RAG2

Chr 11AR

recombination activating 2

Also known as: RAG-2

NCBI Gene: 5897 ENSG00000175097 UniProt: P55895 OMIM: 179616

The RAG2 protein forms a complex with RAG1 that mediates DNA cleavage during V(D)J recombination, the process that assembles diverse immunoglobulin and T-cell receptor genes in developing B and T lymphocytes. Mutations cause autosomal recessive severe combined immunodeficiency including Omenn syndrome, characterized by absent B cells and severe immune dysfunction often presenting in infancy. RAG2 acts as a chromatin sensor that recruits the RAG complex to specific histone modifications and is essential for generating functional adaptive immune responses.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein that is involved in the initiation of V(D)J recombination during B and T cell development. This protein forms a complex with the product of the adjacent recombination activating gene 1, and this complex can form double-strand breaks by cleaving DNA at conserved recombination signal sequences. The recombination activating gene 1 component is thought to contain most of the catalytic activity, while the N-terminal of the recombination activating gene 2 component is thought to form a six-bladed propeller in the active core that serves as a binding scaffold for the tight association of the complex with DNA. A C-terminal plant homeodomain finger-like motif in this protein is necessary for interactions with chromatin components, specifically with histone H3 that is trimethylated at lysine 4. Mutations in this gene cause Omenn syndrome, a form of severe combined immunodeficiency associated with autoimmune-like symptoms. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Combined cellular and humoral immune defects with granulomasMIM #233650

Omenn syndromeMIM #603554

Severe combined immunodeficiency, B cell-negativeMIM #601457

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · recombinase activating gene 2 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

119

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.79

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — RAG2

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.79LOEUF

pLI 0.020

Z-score 2.10

OE 0.38 (0.20–0.79)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.20Z-score

OE missense 0.97 (0.87–1.07)

257 obs / 266.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.38 (0.20–0.79)

0≤0.351.4

Missense OE?0.97 (0.87–1.07)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 5 / 13.3Missense obs/exp: 257 / 266.0Syn Z: 0.23

Background carrier burden — how many people carry a rare variant somewhere in RAG2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 89

668 rare PASS variants

Rare truncating (LoF)

1 in 2,300

74 rare PASS variants

Rare synonymous (reference)

1 in 300

211 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RAG2. 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 110	1 in 2,200
South Asian	~43k	1 in 110	1 in 1,400
Remaining (unassigned)	~30k	1 in 92	1 in 3,300
European (Finnish)	~27k	1 in 200	1 in 4,500
Admixed American	~22k	1 in 84	1 in 1,600
African / African American	~21k	1 in 89	≈ 1 in 4,400
East Asian	~20k	1 in 140	≈ 1 in 9,900
Ashkenazi Jewish	~13k	1 in 190	1 in 1,500
Middle Eastern	~2,884	1 in 100	none seen

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): All 1 coding exons well covered in gnomAD exomes and genomes.? see exons ↓