NSUN4

Chr 1

NOP2/Sun RNA methyltransferase 4

Also known as: SHTAP

The protein is a mitochondrial RNA cytosine methyltransferase that modifies mitochondrial ribosomal RNAs and messenger RNAs, playing a critical role in mitochondrial ribosome biogenesis and function. Mutations cause autosomal recessive combined oxidative phosphorylation deficiency-37, a severe mitochondrial disorder affecting energy metabolism. The gene is extremely intolerant to loss-of-function variants, indicating that complete protein loss is likely incompatible with normal cellular function.

ResearchSummary from RefSeq, UniProt

Enables mRNA (cytidine-5-)-methyltransferase activity and rRNA (cytosine-C5-)-methyltransferase activity. Involved in mitochondrial RNA catabolic process; mitochondrial RNA modification; and rRNA methylation. Located in mitochondrial matrix. Part of mitochondrial large ribosomal subunit. [provided by Alliance of Genome Resources, Jul 2025]

ResearchGenerating clinical summary…

DNmechanismLOEUF 0.91

Clinical Summary— NSUN4

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Population Constraint (gnomAD)

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

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ClinVar Variants

48 VUS of 66 total submissions

Explore recent and relevant literature in Research Assistant →

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

0.91LOEUF

pLI 0.000

Z-score 1.87

OE 0.57 (0.37–0.91)

Tolerant

Typical tolerance to LoF variation

Missense Constraint?

0.83Z-score

OE missense 0.84 (0.74–0.95)

183 obs / 217.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.57 (0.37–0.91)

0≤0.351.4

Missense OE?0.84 (0.74–0.95)

0≤0.61.4

Synonymous OE?0.86

0≤1.21.6

LoF obs/exp: 13 / 22.6Missense obs/exp: 183 / 217.5Syn Z: 1.03

This gene — mechanism propensity

0.6258th %ile

GOF

0.4579th %ile

LOF

0.2969th %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

66 submitted variants in ClinVar

ClinVar

Classification Summary

VUS48

VUS

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Total
Pathogenic	0	0
Likely Pathogenic	0	0
VUS	48	48
Likely Benign	0	0
Benign	0	0
Total	48	48

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

View in ClinVar →

6 pathogenic / likely-pathogenic (of 12) ClinVar copy-number / structural variants overlap NSUN4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →