HINT2

Chr 9

histidine triad nucleotide binding protein 2

Also known as: HIT-17

NCBI Gene: 84681ENSG00000137133UniProt: Q9BX68OMIM: 609997

HINT2 encodes a mitochondrial histidine triad nucleotide hydrolase that exhibits adenosine 5'-monophosphoramidase activity, hydrolyzing purine nucleotide phosphoramidates to yield nucleotide products. Mutations cause autosomal recessive spastic paraplegia with axonal neuropathy, characterized by progressive spasticity and peripheral nerve involvement. The condition presents in childhood with lower limb spasticity and walking difficulties.

OMIMResearchSummary from RefSeq, UniProt
DNmechanismLOEUF 1.72
Clinical Summary— HINT2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
11 unique Pathogenic / Likely Pathogenic of 11 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
1.72LOEUF
pLI 0.000
Z-score -0.01
OE 1.00 (0.58–1.72)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
-0.35Z-score
OE missense 1.11 (0.94–1.31)
95 obs / 85.8 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios
LoF OE1.00 (0.58–1.72)
0≤0.351.4
Missense OE1.11 (0.94–1.31)
0≤0.61.4
Synonymous OE0.89
0≤1.21.6
LoF obs/exp: 8 / 8.0Missense obs/exp: 95 / 85.8Syn Z: 0.47
DN
0.78top 25%
GOF
0.6249th %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

11 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11
11
Pathogenic

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories· variant type breakdown unavailable

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
————11
Likely Pathogenic
————0
VUS
————0
Likely Benign
————0
Benign
————0
Total—11

Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

HINT2 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Histidine triad nucleotide-binding protein 2 attenuates doxorubicin-induced cardiotoxicity through restoring lysosomal function and promoting autophagy in mice
Jiang H et al.·MedComm (2020)
2025
HINT2 deficiency deteriorates oxidative stress in a mouse model of myocardial infarction
Li F et al.·ESC Heart Fail
2023Functional
HINT2 protects against pressure overload-induced cardiac remodelling through mitochondrial pathways
Zhang N et al.·J Cell Mol Med
2024Functional
HINT2 may be One Clinical Significance Target for Patient with Diabetes Mellitus and Reduced ROS-Induced Oxidative Stress and Ferroptosis by MCU.
Bai M et al.·Horm Metab Res
2024
Histidine triad nucleotide-binding protein 2 attenuates metabolic dysfunction-associated steatotic liver disease through NAD+-dependent sirtuin-3 activation
Wang Q et al.·Exp Mol Med
2025
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Acetylation of Hint2 mitigates acute liver failure by suppressing neutrophil chemotaxis and NETosis through maintaining mitochondrial calcium and protein homeostasis.
Guo J et al.·Int Immunopharmacol
2026
From virtual screening to functional discovery: Apigenin ameliorates acute pancreatitis by targeting HINT2 to regulate the mitochondrial acetylome.
Peng Y et al.·Phytomedicine
2026Functional
HINT2-Mediated Mitochondrial Modulation Contributes to G-CSF Neuroprotection in Alcohol Use Disorder-Related Ischemic Stroke.
Guo ZC et al.·Mol Neurobiol
2025
Targeting the HDAC6/Hint2/MICU1 axis to ameliorate acute liver failure via inhibiting NETosis.
Guo J et al.·Life Sci
2025
Genetic and pharmacological targeting of HINT2 promotes OXPHOS to alleviate inflammatory responses and cell necrosis in acute pancreatitis.
Yao J et al.·Pharmacol Res
2025
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients