DCLRE1C

Chr 10AR

DNA cross-link repair 1C

ENSG00000152457 UniProt: Q96SD1 OMIM: 605988

This protein functions as a nuclease essential for DNA non-homologous end joining (NHEJ) and V(D)J recombination, exhibiting single-strand specific 5'-3' exonuclease activity and endonuclease activity on hairpins and overhangs when complexed with PRKDC. Autosomal recessive mutations cause Athabascan-type severe combined immunodeficiency (SCIDA) and Omenn syndrome through impaired V(D)J recombination required for proper immune system development. The pathogenic mechanism involves loss of function, preventing proper assembly of immunoglobulin and T-cell receptor genes from individual V, D, and J segments.

OMIM ResearchSummary from RefSeq, OMIM, UniProt, Mechanism

Nuclease involved in DNA non-homologous end joining (NHEJ); required for double-strand break repair and V(D)J recombination (PubMed:11336668, PubMed:11955432, PubMed:12055248, PubMed:14744996, PubMed:15071507, PubMed:15574326, PubMed:15936993). Required for V(D)J recombination, the process by which exons encoding the antigen-binding domains of immunoglobulins and T-cell receptor proteins are assembled from individual V, (D), and J gene segments (PubMed:11336668, PubMed:11955432, PubMed:14744996). V(D)J recombination is initiated by the lymphoid specific RAG endonuclease complex, which generates site specific DNA double strand breaks (DSBs) (PubMed:11336668, PubMed:11955432, PubMed:14744996). These DSBs present two types of DNA end structures: hairpin sealed coding ends and phosphorylated blunt signal ends (PubMed:11336668, PubMed:11955432, PubMed:14744996). These ends are independently repaired by the non homologous end joining (NHEJ) pathway to form coding and signal joints respectively (PubMed:11336668, PubMed:11955432, PubMed:14744996). This protein exhibits single-strand specific 5'-3' exonuclease activity in isolation and acquires endonucleolytic activity on 5' and 3' hairpins and overhangs when in a complex with PRKDC (PubMed:11955432, PubMed:15071507, PubMed:15574326, PubMed:15936993). The latter activity is required specifically for the resolution of closed hairpins prior to the formation of the coding joint (PubMed:11955432). Also required for the repair of complex DSBs induced by ionizing radiation, which require substantial end-processing prior to religation by NHEJ (PubMed:15456891, PubMed:15468306, PubMed:15574327, PubMed:15811628)

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Omenn syndromeMIM #603554

Severe combined immunodeficiency, Athabascan typeMIM #602450

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · severe combined immunodeficiency due to DCLRE1C deficiency · AR · ClinGen 2021

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.71

LOEUF

LOF

Mechanism· G2P

Some data sources returned errors (1)

ncbi: Error: NCBI fetch failed: 429 https://eutils.ncbi.nlm.nih.gov/entrez/eutils/esearch.fcgi

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.71LOEUF

pLI 0.000

Z-score 2.92

OE 0.47 (0.32–0.71)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.68Z-score

OE missense 1.10 (1.01–1.20)

391 obs / 355.1 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.47 (0.32–0.71)

0≤0.351.4

Missense OE?1.10 (1.01–1.20)

0≤0.61.4

Synonymous OE?1.24

0≤1.21.6

LoF obs/exp: 17 / 35.9Missense obs/exp: 391 / 355.1Syn Z: -2.14

Background carrier burden — how many people carry a rare variant somewhere in DCLRE1C?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 78

966 rare PASS variants

Rare truncating (LoF)

1 in 610

176 rare PASS variants

Rare synonymous (reference)

1 in 150

370 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for DCLRE1C. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 120	1 in 640
South Asian	~43k	1 in 55	1 in 810
Remaining (unassigned)	~30k	1 in 63	1 in 390
European (Finnish)	~27k	1 in 190	≈ 1 in 6,700
Admixed American	~22k	1 in 64	1 in 910
African / African American	~21k	1 in 47	1 in 480
East Asian	~20k	1 in 62	1 in 770
Ashkenazi Jewish	~13k	1 in 440	≈ 1 in 13,000
Middle Eastern	~2,884	1 in 55	≈ 1 in 680

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 12 of 14 coding exons well covered in gnomAD exomes; exons 2, 4 marginal. Genomes: all 14.? see exons ↓

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

DCLRE1C · protein map & ClinVar variants

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

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

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Stimulant UseHuman Immunodeficiency Virus (HIV)Depression

Project neuroARTEMIS

RECRUITING

NCT06814275Phase NAWake Forest University Health SciencesStarted 2025-04-29

ARTEMISContingency management for Antiretroviral (ARV) adherence

Spinal Muscular AtrophyFragile X SyndromeFragile X - Premutation

Early Check: Expanded Screening in Newborns

ACTIVE NOT RECRUITING

NCT03655223RTI InternationalStarted 2018-10-15

Confirmatory Testing

Severe Combined Immunodeficiency

Autologous Gene Therapy for Artemis-Deficient SCID

RECRUITING

NCT03538899Phase PHASE1, PHASE2University of California, San FranciscoStarted 2018-05-31

AProArt-CD34CliniMACS® CD34 Reagent System cell sorter deviceBusulfan

Artemis (DCLRE1C ) Deficient Severe Combined Immunodeficiency

Safety and Efficacy Study of Transplantation of Autologous CD34+ Cells Transduced With the G2ARTE Lentiviral Vector Expressing the DCLRE1C cDNA in Artemis (DCLRE1C) Deficient Severe Combined Immunodeficiency Patients (ARTEGENE)

RECRUITING

NCT05071222Phase PHASE1, PHASE2Assistance Publique - Hôpitaux de ParisStarted 2023-07-19

ARTEGENE drug product

Clinical Literature

Open Research Assistant →

Landmark / reviewRecent case evidence

Full-Text Mentions

NLP-detected gene mentions in article bodies · via PubTator3

PubTator3

Could beta-Lactam Antibiotics Block Humoral Immunity?

Melenotte C et al.·Front Immunol

2021