NRBP2

Chr 8

nuclear receptor binding protein 2

Also known as: TRG16, pp9320

NCBI Gene: 340371 ENSG00000185189 UniProt: Q9NSY0 OMIM: 615563

NRBP2 encodes a protein with serine/threonine kinase activity that negatively regulates macroautophagy and may control apoptosis during neural progenitor cell differentiation. Mutations cause autosomal recessive neurodevelopmental disorders with intellectual disability and epilepsy. The gene shows moderate constraint to loss-of-function variation (LOEUF 0.52).

OMIM ResearchSummary from RefSeq, UniProt

Predicted to enable protein serine/threonine kinase activity. Involved in negative regulation of macroautophagy. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.52

Clinical Summary— NRBP2

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.30) despite low pLI — interpret in context.

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ClinVar Variants

75 VUS of 106 total submissions

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.52LOEUF

pLI 0.016

Z-score 3.57

OE 0.30 (0.18–0.52)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

1.92Z-score

OE missense 0.69 (0.62–0.77)

212 obs / 306.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.30 (0.18–0.52)

0≤0.351.4

Missense OE?0.69 (0.62–0.77)

0≤0.61.4

Synonymous OE?1.09

0≤1.21.6

LoF obs/exp: 9 / 30.2Missense obs/exp: 212 / 306.8Syn Z: -0.80

This gene — mechanism propensity

0.6841th %ile

GOF

0.7027th %ile

LOF

0.3453th %ile

This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

GOFprediction above median

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

106 submitted variants in ClinVar

ClinVar

Classification Summary

VUS75

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	75	75
Likely Benign	0	0
Benign	0	0
Total	75	75

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

View in ClinVar →

63 pathogenic / likely-pathogenic (of 69) ClinVar copy-number / structural variants overlap NRBP2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →