HK1

Chr 10

hexokinase 1

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

NCBI Gene: 3098 ENSG00000156515 UniProt: P19367

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 ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews ResearchGenerating clinical summary…

MultiplemechanismLOEUF 0.33

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

40 unique Pathogenic / Likely Pathogenic· 426 VUS of 855 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — HK1

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Some data sources returned errors (1)

omim: Error: OMIM fetch failed: 429

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 OE?0.19 (0.11–0.33)

0≤0.351.4

Missense OE?0.61 (0.56–0.67)

0≤0.61.4

Synonymous OE?0.94

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

This gene — mechanism propensity

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.

LOF43% 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 HK1.1

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

References

1.PMID 25316723 ↗

ClinVar Variant Classifications

855 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic11

Likely Pathogenic29

VUS426

Likely Benign321

Benign31

Conflicting19

Pathogenic

Likely Pathogenic

426

VUS

321

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	9	2	0	0	11
Likely Pathogenic	8	17	4	0	29
VUS	12	385	24	5	426
Likely Benign	0	4	125	192	321
Benign	0	6	18	7	31
Conflicting	—				19
Total	29	414	171	204	837

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

View in ClinVar →

14 pathogenic / likely-pathogenic (of 17) ClinVar copy-number / structural variants overlap HK1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →