RBBP8

Chr 18AR

RB binding protein 8, endonuclease

Also known as: COM1, CTIP, JAWAD, JWDS, RIM, SAE2, SCKL2

NCBI Gene: 5932 ENSG00000101773 UniProt: Q99708 OMIM: 604124

The RBBP8 protein is an endonuclease that cooperates with the MRE11-RAD50-NBN complex in DNA double-strand break repair through homologous recombination and regulates cell cycle checkpoints. Biallelic mutations cause autosomal recessive Seckel syndrome 2 and Jawad syndrome, both presenting with severe growth restriction and microcephaly from birth. The gene is highly constrained against loss-of-function variants (pLI near 0, LOEUF 0.749), reflecting its essential role in DNA repair.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene is a ubiquitously expressed nuclear protein. It is found among several proteins that bind directly to retinoblastoma protein, which regulates cell proliferation. This protein complexes with transcriptional co-repressor CTBP. It is also associated with BRCA1 and is thought to modulate the functions of BRCA1 in transcriptional regulation, DNA repair, and/or cell cycle checkpoint control. It is suggested that this gene may itself be a tumor suppressor acting in the same pathway as BRCA1. Three transcript variants encoding two different isoforms have been found for this gene. More transcript variants exist, but their full-length natures have not been determined. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 0.753 OMIM phenotypes

Clinical Summary— RBBP8

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

11 unique Pathogenic / Likely Pathogenic· 206 VUS of 458 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.75LOEUF

pLI 0.000

Z-score 2.99

OE 0.54 (0.40–0.75)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

-0.02Z-score

OE missense 1.00 (0.93–1.08)

466 obs / 464.8 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.54 (0.40–0.75)

0≤0.351.4

Missense OE?1.00 (0.93–1.08)

0≤0.61.4

Synonymous OE?0.99

0≤1.21.6

LoF obs/exp: 27 / 49.7Missense obs/exp: 466 / 464.8Syn Z: 0.09

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

definitiveRBBP8-related microcephaly and intellectual disabilityOTHERAR

This gene — mechanism propensity

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

0.6550th %ile

GOF

0.3094th %ile

LOF

0.4332th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

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

458 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic7

VUS206

Likely Benign166

Benign41

Conflicting14

Pathogenic

Likely Pathogenic

206

VUS

166

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	3	0	1	0	4
Likely Pathogenic	7	0	0	0	7
VUS	11	186	9	0	206
Likely Benign	1	12	74	79	166
Benign	0	1	36	4	41
Conflicting	—				14
Total	22	199	120	83	438

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

View in ClinVar →

35 pathogenic / likely-pathogenic (of 41) ClinVar copy-number / structural variants overlap RBBP8 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →