SIRT4

Chr 12

sirtuin 4

Also known as: SIR2L4

NCBI Gene: 23409 ENSG00000089163 UniProt: Q9Y6E7 OMIM: 604482

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.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the sirtuin family of proteins, homologs to the yeast Sir2 protein. Members of the sirtuin family are characterized by a sirtuin core domain and grouped into four classes. The functions of human sirtuins have not yet been determined; however, yeast sirtuin proteins are known to regulate epigenetic gene silencing and suppress recombination of rDNA. Studies suggest that the human sirtuins may function as intracellular regulatory proteins with mono-ADP-ribosyltransferase activity. The protein encoded by this gene is included in class IV of the sirtuin family. [provided by RefSeq, Jul 2008]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 1.77

Clinical Summary— SIRT4

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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

30 unique Pathogenic / Likely Pathogenic· 72 VUS of 126 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.77LOEUF

pLI 0.000

Z-score -0.52

OE 1.17 (0.76–1.77)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

1.01Z-score

OE missense 0.80 (0.70–0.91)

158 obs / 198.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?1.17 (0.76–1.77)

0≤0.351.4

Missense OE?0.80 (0.70–0.91)

0≤0.61.4

Synonymous OE?0.88

0≤1.21.6

LoF obs/exp: 13 / 11.1Missense obs/exp: 158 / 198.2Syn Z: 0.82

This gene — mechanism propensity

0.6455th %ile

GOF

0.4677th %ile

LOF

0.4135th %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

126 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic8

Likely Pathogenic22

VUS72

Likely Benign13

Benign2

Conflicting2

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	0	0	8	0	8
Likely Pathogenic	0	0	22	0	22
VUS	0	44	28	0	72
Likely Benign	0	3	10	0	13
Benign	0	1	0	1	2
Conflicting	—				2
Total	0	48	68	1	119

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

View in ClinVar →

13 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap SIRT4 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →