SIRT5

Chr 6

sirtuin 5

Also known as: SIR2L5

NCBI Gene: 23408ENSG00000124523UniProt: Q9NXA8

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 III of the sirtuin family. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2010]

84
ClinVar variants
23
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— SIRT5
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
23 Pathogenic / Likely Pathogenic· 55 VUS of 84 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.24LOEUF
pLI 0.000
Z-score 0.77
OE 0.81 (0.55–1.24)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.14Z-score
OE missense 0.97 (0.86–1.10)
188 obs / 193.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.81 (0.55–1.24)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.97 (0.86–1.10)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.05
0≤1.21.6
LoF obs/exp: 16 / 19.7Missense obs/exp: 188 / 193.5Syn Z: -0.33

ClinVar Variant Classifications

84 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic22
Likely Pathogenic1
VUS55
Likely Benign5
Benign1
22
Pathogenic
1
Likely Pathogenic
55
VUS
5
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
22
0
22
Likely Pathogenic
0
0
1
0
1
VUS
0
51
4
0
55
Likely Benign
0
5
0
0
5
Benign
0
0
1
0
1
Total05628084

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

View in ClinVar →

Protein Context — Lollipop Plot

SIRT5 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
SIRTUIN 5; SIRT5
MIM #604483 · *
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Loss of SIRT5 promotes bile acid-induced immunosuppressive microenvironment and hepatocarcinogenesis.
Sun R et al.·J Hepatol
2022
Dietary-timing-induced gut microbiota diurnal oscillations modulate inflammatory rhythms in rheumatoid arthritis.
Ma F et al.·Cell Metab
2024
New insights into the pathophysiology of methylmalonic acidemia.
Head PE et al.·J Inherit Metab Dis
2023Review
Metabolic Rewiring by Loss of Sirt5 Promotes Kras-Induced Pancreatic Cancer Progression.
Hu T et al.·Gastroenterology
2021
The AKT2/SIRT5/TFEB pathway as a potential therapeutic target in non-neovascular AMD.
Ghosh S et al.·Nat Commun
2024
SIRT5-mediated BCAT1 desuccinylation and stabilization leads to ferroptosis insensitivity and promotes cell proliferation in glioma.
Wang T et al.·Cell Death Dis
2025
SIRT5 rs12216101 T>G variant is associated with liver damage and mitochondrial dysfunction in patients with non-alcoholic fatty liver disease.
Salomone F et al.·J Hepatol
2024Cohort
SIRT5 exacerbates eosinophilic chronic rhinosinusitis by promoting polarization of M2 macrophage.
Cha XD et al.·J Allergy Clin Immunol
2024
Association between mitochondrial SIRTs (SIRT3, SIRT4, and SIRT5) and PCOS.
Huang L et al.·Eur J Med Res
2025
SIRT5 regulates granulosa cell proliferation and apoptosis in polycystic ovarian syndrome via desuccinylation of GLI1.
Zhang Y et al.·Gynecol Endocrinol
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools