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.

OMIM 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]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Anemia, congenital, nonspherocytic hemolytic, 5, hexokinase deficientMIM #235700

Neurodevelopmental disorder with visual defects and brain anomaliesMIM #618547

Neuropathy, hereditary motor and sensory, Russe typeMIM #605285

Retinitis pigmentosa 79MIM #617460

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Anemia, congenital, nonspherocytic hemolytic, 5, hexokinase deficient; Neurodevelopmental disorder with visual defects and brain anomalies (+2); no ClinGen or GenCC tier

Interpreting a novel variant

This gene is strongly intolerant of loss-of-function variation in the population, so LoF variants warrant close attention. No curated mechanism annotation is available — see the mechanism card for the computational prediction and its caveats.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

193

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

0.33

LOEUF· LoF intol.

Multiple*

Mechanism· predicted

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

Background carrier burden — how many people carry a rare variant somewhere in HK1?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 100

904 rare PASS variants

Rare truncating (LoF)

1 in 1,700

105 rare PASS variants

Rare synonymous (reference)

1 in 85

491 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for HK1. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 120	1 in 1,500
South Asian	~43k	1 in 71	1 in 940
Remaining (unassigned)	~30k	1 in 77	1 in 660
European (Finnish)	~27k	1 in 290	1 in 1,200
Admixed American	~22k	1 in 75	1 in 3,700
African / African American	~21k	1 in 110	1 in 740
East Asian	~20k	1 in 95	1 in 840
Ashkenazi Jewish	~13k	1 in 500	1 in 1,400
Middle Eastern	~2,884	1 in 78	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 18 coding exons well covered in gnomAD exomes and genomes.? see exons ↓