HK1

Chr 10ARAD

hexokinase 1

Also known as: CNSHA5, HK, HK1-ta, HK1-tb, HK1-tc, HKD, HKI, HMSNR

NCBI Gene: 3098ENSG00000156515UniProt: P19367

Hexokinases phosphorylate glucose to produce glucose-6-phosphate, the first step in most glucose metabolism pathways. This gene encodes a ubiquitous form of hexokinase which localizes to the outer membrane of mitochondria. Mutations in this gene have been associated with hemolytic anemia due to hexokinase deficiency. Alternative splicing of this gene results in several transcript variants which encode different isoforms, some of which are tissue-specific. [provided by RefSeq, Apr 2016]

Primary Disease Associations & Inheritance

Anemia, congenital, nonspherocytic hemolytic, 5, hexokinase deficientMIM #235700
AR
Neurodevelopmental disorder with visual defects and brain anomaliesMIM #618547
AD
Neuropathy, hereditary motor and sensory, Russe typeMIM #605285
AR
Retinitis pigmentosa 79MIM #617460
AD
483
ClinVar variants
23
Pathogenic / LP
0.91
pLI score· haploinsufficient
0
Active trials
Clinical Summary— HK1
⚡
Population Constraint (gnomAD)
Highly constrained gene — heterozygous loss-of-function variants are very rare in the population (pLI 0.91). One damaged copy is likely sufficient to cause disease.
📋
ClinVar Variants
23 Pathogenic / Likely Pathogenic· 277 VUS of 483 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Dual constrained — LoF & missense intolerant
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.
0.33LOEUF
pLI 0.915
Z-score 4.96
OE 0.19 (0.11–0.33)
Highly constrained

Highly LoF-intolerant (top ~10% of genes)

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.
3.23Z-score
OE missense 0.61 (0.56–0.67)
341 obs / 555.3 exp
Constrained

Highly missense-constrained (top ~0.1%)

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.0.19 (0.11–0.33)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.61 (0.56–0.67)
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.0.94
0≤1.21.6
LoF obs/exp: 8 / 43.2Missense obs/exp: 341 / 555.3Syn Z: 0.73

ClinVar Variant Classifications

483 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic9
Likely Pathogenic14
VUS277
Likely Benign162
Benign12
Conflicting9
9
Pathogenic
14
Likely Pathogenic
277
VUS
162
Likely Benign
12
Benign
9
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
2
0
7
0
9
Likely Pathogenic
5
6
3
0
14
VUS
9
245
20
3
277
Likely Benign
0
1
63
98
162
Benign
0
3
7
2
12
Conflicting
—9
Total16255100103483

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

View in ClinVar →

Protein Context — Lollipop Plot

HK1 · protein map & ClinVar variants

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

Gene2Phenotype Curations

HK1-related neurodevelopmental disorder with visual defects and brain anomalies

strong
ADUndetermined Non-Loss-Of-FunctionAltered Gene Product Structure
Dev. Disorders
G2P ↗
missense variant

HK1-related retinitis pigmentosa

limited
ADUndeterminedAltered Gene Product Structure
Eye
G2P ↗
missense variantinframe deletioninframe insertion

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

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
HEXOKINASE 1; HK1
MIM #142600 · *

Anemia, congenital, nonspherocytic hemolytic, 5, hexokinase deficient

MIM #235700

Molecular basis of disorder known

Autosomal recessive

Neurodevelopmental disorder with visual defects and brain anomalies

MIM #618547

Molecular basis of disorder known

Autosomal dominant

Neuropathy, hereditary motor and sensory, Russe type

MIM #605285

Molecular basis of disorder known

Autosomal recessive

Retinitis pigmentosa 79

MIM #617460

Molecular basis of disorder known

Autosomal dominant
📖
GeneReview available — HK1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Congenital Hyperinsulinism: Diagnosis and Treatment Update.
Demirbilek H et al.·J Clin Res Pediatr Endocrinol
2017Review
Metabolic phenotype of bladder cancer.
Massari F et al.·Cancer Treat Rev
2016Review
Protein O-GlcNAcylation and hexokinase mitochondrial dissociation drive heart failure with preserved ejection fraction.
Tatekoshi Y et al.·Cell Metab
2025
Congenital hyperinsulinism: recent updates on molecular mechanisms, diagnosis and management.
Giri D et al.·J Pediatr Endocrinol Metab
2021Review
FOXA1 enhances antitumor immunity via repressing interferon-induced PD-L1 expression in nasopharyngeal carcinoma.
Ge J et al.·J Immunother Cancer
2024
5-hydroxymethylfurfural attenuates osteoarthritis by upregulating of glucose metabolism in chondrocytes.
Wang X et al.·Phytomedicine
2025
Hexokinase 2 as a novel selective metabolic target for rheumatoid arthritis.
Bustamante MF et al.·Ann Rheum Dis
2018
Increasing hexokinase 1 expression improves mitochondrial and glycolytic functional deficits seen in sporadic Alzheimer's disease astrocytes.
Bell SM et al.·Mol Psychiatry
2025Functional
Driving with retinitis pigmentosa.
Heath Jeffery RC et al.·Ophthalmic Genet
2023
Non-coding cis-regulatory variants in HK1 cause congenital hyperinsulinism with variable disease severity.
Bennett JJ et al.·Genome Med
2025
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Molecular Networking Reveals Sorbicillinoids Diversity from the Marine-Derived Fungus Trichoderma reesei HK1-12: Key Antibiosis for Biocontrol against Rhizoctonia solani.
Chen M et al.·J Agric Food Chem
2026
Protopanaxadiol Induces Apoptosis in NPC/HK1 Human Nasopharyngeal Carcinoma Cells via the Fas/Caspase-8 Signaling Pathway.
Huang YC et al.·Anticancer Res
2026
An Antioxidative Exopolysaccharide-Protein Complex of Cordyceps Cs-HK1 Fungus and Its Epithelial Barrier-Protective Effects in Caco-2 Cell Culture.
Zhu YY et al.·Antioxidants (Basel)
2025🔓 Open Access
HK1 and HK2 Beyond Glycolysis: Mitochondrial Interactions and Dual Roles in Metabolism and Cell Fate.
Pesce NA et al.·Adv Biol (Weinh)
2026
Irisin targets the HK1-glycolysis-NLRP3 pyroptosis axis to prevent chronic kidney disease-associated vascular calcification.
Xu W et al.·Ren Fail
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