LIG3

Chr 17AR

DNA ligase 3

Also known as: LIG2, LIG3alpha, MTDPS20

NCBI Gene: 3980 ENSG00000005156 UniProt: P49916 OMIM: 600940

LIG3 encodes DNA ligase III, which catalyzes the joining of DNA ends during excision repair in both the nucleus (as part of the XRCC1 complex) and mitochondria. Mutations cause mitochondrial DNA depletion syndrome 20 (MNGIE type) with autosomal recessive inheritance. The gene is highly constrained against loss-of-function mutations, reflecting its essential role in DNA repair across cellular compartments.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

OMIM ResearchGenerating clinical summary…

DNmechanismARLOEUF 0.681 OMIM phenotype

Clinical Summary— LIG3

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Gene-Disease Validity (ClinGen)

mitochondrial disease · 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

14 unique Pathogenic / Likely Pathogenic· 127 VUS of 207 total submissions

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?

0.68LOEUF

pLI 0.000

Z-score 3.39

OE 0.49 (0.35–0.68)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

1.63Z-score

OE missense 0.81 (0.75–0.88)

478 obs / 589.1 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.49 (0.35–0.68)

0≤0.351.4

Missense OE?0.81 (0.75–0.88)

0≤0.61.4

Synonymous OE?0.96

0≤1.21.6

LoF obs/exp: 25 / 51.2Missense obs/exp: 478 / 589.1Syn Z: 0.43

This gene — mechanism propensity

0.6455th %ile

GOF

0.4973th %ile

LOF

0.3648th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

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

ClinVar Variant Classifications

207 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic7

Likely Pathogenic7

VUS127

Likely Benign28

Benign19

Conflicting4

Pathogenic

Likely Pathogenic

127

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	4	1	0	7
Likely Pathogenic	7	0	0	0	7
VUS	3	119	5	0	127
Likely Benign	0	11	4	13	28
Benign	0	1	5	13	19
Conflicting	—				4
Total	12	135	15	26	192

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

View in ClinVar →

7 pathogenic / likely-pathogenic (of 14) ClinVar copy-number / structural variants overlap LIG3 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →