NHEJ1

Chr 2AR

non-homologous end joining factor 1

Also known as: IMD124, MCOPCB13, XLF

NCBI Gene: 79840ENSG00000187736UniProt: Q9H9Q4

Double-strand breaks in DNA result from genotoxic stresses and are among the most damaging of DNA lesions. This gene encodes a DNA repair factor essential for the nonhomologous end-joining pathway, which preferentially mediates repair of double-stranded breaks. Mutations in this gene cause different kinds of severe combined immunodeficiency disorders. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Immunodeficiency 124, severe combinedMIM #611291
AR
Microphthalmia/coloboma 13MIM #620968
AR
0
Active trials
69
Pathogenic / LP
304
ClinVar variants
6
Pubs (1 yr)
0.0
Missense Z
0.74
LOEUF
Clinical Summary— NHEJ1
🧬
Gene-Disease Validity (ClinGen)
Cernunnos-XLF 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.
📋
ClinVar Variants
69 Pathogenic / Likely Pathogenic· 101 VUS of 304 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
0.74LOEUF
pLI 0.004
Z-score 2.37
OE 0.39 (0.22–0.74)
Tolerant

Typical tolerance to LoF variation

Missense Constraint
0.01Z-score
OE missense 1.00 (0.88–1.14)
159 obs / 159.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.39 (0.22–0.74)
0≤0.351.4
Missense OE1.00 (0.88–1.14)
0≤0.61.4
Synonymous OE1.22
0≤1.21.6
LoF obs/exp: 7 / 17.8Missense obs/exp: 159 / 159.5Syn Z: -1.39

ClinVar Variant Classifications

304 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic53
Likely Pathogenic16
VUS101
Likely Benign97
Benign33
Conflicting4
53
Pathogenic
16
Likely Pathogenic
101
VUS
97
Likely Benign
33
Benign
4
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
13
2
38
0
53
Likely Pathogenic
9
3
4
0
16
VUS
1
86
11
3
101
Likely Benign
1
6
33
57
97
Benign
0
2
29
2
33
Conflicting
—4
Total249911562304

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

View in ClinVar →

NHEJ1 · protein map & ClinVar variants

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Landmark / reviewRecent case evidence
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
A novel multiplex polymerase chain reaction assay for the genotypic survey of the non-homologous end-joining factor 1 gene associated with Collie eye anomaly in Thailand
Lerdkrai C et al.·Vet World
2022
Haploidentical Transplant in Radiosensitive Severe Combined Immunodeficiency Disease
Saini M et al.·Cureus
2023
Genotypic and allelic frequency of a mutation in the NHEJ1 gene associated with collie eye anomaly in dogs in Italy
Marelli SP et al.·Vet Rec Open
2022
An XRCC4 mutant mouse, a model for human X4 syndrome, reveals interplays with Xlf, PAXX, and ATM in lymphoid development
Roch B et al.·Elife
2021Functional
Case Report: Refractory Cytopenia With a Switch From a Transient Monosomy 7 to a Disease-Ameliorating del(20q) in a NHEJ1-Deficient Long-term Survivor
Poyer F et al.·Front Immunol
2022Case report
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Loss of NHEJ1 Protein Due to a Novel Splice Site Mutation in a Family Presenting with Combined Immunodeficiency, Microcephaly, and Growth Retardation and Literature Review.
Sheikh F et al.·J Clin Immunol
2017Review
Genetic variants in NHEJ1 and related DNA repair disorders: insights into phenotypic heterogeneity and links to hypoplastic myelodysplastic syndromes and familial hematological malignancies susceptibility.
Elbadry MI et al.·Ann Hematol
2025
Mutations in XLF/NHEJ1/Cernunnos gene results in downregulation of telomerase genes expression and telomere shortening.
Carrillo J et al.·Hum Mol Genet
2017Case report
Severe immunodeficiency spectrum associated with NHEJ1 gene mutation: Cernunnos/XLF deficiency.
Navarro AM et al.·Biomedica
2024Case report
Haploinsufficiency in non-homologous end joining factor 1 induces ovarian dysfunction in humans and mice.
Li G et al.·J Med Genet
2022
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
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