SIRT4
Chr 12sirtuin 4
Also known as: SIR2L4
The protein functions as a mitochondrial NAD-dependent enzyme that regulates cellular metabolism by removing lipoyl and biotinyl modifications from target proteins, inhibiting pyruvate dehydrogenase complex activity, and modulating glutamine metabolism through ADP-ribosylation of GLUD1. Mutations cause autosomal recessive mitochondrial dysfunction with variable presentation including developmental delay, seizures, and metabolic abnormalities. This gene shows high evolutionary constraint, indicating that loss-of-function variants are poorly tolerated.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly tolerant — LoF variants common in population
Mild missense constraint
The highest-scoring mechanism for this gene is dominant-negative.
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
142 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 18 | 0 | 18 |
Likely Pathogenic | 0 | 0 | 25 | 0 | 25 |
VUS | 0 | 44 | 31 | 0 | 75 |
Likely Benign | 0 | 3 | 10 | 0 | 13 |
Benign | 0 | 1 | 0 | 1 | 2 |
Conflicting | — | 2 | |||
| Total | 0 | 48 | 84 | 1 | 135 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
SIRT4 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
3D Protein StructureAlphaFold
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools