ALDOB

Summary

ALDOB (aldolase, fructose-bisphosphate B, HGNC:417) is a protein-coding gene on chromosome 9q31.1, encoding Fructose-bisphosphate aldolase B (P05062). Catalyzes the aldol cleavage of fructose 1,6-biphosphate to form two triosephosphates dihydroxyacetone phosphate and D-glyceraldehyde 3-phosphate in glycolysis as well as the reverse stereospecific aldol addition reaction in gluconeogenesis.

Fructose-1,6-bisphosphate aldolase (EC 4.1.2.13) is a tetrameric glycolytic enzyme that catalyzes the reversible conversion of fructose-1,6-bisphosphate to glyceraldehyde 3-phosphate and dihydroxyacetone phosphate. Vertebrates have 3 aldolase isozymes which are distinguished by their electrophoretic and catalytic properties. Differences indicate that aldolases A, B, and C are distinct proteins, the products of a family of related ‘housekeeping’ genes exhibiting developmentally regulated expression of the different isozymes. The developing embryo produces aldolase A, which is produced in even greater amounts in adult muscle where it can be as much as 5% of total cellular protein. In adult liver, kidney and intestine, aldolase A expression is repressed and aldolase B is produced. In brain and other nervous tissue, aldolase A and C are expressed about equally. There is a high degree of homology between aldolase A and C. Defects in ALDOB cause hereditary fructose intolerance.

Source: NCBI Gene 229 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary fructose intolerance (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 6
• Clinical variants (ClinVar): 609 total — 50 pathogenic, 73 likely-pathogenic
• Phenotypes (HPO): 44
• MANE Select transcript: NM_000035

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:417
Approved symbol	ALDOB
Name	aldolase, fructose-bisphosphate B
Location	9q31.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000136872
Ensembl biotype	protein_coding
OMIM	612724
Entrez	229

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 22 protein_coding, 2 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000468981, ENST00000647789, ENST00000648064, ENST00000648423, ENST00000648758, ENST00000648906, ENST00000649902, ENST00000650613, ENST00000903775, ENST00000903776, ENST00000903777, ENST00000903778, ENST00000903779, ENST00000903780, ENST00000903781, ENST00000903782, ENST00000903783, ENST00000903784, ENST00000903785, ENST00000903786, ENST00000903787, ENST00000903788, ENST00000903789, ENST00000903790, ENST00000903791

RefSeq mRNA: 1 — MANE Select: NM_000035 NM_000035

CCDS: CCDS6756

Canonical transcript exons

ENST00000647789 — 9 exons

Exon	Start	End
ENSE00000926598	101424843	101425042
ENSE00000926599	101425453	101425627
ENSE00000926601	101427482	101427642
ENSE00000926602	101428469	101428523
ENSE00000926603	101429755	101429966
ENSE00003542166	101430776	101430897
ENSE00003681799	101426555	101426638
ENSE00003749708	101435709	101435774
ENSE00003837691	101420560	101421904

Expression profiles

Bgee: expression breadth ubiquitous, 191 present calls, max score 100.00.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 57.2117 / max 23193.6692, expressed in 73 samples.

FANTOM5 promoters (11 alternative TSS)

Promoter ID	TPM avg	Samples expressed
101755	56.8252	72
101749	0.1050	17
101754	0.0924	13
101753	0.0756	16
101756	0.0300	6
101750	0.0248	11
101747	0.0214	9
101757	0.0109	5
101758	0.0105	6
205584	0.0100	7

Top tissues by expression

268 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
jejunal mucosa	UBERON:0000399	100.00	gold quality
nephron tubule	UBERON:0001231	99.96	gold quality
right lobe of liver	UBERON:0001114	99.88	gold quality
adult organism	UBERON:0007023	99.87	gold quality
liver	UBERON:0002107	99.85	gold quality
renal medulla	UBERON:0000362	99.82	gold quality
renal glomerulus	UBERON:0000074	99.78	gold quality
metanephric glomerulus	UBERON:0004736	99.73	gold quality
duodenum	UBERON:0002114	99.70	gold quality
adult mammalian kidney	UBERON:0000082	98.31	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.13	gold quality
small intestine	UBERON:0002108	98.10	gold quality
gall bladder	UBERON:0002110	96.19	gold quality
body of pancreas	UBERON:0001150	96.07	gold quality
kidney	UBERON:0002113	95.58	gold quality
kidney epithelium	UBERON:0004819	95.39	gold quality
cortex of kidney	UBERON:0001225	94.51	gold quality
metanephros cortex	UBERON:0010533	94.17	gold quality
pancreas	UBERON:0001264	93.69	gold quality
islet of Langerhans	UBERON:0000006	93.67	gold quality
metanephros	UBERON:0000081	91.98	gold quality
amniotic fluid	UBERON:0000173	90.77	gold quality
jejunum	UBERON:0002115	90.47	gold quality
pancreatic ductal cell	CL:0002079	87.36	silver quality
colonic epithelium	UBERON:0000397	85.29	gold quality
vermiform appendix	UBERON:0001154	83.09	gold quality
caecum	UBERON:0001153	82.22	gold quality
cardia of stomach	UBERON:0001162	81.07	gold quality
tongue squamous epithelium	UBERON:0006919	80.17	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	79.35	gold quality

Single-cell (SCXA)

Detected in 13 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	13406.02
E-MTAB-10553	yes	13069.26
E-CURD-122	yes	4835.57
E-CURD-46	yes	4402.20
E-CURD-98	yes	2785.60
E-HCAD-9	yes	1437.14
E-MTAB-5061	yes	1061.96
E-CURD-119	yes	55.49
E-CURD-135	no	2288.07
E-MTAB-6058	no	9.88
E-HCAD-31	no	3.65
E-GEOD-83139	no	3.07
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CEBPA, CEBPG, DBP, FOXM1, HNF1A, HNF1B, HNF4A, NCOA1, PPARGC1A, SSRP1

miRNA regulators (miRDB)

67 targeting ALDOB, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5692B	100.00	71.32	2622
HSA-MIR-5692C	100.00	71.32	2622
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-223-3P	99.99	70.14	1140
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3658	99.96	73.87	4379
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-6835-3P	99.93	70.49	2904
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-8063	99.91	69.76	3146
HSA-MIR-4753-3P	99.90	71.03	3786
HSA-MIR-374A-5P	99.90	71.34	2923
HSA-MIR-374B-5P	99.90	69.98	2734
HSA-MIR-153-5P	99.89	73.86	6317
HSA-MIR-3180-5P	99.82	69.12	2422
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-4760-5P	99.80	69.88	1619
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-646	99.68	67.84	1645
HSA-MIR-3679-3P	99.64	69.88	1599
HSA-MIR-8061	99.63	69.44	1411
HSA-MIR-325	99.58	66.55	358

Literature-anchored findings (GeneRIF, showing 31)

• Structural and functional analysis of aldolase B mutants related to hereditary fructose intolerance. (PMID:12417303)
• The enzyme’s structure and function is investigated as a function of temperature.The implications of these structural alterations are discussed with regard to the HFI disease (PMID:12464284)
• expression of three (Beclin 1, RbAp48 and Pir51) were increased and one (aldolase b) was decreased in liver tumor tissues (PMID:14966907)
• six new aldolase B mutations in seven unrelated hereditary fructose intolerant (HFI) Italian patients (PMID:15532022)
• Based on these data and after correction for less common and private ALDOB mutations, hereditary fructose intolerance (HFI) prevalence in central Europe is estimated to be 1:26,100 (95% confidence interval 1: 12,600-79,000). (PMID:15880727)
• Reverse-hybridization assay tested for an accurate and robust screening tool to identify common ALDOB mutations. (PMID:17292585)
• Usefulness of ALDOB mutation in screening for diagnosis of hereditary fructose intolerance. (PMID:17457694)
• there is an important role for physical association between aldolase and the A, B and E subunits of V-ATPase in the regulation of the proton pump (PMID:17576770)
• Hereditary fructose intolerance with the mutation c.479_482 del AACA (PMID:17955389)
• Sixteen different mutations of the aldolase B (ALDOB) gene were identified in hereditary fructose intolerance patients. (PMID:18541450)
• The five gene transcripts (aldolase B, elafin, MST-1, simNIPhom and SLC6A14) were changed in patients with ulcerative colitis, and were related to the disease activity. (PMID:18700007)
• Biochemical study of defective aldolase B enzymes is key to revealing the molecular basis of the disease and providing a stronger basis for improved treatment and diagnosis (PMID:20162364)
• This is the first report of six unrelated patients sharing the same ALDOB deletion, thus indicating a founder effect for this allele. (PMID:20848650)
• These novel mutations in ALDOB represent 2% of alleles in American HFI (hereditary fructose intolerance) patients, with IVS1+1G>C representing a significantly higher allele frequency (6%) among HFI patients of Hispanic and African-American ethnicity. (PMID:20882353)
• Aldolase B with the A149P substitution has activity that is <100-fold that of the wild type. (PMID:21166391)
• Efficient inhibition of aldolase B can prevent high glucose-induced overproduction of methylglyoxal and related cellular dysfunction in endothelial cells. (PMID:22911800)
• ALDOC, Aldolase A (ALDOA) and Aldolase B (ALDOB) activate Wnt signaling. (PMID:24993527)
• both of exogenous and endogenous ALDOB proteins bind to hepatitis B surface antigen and colocalize in the cytoplasm in vitro and inhibit apoptosis of cisplatin-induced HepG2 cells. (PMID:25072145)
• Single nucleotide polymorphisms in ALDOB, MAP3K1, and MEF2C are associated with cataract. (PMID:25352737)
• The downregulation of ALDOB could indicate a poor prognosis for HCC patients, and therefore, ALDOB might be considered a prognostic biomarker for HCC, especially at the early stage. (PMID:26376879)
• Silencing Aldolase B activated epithelial markers and repressed mesenchymal markers, indicating inactivation of Aldolase B may lead to inhibition of epithelial-mesenchymal transition (PMID:28558381)
• ALDOB knockdown or dietary fructose restriction suppresses growth of colorectal cancer (CRC) liver metastases, but not primary tumors or lung metastases, highlighting the importance of tumor microenvironment. (PMID:29706565)
• Differential gene expression between islets from normoglycemic and hyperglycemic patients was prominent for the glycolytic enzyme ALDOB, mRNA level of ALDOB correlated negatively with insulin secretion and positively with HbA1c. The minor allele of the ALDOB variant rs550915 associated with significantly higher levels of C-peptide and insulin during oral glucose tolerance test and hyperglycemic clamp, respectively. (PMID:30202879)
• downregulation of aldolase B and accumulation of fructose 1,6-bisphosphate promote clear cell renal cell carcinoma growth by counteracting oxidative stress (PMID:30760861)
• high ALDOB expression impairs DNA mismatch repair and induces apoptosis in colon adenocarcinoma (PMID:31564566)
• Aldolase B suppresses hepatocellular carcinogenesis by inhibiting G6PD and pentose phosphate pathways. (PMID:35122041)
• Metabolic classification suggests the GLUT1/ALDOB/G6PD axis as a therapeutic target in chemotherapy-resistant pancreatic cancer. (PMID:37597521)
• Associations between ALDOB polymorphisms and intrahepatic cholestasis of pregnancy susceptibility in the Chinese Han population. (PMID:37743645)
• Aldolase B-driven lactagenesis and CEACAM6 activation promote cell renewal and chemoresistance in colorectal cancer through the Warburg effect. (PMID:37816733)
• MRTO4 Enhances Glycolysis to Facilitate HCC Progression by Inhibiting ALDOB. (PMID:38778508)
• Fructose-1, 6-Bisphosphate Aldolase B Suppresses Glycolysis and Tumor Progression of Gastric Cancer. (PMID:39068380)

Cross-species orthologs

7 orthologs

Organism	Symbol	Gene ID
danio_rerio	aldob	ENSDARG00000053684
mus_musculus	Aldob	ENSMUSG00000028307
rattus_norvegicus	Aldob	ENSRNOG00000006807
drosophila_melanogaster	Ald1	FBGN0000064
drosophila_melanogaster	Ald2	FBGN0039425
caenorhabditis_elegans		WBGENE00011474
caenorhabditis_elegans		WBGENE00017166

