HINT1

Chr 5AR

histidine triad nucleotide binding protein 1

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

NCBI Gene: 3094ENSG00000169567UniProt: P49773OMIM: 601314

The HINT1 protein hydrolyzes purine nucleotide phosphoramidates substrates through a histidine triad motif and functions as a tumor suppressor. Mutations cause autosomal recessive neuromyotonia and axonal neuropathy through a dominant-negative mechanism.

GeneReviewsOMIMResearchSummary from RefSeq, OMIM, UniProt, Mechanism
LOFmechanismARLOEUF 1.811 OMIM phenotype
Clinical Summary— HINT1
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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.
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ClinVar Variants
46 unique Pathogenic / Likely Pathogenic· 61 VUS of 169 total submissions
Explore recent and relevant literature in Research Assistant →
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GeneReview available — HINT1
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
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
0.44Z-score
OE missense 0.86 (0.70–1.05)
63 obs / 73.7 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.95 (0.46–1.81)
0≤0.351.4
Missense OE0.86 (0.70–1.05)
0≤0.61.4
Synonymous OE0.83
0≤1.21.6
LoF obs/exp: 4 / 4.2Missense obs/exp: 63 / 73.7Syn Z: 0.65
Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗
definitiveHINT1-related neuromyotonia and axonal neuropathyLOFAR

Predictions shown for reference only — model trained on dominant genes, not applicable to AR conditions.

DN
0.6647th %ile
GOF
0.5758th %ile
LOF
0.3550th %ile

The Badonyi & Marsh prediction model was trained exclusively on dominant disease genes. Predictions are not reliable for genes with autosomal recessive inheritance and are shown at reduced opacity for reference only.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

169 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic35
Likely Pathogenic11
VUS61
Likely Benign41
Benign16
Conflicting3
35
Pathogenic
11
Likely Pathogenic
61
VUS
41
Likely Benign
16
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
11
4
20
0
35
Likely Pathogenic
3
7
1
0
11
VUS
3
51
7
0
61
Likely Benign
0
1
24
16
41
Benign
0
0
14
2
16
Conflicting
—3
Total17636618167

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.

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
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
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
2026Open Access
S-nitrosylation of HINT1 in macrophages aggravates foam cell formation and atherosclerosis.
Tang K et al.·Redox Biol
2026Open Access
The nucleocytoplasmic translocation of HINT1 regulates the maturation of cell density.
Zhang X et al.·Life Sci Alliance
2025Open 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
2025Open 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
2025Open Access
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