NOP56

Chr 20

NOP56 ribonucleoprotein

Also known as: NOL5A, SCA36

NCBI Gene: 10528 ENSG00000101361 UniProt: O00567

NOP56 encodes a nucleolar protein that is essential for 60S ribosomal subunit biogenesis and functions as a core component of box C/D small nucleolar ribonucleoprotein complexes involved in ribosomal RNA methylation. Expansion of a GGCCTG repeat in an intron causes spinocerebellar ataxia 36, an autosomal dominant progressive cerebellar disorder. The gene shows high constraint against loss-of-function variants (LOEUF 0.404), indicating intolerance to haploinsufficiency.

GeneReviews ResearchSummary from RefSeq, OMIM, UniProt

Nop56p is a yeast nucleolar protein that is part of a complex with the nucleolar proteins Nop58p and fibrillarin. Nop56p is required for assembly of the 60S ribosomal subunit and is involved in pre-rRNA processing. The protein encoded by this gene is similar in sequence to Nop56p and is also found in the nucleolus. Expansion of a GGCCTG repeat from 3-8 copies to 1500-2500 copies in an intron of this gene results in spinocerebellar ataxia 36. Multiple transcript variants encoding several different isoforms have been found for this gene, but the full-length nature of most of them has not been determined. [provided by RefSeq, Jul 2016]

GeneReviews ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.40

Clinical Summary— NOP56

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.62) — some intolerance to loss-of-function variants.

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ClinVar Variants

3 unique Pathogenic / Likely Pathogenic· 80 VUS of 131 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — NOP56

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.40LOEUF

pLI 0.621

Z-score 3.99

OE 0.20 (0.11–0.40)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.60Z-score

OE missense 0.91 (0.82–1.00)

299 obs / 329.9 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.20 (0.11–0.40)

0≤0.351.4

Missense OE?0.91 (0.82–1.00)

0≤0.61.4

Synonymous OE?1.11

0≤1.21.6

LoF obs/exp: 6 / 29.3Missense obs/exp: 299 / 329.9Syn Z: -1.00

This gene — mechanism propensity

0.6161th %ile

GOF

0.3689th %ile

LOF

0.57top 25%

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

DNprediction above median

GOF1 literature citation

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.

Literature Evidence

GOFThe findings indicated that SCA36 is caused by hexanucleotide repeat expansions through a toxic gain of function.1

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

References

1.PMID 21683323 ↗

ClinVar Variant Classifications

131 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic2

Likely Pathogenic1

VUS80

Likely Benign15

Benign12

Conflicting1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	2	0	2
Likely Pathogenic	0	0	0	1	1
VUS	0	80	0	0	80
Likely Benign	1	3	4	7	15
Benign	0	4	2	6	12
Conflicting	—				1
Total	1	87	8	14	111

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

View in ClinVar →

24 pathogenic / likely-pathogenic (of 32) ClinVar copy-number / structural variants overlap NOP56 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →