.10	Ensembl	ENSP00000262327.4	19	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
lig3	Danio rerio	Structure: double-strand break repair via alternative nonhomologous end joining Quality: decreased process quality abnormal

Gene / Model

Organism

Observed Phenotype

lig3

Danio rerio

Structure: double-strand break repair via alternative nonhomologous end joining

Quality: decreased process quality

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Base excision repair - Homo sapiens (human)
HDR through MMEJ (alt-NHEJ)
DNA Repair
DNA Double-Strand Break Repair
Homology Directed Repair

Biological Process

double-strand break repair via homologous recombination
lagging strand elongation
transcription-coupled nucleotide-excision repair
base-excision repair, DNA ligation
nucleotide-excision repair, DNA gap filling

Molecular Function

DNA binding
DNA ligase activity
DNA ligase (ATP) activity
protein binding
ATP binding

Cellular Component

nucleus
nucleoplasm
cytoplasm
mitochondrion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000378526
Coding exons: 19
Length: 24571
Individuals with no LoFs: 125660
Homozygous LoFs: 0
Heterozygous LoFs: 88
Defined: 125748
p: 0.000350

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.63	478	589	0.811	0.0000341	6638
Missense (PolyPhen)		128	197.58	0.64783		2160
Synonymous	0.426	215	223	0.964	0.0000126	1961
Loss of Function	3.39	25	51.2	0.488	0.00000304	579

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00023	0.00020	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00022	0.00022	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00062	0.00056	rare
South Asian	0.00020	0.00020	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Isoform 3 functions as heterodimer with DNA-repair protein XRCC1 in the nucleus and can correct defective DNA strand- break repair and sister chromatid exchange following treatment with ionizing radiation and alkylating agents. Isoform 1 is targeted to mitochondria, where it functions as DNA ligase in mitochondrial base-excision DNA repair (PubMed:10207110, PubMed:24674627). {ECO:0000269|PubMed:10207110, ECO:0000269|PubMed:24674627}.;

Recessive Scores

pRec: 0.222

Intolerance Scores

LoFtool: 0.853
RVIS EVS: -1.39
RVIS percentile EVS: 4.25

Essentials

Essential (CRISPR): E
Essential (CRISPR2): N
Essential (gene trap): K
Indispensability pred.: E
Indispensability score: 0.649

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium