HK1

Chr 10ARAD

hexokinase 1

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

NCBI Gene: 3098 ENSG00000156515 UniProt: P19367 OMIM: 142600

Hexokinase 1 catalyzes the phosphorylation of glucose to glucose-6-phosphate, the initial step of glycolysis, and localizes to the mitochondrial outer membrane where it links glucose metabolism to mitochondrial function. Mutations cause a spectrum of disorders including congenital nonspherocytic hemolytic anemia, neurodevelopmental disorder with visual defects and brain anomalies, hereditary motor and sensory neuropathy (Russe type), and retinitis pigmentosa. Inheritance is both autosomal recessive and autosomal dominant depending on the specific phenotype.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

MultiplemechanismAR/ADLOEUF 0.334 OMIM phenotypes

Clinical Summary— HK1

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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.

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ClinVar Variants

15 unique Pathogenic / Likely Pathogenic· 214 VUS of 400 total submissions

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GeneReview available — HK1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Dual constrained — LoF & missense intolerant

LoF Constraint

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

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

LoF OE0.19 (0.11–0.33)

0≤0.351.4

Missense OE0.61 (0.56–0.67)

0≤0.61.4

Synonymous OE0.94

0≤1.21.6

LoF obs/exp: 8 / 43.2Missense obs/exp: 341 / 555.3Syn Z: 0.73

Curated Mechanism (G2P)Gene2Phenotype (DDG2P) ↗

strongHK1-related neurodevelopmental disorder with visual defects and brain anomaliesOTHERAD

limitedHK1-related retinitis pigmentosaOTHERAD

0.5280th %ile

GOF

0.5660th %ile

LOF

0.4430th %ile

This gene has evidence for multiple mechanisms of pathogenicity (loss-of-function and gain-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports loss-of-function (haploinsufficiency). Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

LOF53% of P/LP variants are LoF · LOEUF 0.33

GOF1 literature citation

Literature Evidence

GOFBiochemical assays showed that the E847K mutation does not affect hexokinase enzymatic activity or the protein stability, suggesting that the mutation may impact other uncharacterized function or result in a gain of function of HK1.PMID:25316723

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.