HINT1

Chr 5AR

histidine triad nucleotide binding protein 1

Also known as: HINT, NMAN, PKCI-1, PRKCNH1

NCBI Gene: 3094ENSG00000169567UniProt: P49773

This gene encodes a protein that hydrolyzes purine nucleotide phosphoramidates substrates, including AMP-morpholidate, AMP-N-alanine methyl ester, AMP-alpha-acetyl lysine methyl ester, and AMP-NH2. The encoded protein interacts with these substrates via a histidine triad motif. This gene is considered a tumor suppressor gene. In addition, mutations in this gene can cause autosomal recessive neuromyotonia and axonal neuropathy. There are several related pseudogenes on chromosome 7. Several transcript variants have been observed. [provided by RefSeq, Dec 2015]

Primary Disease Associations & Inheritance

Neuromyotonia and axonal neuropathy, autosomal recessiveMIM #137200
AR
166
ClinVar variants
46
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— HINT1
🧬
Gene-Disease Validity (ClinGen)
Charcot-Marie-Tooth disease · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
46 Pathogenic / Likely Pathogenic· 60 VUS of 166 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.
1.81LOEUF
pLI 0.002
Z-score 0.09
OE 0.95 (0.46–1.81)
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.
0.44Z-score
OE missense 0.86 (0.70–1.05)
63 obs / 73.7 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.0.95 (0.46–1.81)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.86 (0.70–1.05)
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.0.83
0≤1.21.6
LoF obs/exp: 4 / 4.2Missense obs/exp: 63 / 73.7Syn Z: 0.65

ClinVar Variant Classifications

166 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic35
Likely Pathogenic11
VUS60
Likely Benign41
Benign16
Conflicting3
35
Pathogenic
11
Likely Pathogenic
60
VUS
41
Likely Benign
16
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
5
4
26
0
35
Likely Pathogenic
3
7
1
0
11
VUS
2
50
8
0
60
Likely Benign
0
1
24
16
41
Benign
0
0
14
2
16
Conflicting
—3
Total10627318166

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

View in ClinVar →

Protein Context — Lollipop Plot

HINT1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

HINT1-related neuromyotonia and axonal neuropathy

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM

Neuromyotonia and axonal neuropathy, autosomal recessive

MIM #137200

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — HINT1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Neuromuscular hyperexcitability syndromes.
De Wel B et al.·Curr Opin Neurol
2021Review
Multi-omic insight into the molecular networks of mitochondrial dysfunction in the pathogenesis of inflammatory bowel disease.
Chen J et al.·EBioMedicine
2024
HINT1 neuropathy: Expanding the genotype and phenotype spectrum.
Morel V et al.·Clin Genet
2022Review
HINT1 in Neuropsychiatric Diseases: A Potential Neuroplastic Mediator.
Liu P et al.·Neural Plast
2017Review
HINT1 neuropathy in Norway: clinical, genetic and functional profiling.
Amor-Barris S et al.·Orphanet J Rare Dis
2021Functional
HINT1 neuropathy in Lithuania: clinical, genetic, and functional profiling.
Malcorps M et al.·Orphanet J Rare Dis
2022Functional
Axonal neuropathy with neuromyotonia: there is a HINT.
Peeters K et al.·Brain
2017Review
Generalized myokymia, or neuromyotonia, or both in dogs with or without spinocerebellar ataxia.
Vanhaesebrouck A et al.·J Vet Intern Med
2023
Pinpointing Novel Plasma and Brain Proteins for Common Ocular Diseases: A Comprehensive Cross-Omics Integration Analysis.
Mo Q et al.·Int J Mol Sci
2024
A novel mutation in HINT1 gene causes autosomal recessive axonal neuropathy with neuromyotonia, effective treatment with carbamazepine and review of the literature.
Xu L et al.·Acta Neurol Belg
2022Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Broadening the Clinical Spectrum of Axonal Hereditary Neuropathies: A Comparative Case Study on DNAJB2- and HINT1-Related Disease.
Bjelica B et al.·J Peripher Nerv Syst
2026🔓 Open Access
S-nitrosylation of HINT1 in macrophages aggravates foam cell formation and atherosclerosis.
Tang K et al.·Redox Biol
2026🔓 Open Access
The nucleocytoplasmic translocation of HINT1 regulates the maturation of cell density.
Zhang X et al.·Life Sci Alliance
2025🔓 Open Access
Serendipitous and Systematic Chemoproteomic Discovery of MBLAC2, HINT1, and NME1-4 Inhibitors from Histone Deacetylase-Targeting Pharmacophores.
Lechner S et al.·ACS Chem Biol
2025🔓 Open Access
VANGL2 downregulates HINT1 to inhibit the ATM-p53 pathway and promote cisplatin resistance in small cell lung cancer.
Xie J et al.·Cell Death Discov
2025🔓 Open Access
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