RBL2

Chr 16AR

RB transcriptional corepressor like 2

Also known as: BRUWAG, P130, Rb2

NCBI Gene: 5934 ENSG00000103479 UniProt: Q08999 OMIM: 180203

The protein encoded by this gene regulates cell cycle entry and acts as a transcriptional repressor by recruiting chromatin-modifying enzymes and controlling histone methylation, particularly maintaining heterochromatin structure. Mutations cause developmental and epileptic encephalopathy with microcephaly and growth retardation, typically presenting in early infancy with seizures, developmental delays, and failure to thrive. This gene follows autosomal recessive inheritance and is highly constrained against loss-of-function variants in the population.

OMIM ResearchSummary from RefSeq, UniProt

Enables promoter-specific chromatin binding activity. Involved in regulation of lipid kinase activity. Acts upstream of or within negative regulation of gene expression. Located in nucleolus and nucleoplasm. Implicated in Brunet-Wagner neurodevelopmental syndrome. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Brunet-Wagner neurodevelopmental syndromeMIM #619690

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Brunet-Wagner neurodevelopmental syndrome; no ClinGen or GenCC tier

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Based on population constraint only.

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.27

LOEUF· LoF intol.

LOF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.27LOEUF

pLI 0.998

Z-score 5.80

OE 0.15 (0.09–0.27)

Highly constrained

Highly LoF-intolerant (top ~10% of genes)

Missense Constraint?

1.23Z-score

OE missense 0.86 (0.80–0.92)

519 obs / 603.7 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.15 (0.09–0.27)

0≤0.351.4

Missense OE?0.86 (0.80–0.92)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 8 / 54.0Missense obs/exp: 519 / 603.7Syn Z: 1.61

Background carrier burden — how many people carry a rare variant somewhere in RBL2?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 54

1,330 rare PASS variants

Rare truncating (LoF)

1 in 1,800

137 rare PASS variants

Rare synonymous (reference)

1 in 180

492 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RBL2. 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 66	1 in 2,000
South Asian	~43k	1 in 40	1 in 1,900
Remaining (unassigned)	~30k	1 in 48	1 in 2,700
European (Finnish)	~27k	1 in 160	1 in 1,900
Admixed American	~22k	1 in 51	1 in 1,000
African / African American	~21k	1 in 44	1 in 1,600
East Asian	~20k	1 in 58	1 in 880
Ashkenazi Jewish	~13k	1 in 310	≈ 1 in 4,100
Middle Eastern	~2,884	1 in 47	≈ 1 in 2,700

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): 20 of 22 coding exons well covered in gnomAD exomes; exons 4, 11 marginal. Genomes: all 22.? see exons ↓