KHK

protein-coding

ketohexokinase

Gene summary

This gene encodes ketohexokinase that catalyzes conversion of fructose to fructose-1-phosphate. The product of this gene is the first enzyme with a specialized pathway that catabolizes dietary fructose. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

MANE transcript

NM_006488.3

Inheritance

ClinVar variants

P:1U:53B:10

Top phenotype

Fructosuria, essential

gnomAD constraint

pLI —, LoF o/e 0.93

Max pathogenic AF

—

Genomic locus

chr2:27,086,772-27,100,762

External References & Databases

Ensembl (ENSG00000138030)

Transcript & Mutation Effects

hg38 • Region Span ~14.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

essential fructosuriaMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009252

Submitter: PanelApp Australia

essential fructosuriaSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009252

Submitter: Orphanet

Clinical Genomic Database (CGD)

Fructosuria, essentialAR

Manifestation: Biochemical

Intervention: General

Rationale: The clinical relevance of the condition is unclear

Refs: 13759156; 14063525; 6268573; 7816517; 7833921

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KHK variants in ClinVar

4 Conditions Cataloged

Essential fructosuriaTotal: 40

not specifiedTotal: 38

KHK-related disorderTotal: 7

not providedTotal: 5

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_006488.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			5 clinvar	5 clinvar	1 clinvar	11
missense	1 clinvar		43 clinvar	4 clinvar		48
nonsense			2 clinvar			2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			3 clinvar			3
Total	1	0	53	9	1	64

Highest pathogenic variant AF is 0.000070659815

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 75 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_006488.3	RefSeq	NP_006479.1	8	MANE Select
ENST00000260598.10	Ensembl	ENSP00000260598.5	8	MANE Select
NM_000221.3	RefSeq	NP_000212.1	8	Standard
ENST00000260599.11	Ensembl	ENSP00000260599.6	8	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Fructose and mannose metabolism - Homo sapiens (human)
Uric Acid-Lowering Drugs Pathway, Pharmacodynamics
Fructose intolerance, hereditary
Fructose and Mannose Degradation
Fructosuria

Biological Process

fructose metabolic process
response to sucrose
response to glucose
response to fructose
response to zinc ion

Molecular Function

ketohexokinase activity
protein binding
ATP binding
carbohydrate kinase activity

Cellular Component

cytoplasm
cytosol
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000260599
Coding exons: 8
Length: 14026
Individuals with no LoFs: 125662
Homozygous LoFs: 0
Heterozygous LoFs: 86
Defined: 125748
p: 0.000342

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.451	193	176	1.10	0.0000118	1927
Missense (PolyPhen)		72	68.539	1.0505		722
Synonymous	-0.898	86	76.0	1.13	0.00000574	601
Loss of Function	0.267	14	15.1	0.926	7.63e-7	172

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00016	0.000062	rare
Latino/Admixed American	0.00038	0.00038	rare
Ashkenazi Jewish	0.0016	0.0016	notable
East Asian	0.00023	0.00022	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00023	0.00023	rare
South Asian	0.00082	0.00082	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the phosphorylation of the ketose sugar fructose to fructose-1-phosphate. {ECO:0000269|PubMed:12941785}.;

Recessive Scores

pRec: 0.249

Intolerance Scores

LoFtool: 0.553
RVIS EVS: 0.13
RVIS percentile EVS: 63.49

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.989

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium