RPUSD4

Chr 11

RNA pseudouridine synthase D4

NCBI Gene: 84881 ENSG00000165526 UniProt: Q96CM3 OMIM: 617488

The RPUSD4 protein is a pseudouridine synthase that modifies mitochondrial ribosomal RNA and tRNA, playing an essential role in mitochondrial ribosome assembly and translation, while also regulating nuclear pre-mRNA splicing through RNA modifications. Mutations cause autosomal recessive mitochondrial complex IV deficiency presenting in infancy with severe neurological deterioration, developmental delay, and multi-organ dysfunction. This gene shows very low constraint against loss-of-function variants, consistent with recessive inheritance where heterozygous carriers are typically unaffected.

OMIM ResearchSummary from RefSeq, UniProt

Enables mitochondrial ribosomal large subunit rRNA binding activity; pseudouridine synthase activity; and tRNA binding activity. Involved in positive regulation of mitochondrial translation and pseudouridine synthesis. Located in mitochondrial matrix and ribonucleoprotein granule. [provided by Alliance of Genome Resources, Jun 2026]

OMIM ResearchGenerating clinical summary…

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.16

LOEUF

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.16LOEUF

pLI 0.000

Z-score 1.07

OE 0.72 (0.46–1.16)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

-0.40Z-score

OE missense 1.08 (0.97–1.20)

244 obs / 227.0 exp

Tolerant

Tolerant to missense variation

Observed / Expected Ratios?

LoF OE?0.72 (0.46–1.16)

0≤0.351.4

Missense OE?1.08 (0.97–1.20)

0≤0.61.4

Synonymous OE?1.05

0≤1.21.6

LoF obs/exp: 12 / 16.7Missense obs/exp: 244 / 227.0Syn Z: -0.39

Background carrier burden — how many people carry a rare variant somewhere in RPUSD4?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 74

561 rare PASS variants

Rare truncating (LoF)

1 in 1,900

91 rare PASS variants

Rare synonymous (reference)

1 in 380

204 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for RPUSD4. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 92	1 in 2,100
South Asian	~43k	1 in 81	1 in 760
Remaining (unassigned)	~30k	1 in 87	1 in 1,100
European (Finnish)	~27k	1 in 430	1 in 4,400
Admixed American	~22k	1 in 70	1 in 730
African / African American	~21k	1 in 98	1 in 860
East Asian	~20k	1 in 100	1 in 3,300
Ashkenazi Jewish	~13k	1 in 490	1 in 1,900
Middle Eastern	~2,884	1 in 78	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 7 coding exons well covered in gnomAD exomes and genomes.? see exons ↓