EXOSC5

Chr 19AR

exosome component 5

Also known as: CABAC, RRP41B, RRP46, Rrp46p, hRrp46p, p12B

NCBI Gene: 56915 ENSG00000077348 OMIM: 606492

EXOSC5 encodes a non-catalytic component of the RNA exosome complex, which degrades and processes various RNA species in both the nucleus and cytoplasm. Biallelic mutations cause autosomal recessive cerebellar ataxia with brain abnormalities and cardiac conduction defects. The gene is not highly constrained against loss-of-function variants in the general population.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

Predicted to enable RNA binding activity. Involved in DNA deamination; RNA processing; and mRNA catabolic process. Acts upstream of or within defense response to virus. Located in cytosol; euchromatin; and nuclear lumen. Part of exosome (RNase complex). [provided by Alliance of Genome Resources, Jul 2025]

OMIM ResearchGenerating clinical summary…

MultiplemechanismARLOEUF 1.141 OMIM phenotype

Clinical Summary— EXOSC5

⚡

Population Constraint (gnomAD)

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

📋

ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 52 VUS of 74 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?

1.14LOEUF

pLI 0.004

Z-score 1.29

OE 0.54 (0.28–1.14)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.48Z-score

OE missense 0.89 (0.77–1.03)

131 obs / 147.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.54 (0.28–1.14)

0≤0.351.4

Missense OE?0.89 (0.77–1.03)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 5 / 9.2Missense obs/exp: 131 / 147.5Syn Z: 0.21

This gene — mechanism propensity

0.6358th %ile

GOF

0.4283th %ile

LOF

0.4332th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and loss-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

LOF50% of P/LP variants are LoF

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. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

74 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic3

Likely Pathogenic3

VUS52

Likely Benign7

Benign1

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Synonymous	Total
Pathogenic	2	1	0	3
Likely Pathogenic	1	2	0	3
VUS	1	51	0	52
Likely Benign	0	2	5	7
Benign	0	1	0	1
Total	4	57	5	66

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

View in ClinVar →

6 pathogenic / likely-pathogenic (of 10) ClinVar copy-number / structural variants overlap EXOSC5 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →