Essential fructosuria

Summary

Essential fructosuria (MONDO:0009252) is a disease with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 2
• ClinVar variants: 80
• Phenotypes (HPO): 6

Clinical features

Signs & symptoms

Clinical features (HPO)

6 HPO clinical features (Orphanet curated; top 6 by frequency):

HPO ID	Term	Frequency
HP:0011033	Impairment of fructose metabolism	Obligate (100%)
HP:0012379	Abnormal enzyme/coenzyme activity	Obligate (100%)
HP:0010969	Abnormality of glycolipid metabolism	Very frequent (80-99%)
HP:0030272	Abnormal erythrocyte enzyme activity	Very frequent (80-99%)
HP:0031979	Abnormal urine carbohydrate level	Very frequent (80-99%)
HP:0003074	Hyperglycemia	Excluded (0%)

Identifiers

Disease identifiers

Field	Value
Canonical name	essential fructosuria
Mondo ID	MONDO:0009252
MeSH	C538068
OMIM	229800
Orphanet	2056
DOID	DOID:0111680
ICD-10-CM	E74.11
ICD-11	1362211287
SNOMED CT	40278002
UMLS	C0268160
MedGen	78645
GARD	0006471
MedDRA	10015487
Is cancer (heuristic)	no

Also known as: fructokinase deficiency · fructosuria, essential · ketohexokinase deficiency

Data availability: 80 ClinVar variants · 2 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn carbohydrate metabolic disorder › disorder of fructose metabolism › essential fructosuria

Related subtypes (2): hereditary fructose intolerance, acquired fructose intolerance

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

80 retrieved; paginated sample, class counts are floors:

52 uncertain significance, 20 benign, 5 likely benign, 2 conflicting classifications of pathogenicity, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
12032	NM_006488.3(KHK):c.127G>A (p.Ala43Thr)	KHK	Pathogenic	no assertion criteria provided
335497	NM_006488.3(KHK):c.790G>A (p.Val264Ile)	CGREF1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
897186	NM_006488.3(KHK):c.210-253G>A	KHK	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
335498	NM_006488.3(KHK):c.818G>A (p.Ser273Asn)	CGREF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
335499	NM_006488.3(KHK):c.820G>A (p.Val274Met)	CGREF1	Uncertain significance	criteria provided, single submitter
335502	NM_006488.3(KHK):c.*28T>C	CGREF1	Uncertain significance	criteria provided, single submitter
335503	NM_006488.3(KHK):c.*49C>T	CGREF1	Uncertain significance	criteria provided, single submitter
335504	NM_006488.3(KHK):c.*52C>T	CGREF1	Uncertain significance	criteria provided, single submitter
335506	NM_006488.3(KHK):c.*159G>A	CGREF1	Uncertain significance	criteria provided, single submitter
335507	NM_006488.3(KHK):c.*198A>C	CGREF1	Uncertain significance	criteria provided, single submitter
335508	NM_006488.3(KHK):c.*200A>G	CGREF1	Uncertain significance	criteria provided, single submitter
335510	NM_006488.3(KHK):c.*469G>A	CGREF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
335516	NM_006488.3(KHK):c.*791G>A	CGREF1	Uncertain significance	criteria provided, single submitter
335518	NM_006488.3(KHK):c.*810A>C	CGREF1	Uncertain significance	criteria provided, single submitter
895373	NM_006488.3(KHK):c.687C>T (p.Gly229=)	CGREF1	Uncertain significance	criteria provided, single submitter
895374	NM_006488.3(KHK):c.688G>A (p.Ala230Thr)	CGREF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
895375	NM_006488.3(KHK):c.698T>G (p.Leu233Arg)	CGREF1	Uncertain significance	criteria provided, single submitter
895377	NM_006488.3(KHK):c.826G>A (p.Glu276Lys)	CGREF1	Uncertain significance	criteria provided, multiple submitters, no conflicts
895443	NM_006488.3(KHK):c.*896T>G	CGREF1	Uncertain significance	criteria provided, single submitter
896778	NM_006488.3(KHK):c.866G>A (p.Cys289Tyr)	CGREF1	Uncertain significance	criteria provided, single submitter
896844	NM_006488.3(KHK):c.*954C>T	CGREF1	Uncertain significance	criteria provided, single submitter
897260	NM_006488.3(KHK):c.*176G>A	CGREF1	Uncertain significance	criteria provided, single submitter
897261	NM_006488.3(KHK):c.*214G>A	CGREF1	Uncertain significance	criteria provided, single submitter
897262	NM_006488.3(KHK):c.*259T>G	CGREF1	Uncertain significance	criteria provided, single submitter
898434	NM_006488.3(KHK):c.*596C>T	CGREF1	Uncertain significance	criteria provided, single submitter
898436	NM_006488.3(KHK):c.*739G>C	CGREF1	Uncertain significance	criteria provided, single submitter
12031	NM_006488.3(KHK):c.118G>A (p.Gly40Arg)	KHK	Uncertain significance	criteria provided, single submitter
2433096	NM_006488.3(KHK):c.112C>T (p.Gln38Ter)	KHK	Uncertain significance	criteria provided, single submitter
335476	NM_006488.3(KHK):c.-379T>A	KHK	Uncertain significance	criteria provided, single submitter
335479	NM_006488.3(KHK):c.-140G>A	KHK	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
KHK	Moderate	Autosomal recessive	essential fructosuria	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KHK	Orphanet:2056	Essential fructosuria

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KHK	HGNC:6315	ENSG00000138030	P50053	Ketohexokinase	gencc,clinvar
CGREF1	HGNC:16962	ENSG00000138028	Q99674	Cell growth regulator with EF hand domain protein 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KHK	Ketohexokinase	Catalyzes the phosphorylation of the ketose sugar fructose to fructose-1-phosphate.
CGREF1	Cell growth regulator with EF hand domain protein 1	Mediates cell-cell adhesion in a calcium-dependent manner.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KHK	Kinase	yes	2.7.1.3	PfkB_dom, Ribokinase-like, KHK
CGREF1	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ileal mucosa	1
liver	1
right lobe of liver	1
nucleus accumbens	1
right frontal lobe	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KHK	213	ubiquitous	marker	right lobe of liver, liver, ileal mucosa
CGREF1	191	ubiquitous	marker	right frontal lobe, nucleus accumbens, right hemisphere of cerebellum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KHK	970
CGREF1	590

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KHK	P50053	38

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CGREF1	Q99674	62.75

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 2 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Essential fructosuria	1	11420.0×	7e-04	KHK
Fructose metabolism	1	2284.0×	0.001	KHK
Fructose catabolism	1	2284.0×	0.001	KHK
Diseases of carbohydrate metabolism	1	815.7×	0.002	KHK
Metabolism of carbohydrates and carbohydrate derivatives	1	120.2×	0.013	KHK
Diseases of metabolism	1	80.4×	0.017	KHK
Disease	1	13.1×	0.086	KHK
Metabolism	1	11.6×	0.086	KHK

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to sucrose	1	1685.2×	0.003	KHK
regulation of glycogen metabolic process	1	1685.2×	0.003	KHK
response to fructose	1	1203.7×	0.003	KHK
fructose metabolic process	1	842.6×	0.003	KHK
response to zinc ion	1	312.1×	0.006	KHK
response to glucose	1	127.7×	0.012	KHK
response to insulin	1	115.4×	0.012	KHK
regulation of cell cycle	1	37.3×	0.033	CGREF1
negative regulation of cell population proliferation	1	21.1×	0.052	CGREF1
cell adhesion	1	18.7×	0.053	CGREF1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KHK	2	2
CGREF1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PF-06835919	2	KHK
LY-3522348	1	KHK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
KHK	57	Binding:57

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
KHK	2.7.1.3	ketohexokinase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

2 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
PF-06835919	2	KHK
LY-3522348	1	KHK

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	KHK
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	CGREF1

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CGREF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.