Fructose-1,6-bisphosphatase deficiency

Summary

Fructose-1,6-bisphosphatase deficiency (MONDO:0009251) is a disease caused by FBP1 (GenCC Definitive), with 1 cohort gene and 2 clinical trials.

At a glance

• Prevalence: 1-9 / 1 000 000 (Italy) [Orphanet-validated]
• Causal gene: FBP1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 293
• Phenotypes (HPO): 34
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.67	Italy	Validated

Signs & symptoms

Clinical features (HPO)

34 HPO clinical features (Orphanet curated; top 34 by frequency):

HPO ID	Term	Frequency
HP:0001942	Metabolic acidosis	Very frequent (80-99%)
HP:0001943	Hypoglycemia	Very frequent (80-99%)
HP:0003128	Lactic acidosis	Very frequent (80-99%)
HP:0012379	Abnormal enzyme/coenzyme activity	Very frequent (80-99%)
HP:0002013	Vomiting	Frequent (30-79%)
HP:0002014	Diarrhea	Frequent (30-79%)
HP:0002149	Hyperuricemia	Frequent (30-79%)
HP:0003162	Fasting hypoglycemia	Frequent (30-79%)
HP:0004913	Intermittent lactic acidemia	Frequent (30-79%)
HP:0000737	Irritability	Occasional (5-29%)
HP:0000980	Pallor	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001252	Hypotonia	Occasional (5-29%)
HP:0001259	Coma	Occasional (5-29%)
HP:0001262	Excessive daytime somnolence	Occasional (5-29%)
HP:0001397	Hepatic steatosis	Occasional (5-29%)
HP:0001649	Tachycardia	Occasional (5-29%)
HP:0001946	Ketosis	Occasional (5-29%)
HP:0001998	Neonatal hypoglycemia	Occasional (5-29%)
HP:0002094	Dyspnea	Occasional (5-29%)
HP:0002098	Respiratory distress	Occasional (5-29%)
HP:0002119	Ventriculomegaly	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0002329	Drowsiness	Occasional (5-29%)
HP:0002876	Episodic tachypnea	Occasional (5-29%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Occasional (5-29%)
HP:0003265	Neonatal hyperbilirubinemia	Occasional (5-29%)
HP:0004372	Reduced consciousness/confusion	Occasional (5-29%)
HP:0004879	Intermittent hyperventilation	Occasional (5-29%)
HP:0005949	Apneic episodes in infancy	Occasional (5-29%)
HP:0006582	Reye syndrome-like episodes	Occasional (5-29%)
HP:0040301	Increased urinary glycerol	Occasional (5-29%)
HP:0003348	Hyperalaninemia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	fructose-1,6-bisphosphatase deficiency
Mondo ID	MONDO:0009251
OMIM	229700
Orphanet	348
DOID	DOID:5204
NCIT	C128119
SNOMED CT	28183005
UMLS	C0016756
MedGen	42106
GARD	0002400
Is cancer (heuristic)	no

Also known as: baker-Winegrad disease · FBP1D · fructose 1,6 diphosphatase deficiency · fructose-1,6-bisphosphatase deficiency · fructose-1,6-diphosphatase deficiency

Data availability: 293 ClinVar variants · 5 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › glucose metabolism disease › disorder of gluconeogenesis › fructose-1,6-bisphosphatase deficiency

Related subtypes (6): pyruvate carboxylase deficiency disease, hyperammonemic encephalopathy due to carbonic anhydrase VA deficiency, glycerol kinase deficiency, infantile form, glycerol kinase deficiency, juvenile form, glycerol kinase deficiency, adult form, phosphoenolpyruvate carboxykinase deficiency

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

293 retrieved; paginated sample, class counts are floors:

146 likely benign, 47 uncertain significance, 37 pathogenic, 22 conflicting classifications of pathogenicity, 14 likely pathogenic, 11 benign, 8 pathogenic/likely pathogenic, 7 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1322891	NM_000507.4(FBP1):c.426+1G>A	FBP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1322892	NM_000507.4(FBP1):c.392del (p.Val131fs)	FBP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1453508	NM_000507.4(FBP1):c.127A>T (p.Lys43Ter)	FBP1	Pathogenic	criteria provided, single submitter
1803969	NM_000507.4(FBP1):c.881G>A (p.Gly294Glu)	FBP1	Pathogenic	criteria provided, single submitter
214364	NM_000507.4(FBP1):c.355G>A (p.Asp119Asn)	FBP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2506540	GRCh37/hg19 9q22.32(chr9:97401423-97401592)	FBP1	Pathogenic	criteria provided, single submitter
2579730	NM_000507.4(FBP1):c.333+2T>G	FBP1	Pathogenic	criteria provided, single submitter
2719715	NM_000507.4(FBP1):c.56dup (p.Met19fs)	FBP1	Pathogenic	criteria provided, single submitter
2753761	NM_000507.4(FBP1):c.343_347del (p.Val115fs)	FBP1	Pathogenic	criteria provided, single submitter
2758463	NM_000507.4(FBP1):c.846C>A (p.Cys282Ter)	FBP1	Pathogenic	criteria provided, single submitter
2772871	NM_000507.4(FBP1):c.131_132del (p.Ala44fs)	FBP1	Pathogenic	criteria provided, single submitter
2797845	NM_000507.4(FBP1):c.960del (p.Ser321fs)	FBP1	Pathogenic	criteria provided, single submitter
2809502	NM_000507.4(FBP1):c.961dup (p.Ser321fs)	FBP1	Pathogenic	criteria provided, single submitter
2819827	NM_000507.4(FBP1):c.504T>A (p.Tyr168Ter)	FBP1	Pathogenic	criteria provided, single submitter
2828070	NM_000507.4(FBP1):c.860_863dup (p.Met289fs)	FBP1	Pathogenic	criteria provided, single submitter
2832764	NM_000507.4(FBP1):c.740dup (p.Ser248fs)	FBP1	Pathogenic	criteria provided, single submitter
2866196	NM_000507.4(FBP1):c.325G>T (p.Glu109Ter)	FBP1	Pathogenic	criteria provided, single submitter
2872419	NM_000507.4(FBP1):c.282_289del (p.Leu95fs)	FBP1	Pathogenic	criteria provided, single submitter
2875401	NM_000507.4(FBP1):c.723T>G (p.Tyr241Ter)	FBP1	Pathogenic	criteria provided, single submitter
3245071	NC_000009.11:g.(?97401403)(97401592_?)del	FBP1	Pathogenic	criteria provided, single submitter
3245072	NC_000009.11:g.(?97380030)(97382793_?)del	FBP1	Pathogenic	criteria provided, single submitter
3245073	NC_000009.11:g.(?97355088)(97365840_?)del	FBP1	Pathogenic	criteria provided, single submitter
3384130	NM_000507.4(FBP1):c.616_619del (p.Lys206fs)	FBP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372364	NM_000507.4(FBP1):c.960delinsGG (p.Ser321fs)	FBP1	Pathogenic	criteria provided, multiple submitters, no conflicts
381580	NM_000507.4(FBP1):c.841G>A (p.Glu281Lys)	FBP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
403701	NM_000507.4(FBP1):c.720_729del (p.Tyr241fs)	FBP1	Pathogenic	criteria provided, single submitter
403705	NM_000507.4(FBP1):c.704del (p.Pro235fs)	FBP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
403706	NM_000507.4(FBP1):c.825+1G>A	FBP1	Pathogenic	criteria provided, single submitter
4731288	NM_000507.4(FBP1):c.582_585del (p.Ile195fs)	FBP1	Pathogenic	criteria provided, single submitter
526506	NM_000507.4(FBP1):c.779del (p.Gly260fs)	FBP1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · 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
FBP1	Definitive	Autosomal recessive	fructose-1,6-bisphosphatase deficiency	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FBP1	Orphanet:348	Fructose-1,6-bisphosphatase deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FBP1	HGNC:3606	ENSG00000165140	P09467	Fructose-1,6-bisphosphatase 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FBP1	Fructose-1,6-bisphosphatase 1	Catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate in the presence of divalent cations, acting as a rate-limiting enzyme in gluconeogenesis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Phosphatase	1	83.9×	0.012

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FBP1	Phosphatase	yes	3.1.3.11	FBPase_class-1, Fructose_bisphosphatase_AS, FBPtase

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endometrium epithelium	1
jejunal mucosa	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FBP1	213	broad	marker	right lobe of liver, endometrium epithelium, jejunal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FBP1	3,376

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
FBP1	P09467	51

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 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
Gluconeogenesis	1	439.2×	0.005	FBP1
Interaction of NuRD complexes with transcription factors	1	126.9×	0.008	FBP1

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cellular hypotonic salinity response	1	5617.3×	0.002	FBP1
cellular response to raffinose	1	5617.3×	0.002	FBP1
cellular hyperosmotic salinity response	1	2808.7×	0.002	FBP1
cellular response to magnesium ion	1	2407.4×	0.002	FBP1
fructose 1,6-bisphosphate metabolic process	1	2106.5×	0.002	FBP1
fructose metabolic process	1	1685.2×	0.002	FBP1
cellular response to phorbol 13-acetate 12-myristate	1	1296.3×	0.002	FBP1
fructose 6-phosphate metabolic process	1	1123.5×	0.002	FBP1
regulation of gluconeogenesis	1	1123.5×	0.002	FBP1
negative regulation of glycolytic process	1	1053.2×	0.002	FBP1
negative regulation of Ras protein signal transduction	1	674.1×	0.002	FBP1
response to nutrient levels	1	366.4×	0.004	FBP1
gluconeogenesis	1	324.1×	0.004	FBP1
cellular response to cAMP	1	290.6×	0.004	FBP1
cellular response to xenobiotic stimulus	1	240.7×	0.005	FBP1
cellular response to insulin stimulus	1	170.2×	0.007	FBP1
negative regulation of cell growth	1	144.0×	0.007	FBP1
negative regulation of transcription by RNA polymerase II	1	17.7×	0.056	FBP1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
FBP1	ADENOSINE PHOSPHATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FBP1	5	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ADENOSINE PHOSPHATE	4	FBP1
DISULFIRAM	4	FBP1
THIRAM	2	FBP1
MB-05032	2	FBP1
BAICALEIN	2	FBP1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
FBP1	125	Binding:125

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
FBP1	3.1.3.11	fructose-bisphosphatase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
FBP1	125

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

5 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)
ADENOSINE PHOSPHATE	4	FBP1
DISULFIRAM	4	FBP1
THIRAM	2	FBP1
MB-05032	2	FBP1
BAICALEIN	2	FBP1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	FBP1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening