EXOSC4

Chr 8

exosome component 4

Also known as: RRP41, RRP41A, Rrp41p, SKI6, Ski6p, hRrp41p, p12A

NCBI Gene: 54512 ENSG00000178896 UniProt: Q9NPD3 OMIM: 606491

The EXOSC4 protein is a non-catalytic component of the RNA exosome complex that processes and degrades various cellular RNAs, including rRNA maturation, mRNA turnover, and elimination of aberrant transcripts. Mutations in EXOSC4 cause autosomal recessive short stature, hearing loss, retinitis pigmentosa, and distinctive facies (SHRF) syndrome, affecting growth, sensory organs, and development. This gene shows relatively low constraint to loss-of-function variation, suggesting the recessive inheritance pattern aligns with its tolerance profile.

OMIM ResearchSummary from RefSeq, UniProt

Enables mRNA 3'-UTR AU-rich region binding activity. Involved in several processes, including DNA deamination; maturation of 5.8S rRNA; and nuclear-transcribed 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…

DNmechanismLOEUF 0.98

Clinical Summary— EXOSC4

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.07) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

31 VUS of 35 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?

0.98LOEUF

pLI 0.068

Z-score 1.62

OE 0.38 (0.17–0.98)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.56Z-score

OE missense 0.87 (0.75–1.01)

128 obs / 147.0 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.38 (0.17–0.98)

0≤0.351.4

Missense OE?0.87 (0.75–1.01)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 3 / 7.9Missense obs/exp: 128 / 147.0Syn Z: 0.73

This gene — mechanism propensity

0.6551th %ile

GOF

0.4875th %ile

LOF

0.3744th %ile

The highest-scoring mechanism for this gene is dominant-negative.

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

35 submitted variants in ClinVar

ClinVar

Classification Summary

VUS31

Likely Benign2

Benign1

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	31	0	31
Likely Benign	0	2	2
Benign	0	1	1
Total	31	3	34

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

View in ClinVar →

61 pathogenic / likely-pathogenic (of 72) ClinVar copy-number / structural variants overlap EXOSC4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →