FBP1

protein-coding

fructose-bisphosphatase 1, the group of Fructose-1,6-bisphosphatases

Gene summary

Fructose-1,6-bisphosphatase 1, a gluconeogenesis regulatory enzyme, catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate and inorganic phosphate. Fructose-1,6-diphosphatase deficiency is associated with hypoglycemia and metabolic acidosis. [provided by RefSeq, Jul 2008]

Previous symbols:

MANE transcript

NM_000507.4

Inheritance

ClinVar variants

P:62U:68B:121

Top phenotype

Fructose-1,6-bisphosphatase deficiency

gnomAD constraint

pLI —, LoF o/e 0.32

Max pathogenic AF

—

Genomic locus

chr9:94,603,133-94,640,249

External References & Databases

Ensembl (ENSG00000165140)

Transcript & Mutation Effects

hg38 • Region Span ~37.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

fructose-1,6-bisphosphatase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009251

Submitter: Labcorp Genetics (formerly Invitae)

fructose-1,6-bisphosphatase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009251

Submitter: PanelApp Australia

fructose-1,6-bisphosphatase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009251

Submitter: G2P

fructose-1,6-bisphosphatase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009251

Submitter: ClinGen

The FBP1 gene encodes fructose-1,6-bisphosphatase (FBPase), an enzyme primarily expressed in the liver. Its main function is to catalyze the conversion of fructose-1,6-bisphosphate to fructose-6-phosphate during gluconeogenesis (PMID: 16497803). Fructose-1,6-bisphosphatase deficiency (FBP1D) was clinically recognized prior to 1995, when pathogenic variants in the FBP1 gene were first implicated as the cause of this autosomal recessive inborn error of metabolism (Kikawa et al., PMID: 7763253). FBP1D is characterized by hypoglycemia and metabolic acidosis due to reduced or absent FBP1 enzyme activity. Clinical manifestations may include vomiting, lethargy, seizures, apneic spells, coma, hepatomegaly, and, without treatment, early death. Biochemical findings typically include elevated serum lactate, hepatic transaminases, and increased urinary levels of glycerol, lactate, pyruvate, and during acute episodes elevated glycerol-3-phosphate. The disorder usually presents in the neonatal or infantile period, and metabolic crises are often triggered by fasting, fever, infection, or illness. A total of 31 FBP1 variants including missense, nonsense, splicing, and small indels that have been identified in 29 unrelated probands was curated (PMIDs: 7763253, 9382095, 28420223, 29026278, 29203193, 32020156, 33576950, 33999094, 34716126, 37507476, 38111981, 39036704, 23881342, 29774539, 25601412, 37142076). Large copy number variations involving multiple exons or the entire gene were excluded from this curation. The gene disease relationship is strongly supported by case-level evidence, exceeding the maximum ClinGen scoring threshold of 12 points. Additional evidence comes from animal models and functional studies. Transgenic mice overexpressing human FBPase demonstrated significantly increased glycerol-driven gluconeogenesis compared to controls, correlating with elevated protein expression and enzyme activity (PMID: 16497803). Conversely, liver-specific FBP1 knockout mice exhibited decreased levels of intermittent metabolites (e.g., fructose-6-phosphate, glucose-6-phosphate) and recapitulated key features of the human phenotype, including fasting-induced hypoglycemia, hepatomegaly, lactic acidosis, hepatic lipid accumulation, and elevated liver enzymes following fructose exposure (PMID: 36964915). In vitro studies have shown that missense variants identified in affected individuals lead to reduced FBPase protein expression and/or significantly decreased enzymatic activity, possibly due to protein misfolding and aggregation within the endoplasmic reticulum (PMID: 37507476). Furthermore, these mutant proteins were unstable and underwent ubiquitin-mediated degradation (PMID: 37142076). In summary, there is definitive evidence supporting the association between FBP1 and autosomal recessive fructose-1,6-bisphosphatase deficiency. This relationship has been consistently demonstrated in both research and clinical diagnostic settings and remains robust over time. This classification was approved by the ClinGen IEM GCEP at the meeting on November 14, 2025 (SOP Version 11).

fructose-1,6-bisphosphatase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009251

Submitter: Genomics England PanelApp

fructose-1,6-bisphosphatase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009251

Submitter: Orphanet

Clinical Genomic Database (CGD)

Fructose-1,6-bisphosphatase deficiencyAR

Manifestation: Biochemical

Intervention: Biochemical

Rationale: The condition may be lethal in the perinatal period, but prompt recognition and treatment of lactic acidosis and hypoglycemia (eg, with IV/oral glucose, sodium bicarbonate) can be effective

Refs: 4193749; 4335192; 4341454; 4341015; 175754; 2347355; 1995492; 9382095; 12126934; 17705024; 19259699; 20096900; 22158280

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FBP1 variants in ClinVar

11 Conditions Cataloged

Fructose-biphosphatase deficiencyTotal: 264

not providedTotal: 53

Inborn genetic diseasesTotal: 30

not specifiedTotal: 27

FBP1-related disorderTotal: 8

Glycogen storage diseaseTotal: 2

Deficiency of fructose-bisphosphataseTotal: 1

Impaired gluconeogenesisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000507.4. 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			3 clinvar	109 clinvar	1 clinvar	113
missense	5 clinvar	12 clinvar	62 clinvar	10 clinvar	1 clinvar	90
nonsense	9 clinvar	3 clinvar				12
start loss	1 clinvar					1
frameshift	17 clinvar	9 clinvar	1 clinvar			27
splice donor/acceptor (+/-2bp)	3 clinvar	3 clinvar	2 clinvar			8
Total	35	27	68	119	2	251

Highest pathogenic variant AF is 0.00013076708

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 34 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000507.4	RefSeq	NP_000498.2	7	MANE Select
ENST00000375326.9	Ensembl	ENSP00000364475.5	7	MANE Select
NM_001127628.2	RefSeq	NP_001121100.1	7	Standard
ENST00000414122.1	Ensembl	ENSP00000411619.1	4	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Glycolysis / Gluconeogenesis - Homo sapiens (human)
Fructose and mannose metabolism - Homo sapiens (human)
AMPK signaling pathway - Homo sapiens (human)
Glucagon signaling pathway - Homo sapiens (human)
Pentose phosphate pathway - Homo sapiens (human)

Biological Process

negative regulation of transcription by RNA polymerase II
sucrose biosynthetic process
fructose metabolic process
fructose 6-phosphate metabolic process
gluconeogenesis

Molecular Function

protein binding
AMP binding
fructose 1,6-bisphosphate 1-phosphatase activity
identical protein binding
metal ion binding

Cellular Component

nucleus
cytoplasm
cytosol
extracellular exosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000415431
Coding exons: 7
Length: 37117
Individuals with no LoFs: 125738
Homozygous LoFs: 0
Heterozygous LoFs: 10
Defined: 125748
p: 0.0000398

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.740	170	199	0.853	0.0000110	2189
Missense (PolyPhen)		50	73.921	0.67639		787
Synonymous	-1.45	100	83.2	1.20	0.00000532	673
Loss of Function	2.25	4	12.7	0.316	5.40e-7	174

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00011	0.00011	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000044	0.000044	rare
South Asian	0.00013	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: 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. Plays a role in regulating glucose sensing and insulin secretion of pancreatic beta-cells. Appears to modulate glycerol gluconeogenesis in liver. Important regulator of appetite and adiposity; increased expression of the protein in liver after nutrient excess increases circulating satiety hormones and reduces appetite-stimulating neuropeptides and thus seems to provide a feedback mechanism to limit weight gain. {ECO:0000269|PubMed:16497803, ECO:0000269|PubMed:18375435, ECO:0000269|PubMed:22517657}.;
Disease: DISEASE: Fructose-1,6-bisphosphatase deficiency (FBP1D) [MIM:229700]: An autosomal recessive metabolic disorder characterized by impaired gluconeogenesis, and episodes of hypoglycemia and metabolic acidosis that can be lethal in newborn infants or young children. {ECO:0000269|PubMed:12126934, ECO:0000269|PubMed:25601412, ECO:0000269|PubMed:9382095}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.507

Intolerance Scores

LoFtool: 0.460
RVIS EVS: -0.01
RVIS percentile EVS: 53.51

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.990

Gene Damage Prediction

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