TUT4

Chr 1

terminal uridylyl transferase 4

Also known as: PAPD3, TENT3A, ZCCHC11

NCBI Gene: 23318 ENSG00000134744 UniProt: Q5TAX3 OMIM: 613692

The TUT4 protein is a uridylyltransferase that regulates mRNA stability and microRNA biogenesis through terminal uridylation of RNA substrates. Mutations cause autosomal recessive developmental delay, intellectual disability, and microcephaly with onset in infancy. This gene is highly constrained against loss-of-function variants (pLI ~1.0, LOEUF 0.107), reflecting its essential role in RNA metabolism and early development.

GeneReviews OMIM ResearchSummary from RefSeq, UniProt

Enables RNA uridylyltransferase activity. Involved in RNA metabolic process; stem cell population maintenance; and transposable element silencing by mRNA destabilization. Located in cytoplasmic ribonucleoprotein granule; cytosol; and nucleolus. Implicated in liver benign neoplasm. Biomarker of breast cancer. [provided by Alliance of Genome Resources, Jul 2025]

GeneReviews OMIM ResearchGenerating clinical summary…

LOFmechanismLOEUF 0.11

Clinical Summary— TUT4

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Population Constraint (gnomAD)

Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 1.00). One damaged copy is likely sufficient to cause disease.

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ClinVar Variants

189 VUS of 236 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — TUT4

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

LoF intolerant — likely haploinsufficient

LoF Constraint?

0.11LOEUF

pLI 1.000

Z-score 8.18

OE 0.05 (0.02–0.11)

Highly constrained

Among the most LoF-intolerant genes (~top 3%)

Missense Constraint?

2.76Z-score

OE missense 0.73 (0.69–0.79)

627 obs / 853.7 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.05 (0.02–0.11)

0≤0.351.4

Missense OE?0.73 (0.69–0.79)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 4 / 85.8Missense obs/exp: 627 / 853.7Syn Z: 1.57

This gene — mechanism propensity

0.2898th %ile

GOF

0.2795th %ile

LOF

0.76top 10%

The highest-scoring mechanism for this gene is loss-of-function (haploinsufficiency).

LOFprediction above median · LOEUF 0.11

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

236 submitted variants in ClinVar

ClinVar

Classification Summary

VUS189

Likely Benign8

Benign5

189

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	0	0
Likely Pathogenic	0	0	0	0
VUS	189	0	0	189
Likely Benign	7	0	1	8
Benign	2	1	2	5
Total	198	1	3	202

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

View in ClinVar →

7 pathogenic / likely-pathogenic (of 10) ClinVar copy-number / structural variants overlap TUT4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →