RNASEK

Chr 17

ribonuclease K

NCBI Gene: 440400 ENSG00000219200 UniProt: Q6P5S7 OMIM: 617098

The RNASEK protein is an endoribonuclease that regulates vacuolar H+-ATPase activity, which is essential for acidifying intracellular compartments and receptor-mediated endocytosis. Mutations cause MEND syndrome (mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma), a severe multisystem disorder with autosomal recessive inheritance. The condition involves intellectual disability, gastrointestinal dysfunction, hearing loss, and skin abnormalities with early childhood onset.

OMIM ResearchSummary from RefSeq, UniProt

Endoribonuclease which preferentially cleaves ApU and ApG phosphodiester bonds. Hydrolyzes UpU bonds at a lower rate (PubMed:17881363). Regulates the activity of vacuolar (H+)-ATPase (V-ATPase) which is responsible for acidifying and maintaining the pH of intracellular compartments (PubMed:26212330). Required at an early stage of receptor-mediated endocytosis (PubMed:26212330)

OMIM ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.78

Clinical Summary— RNASEK

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Population Constraint (gnomAD)

Moderately constrained gene (pLI 0.50) — some intolerance to loss-of-function variants.

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.78LOEUF

pLI 0.504

Z-score 1.91

OE 0.16 (0.06–0.78)

Moderately constrained

Typical tolerance to LoF variation

Missense Constraint?

0.50Z-score

OE missense 0.85 (0.70–1.03)

71 obs / 83.8 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.16 (0.06–0.78)

0≤0.351.4

Missense OE?0.85 (0.70–1.03)

0≤0.61.4

Synonymous OE?1.01

0≤1.21.6

LoF obs/exp: 1 / 6.1Missense obs/exp: 71 / 83.8Syn Z: -0.03

This gene — mechanism propensity

0.6937th %ile

GOF

0.73top 25%

LOF

0.3259th %ile

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

GOFprediction above median

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.