RB1

Chr 13ADSomatic

RB transcriptional corepressor 1

Also known as: OSRC, PPP1R130, RB, p105-Rb, p110-RB1, pRb, pp110

NCBI Gene: 5925 ENSG00000139687 UniProt: P06400

The protein encoded by this gene is a negative regulator of the cell cycle and was the first tumor suppressor gene found. The encoded protein also stabilizes constitutive heterochromatin to maintain the overall chromatin structure. The active, hypophosphorylated form of the protein binds transcription factor E2F1. Defects in this gene are a cause of childhood cancer retinoblastoma (RB), bladder cancer, and osteogenic sarcoma. [provided by RefSeq, Jul 2008]

Primary Disease Associations & Inheritance

Bladder cancer, somaticMIM #109800

Osteosarcoma, somaticMIM #259500

RetinoblastomaMIM #180200

ADSomatic

Retinoblastoma, trilateralMIM #180200

ADSomatic

Small cell cancer of the lung, somaticMIM #182280

RetinoblastomaMIM #180200

ADSomatic

Retinoblastoma, trilateralMIM #180200

ADSomatic

UniProtChildhood cancer retinoblastoma

UniProtOsteogenic sarcoma

Active trials

Pathogenic / LP

ClinVar variants

Pubs (1 yr)

2.7

Missense Z

0.13

LOEUF· LoF intolerant

Clinical Summary— RB1

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Gene-Disease Validity (ClinGen)

retinoblastoma · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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Clinical Trials

12 active or recruiting trials — potential therapeutic options may be available

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GeneReview available — RB1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.

0.13LOEUF

pLI 1.000

Z-score 6.93

OE 0.05 (0.02–0.13)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.

2.67Z-score

OE missense 0.65 (0.60–0.72)

311 obs / 474.9 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.

LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.05 (0.02–0.13)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.65 (0.60–0.72)

0≤0.61.4

Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.95

0≤1.21.6

LoF obs/exp: 3 / 61.8Missense obs/exp: 311 / 474.9Syn Z: 0.49

0.2997th %ile

GOF

0.2597th %ile

LOF

0.78top 5%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · 1 literature citation · LOEUF 0.13

Literature Evidence

LOFHaploinsufficiency of RB1 accelerates cancer pathogenesis in concert with inactivation of tumor protein p53.PMID:27308386

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

0 submitted variants in ClinVar

ClinVar

Protein Context — Lollipop Plot

RB1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

RB1-related retinoblastoma

definitive

ADLoss Of FunctionAbsent Gene Product

EyeCancer

G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

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

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GeneReview available — RB1

Authoritative clinical overview · NCBI Bookshelf · Recommended first read

Open GeneReview ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

Advanced Malignant Solid NeoplasmRecurrent Ependymal TumorRecurrent Ewing Sarcoma

Ulixertinib in Treating Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With MAPK Pathway Mutations (A Pediatric MATCH Treatment Trial)

ACTIVE NOT RECRUITING

NCT03698994Phase PHASE2National Cancer Institute (NCI)Started 2018-11-14

Pharmacokinetic StudyUlixertinib

Solid TumorsCNS Tumors

Study Of Entrectinib (Rxdx-101) in Children and Adolescents With Locally Advanced Or Metastatic Solid Or Primary CNS Tumors And/Or Who Have No Satisfactory Treatment Options

ACTIVE NOT RECRUITING

NCT02650401Phase PHASE1, PHASE2Hoffmann-La RocheStarted 2016-05-03

Entrectinib

Advanced Solid TumorMetastatic Solid TumorRefractory Solid Tumor

Safety/Efficacy Study of CID-078 in Patients With Advanced Solid Tumor Malignancies

RECRUITING

NCT06577987Phase PHASE1Circle PharmaStarted 2024-08-14

CID-078 Monotherapy

RetinoblastomaCancer SurvivorBiological Sibling

Studying Health Outcomes After Treatment in Patients With Retinoblastoma

RECRUITING

NCT03932786Vanderbilt-Ingram Cancer CenterStarted 2019-01-24

Biospecimen collectionVision assessmentQuestionnaire administration

NeuroblastomaEwing Sarcoma

Fertility Preservation in Children With Solid Tumors: Detection of Residual Disease by a Sensitive Method

RECRUITING

NCT07141862University Hospital, Clermont-FerrandStarted 2025-02-01

RT-qPCRddPCR

Hematopoietic and Lymphatic System NeoplasmRecurrent EpendymomaRecurrent Ewing Sarcoma

Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediatric MATCH Treatment Trial

ACTIVE NOT RECRUITING

NCT04320888Phase PHASE2National Cancer Institute (NCI)Started 2021-05-03

Computed TomographyMagnetic Resonance ImagingPositron Emission Tomography

Relapsed NeuroblastomaRefractory NeuroblastomaRelapsed Osteosarcoma

NKG2D.Zeta-NK Cell Conditioning With C7R.GD2.CAR-T Cells for Patients With Relapsed or Refractory Osteosarcoma or Neuroblastoma

NOT YET RECRUITING

NCT07211737Phase PHASE1Baylor College of MedicineStarted 2026-05

i15.NKG2D.zeta NK cells and C7R.GD2.CARTs cellsi15.NKG2D.zeta NK cells and C7R.GD2.CARTs cellsi15.NKG2D.zeta NK cells and C7R.GD2.CARTs cells

Prostate Cancer Metastatic

Pembrolizumab, Carboplatin and Cabazitaxel in Aggressive Metastatic Castration Resistant Prostate Cancer (PEAPOD_FOS)

RECRUITING

NCT05563558Phase PHASE2Fundacion OncosurStarted 2023-05-05