Paralogs (2): ALDOC (ENSG00000109107), ALDOA (ENSG00000149925)

Protein

Protein identifiers

Fructose-bisphosphate aldolase B — P05062 (reviewed: P05062)

Alternative names: Liver-type aldolase

All UniProt accessions (3): A0A3B3IS80, A0A3B3ITZ0, P05062

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the aldol cleavage of fructose 1,6-biphosphate to form two triosephosphates dihydroxyacetone phosphate and D-glyceraldehyde 3-phosphate in glycolysis as well as the reverse stereospecific aldol addition reaction in gluconeogenesis. In fructolysis, metabolizes fructose 1-phosphate derived from the phosphorylation of dietary fructose by fructokinase into dihydroxyacetone phosphate and D-glyceraldehyde. Acts as an adapter independently of its enzymatic activity, exerts a tumor suppressor role by stabilizing the ternary complex with G6PD and TP53 to inhibit G6PD activity and keep oxidative pentose phosphate metabolism in check.

Subunit / interactions. Homotetramer. Interacts with BBS1, BBS2, BBS4 and BBS7. Forms a ternary complex with G6PD and TP53; this interaction is direct.

Subcellular location. Cytoplasm. Cytosol. Cytoskeleton. Microtubule organizing center. Centrosome. Centriolar satellite.

Disease relevance. Hereditary fructose intolerance (HFI) [MIM:229600] Autosomal recessive disease that results in an inability to metabolize fructose and related sugars. Complete exclusion of fructose results in dramatic recovery; however, if not treated properly, HFI subjects suffer episodes of hypoglycemia, general ill condition, and risk of death the remainder of life. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Carbohydrate degradation; glycolysis; D-glyceraldehyde 3-phosphate and glycerone phosphate from D-glucose: step 4/4. Carbohydrate biosynthesis; gluconeogenesis. Carbohydrate metabolism; fructose metabolism.

Miscellaneous. In vertebrates, 3 forms of this ubiquitous glycolytic enzyme are found, aldolase A in muscle, aldolase B in liver and aldolase C in brain.

Similarity. Belongs to the class I fructose-bisphosphate aldolase family.

RefSeq proteins (1): NP_000026* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000741	FBA_I	Family
IPR013785	Aldolase_TIM	Homologous_superfamily
IPR029768	Aldolase_I_AS	Conserved_site

Pfam: PF00274

Enzyme classification (BRENDA):

• EC 4.1.2.13 — fructose-bisphosphate aldolase (BRENDA: 162 organisms, 156 substrates, 386 inhibitors, 299 Km, 175 kcat entries)

Substrate kinetics (BRENDA)

12 substrates with measured Km, best-characterized 12. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
D-FRUCTOSE 1,6-BISPHOSPHATE	0.0002–20	190
FRUCTOSE 1-PHOSPHATE	0.007–27	42
D-FRUCTOSE 1-PHOSPHATE	0.0017–40	20
D-FRUCTOSE-1,6-BISPHOSPHATE	0.015–0.45	16
D-GLYCERALDEHYDE 3-PHOSPHATE	0.052–1.17	9
GLYCERONE PHOSPHATE	0.065–2	8
SEDOHEPTULOSE 1,7-BISPHOSPHATE	0.008–0.19	3
FRUCTOSE 1,6-BISPHOSPHATE	0.0036–0.009	2
SEDOHEPTULOSE 1,7-DIPHOSPHATE	0.006–10	2
SEDOHEPTULOSE 7-PHOSPHATE	0.0167–0.0195	2
D-XYLULOSE 1-PHOSPHATE	0.0016	1
DIHYDROXYACETONE PHOSPHATE	0.095	1

Catalyzed reactions (Rhea), 2 shown:

• beta-D-fructose 1,6-bisphosphate = D-glyceraldehyde 3-phosphate + dihydroxyacetone phosphate (RHEA:14729)
• beta-D-fructose 1-phosphate = D-glyceraldehyde + dihydroxyacetone phosphate (RHEA:30851)

UniProt features (87 total): sequence variant 21, helix 17, modified residue 14, strand 11, mutagenesis site 7, sequence conflict 5, turn 4, binding site 3, active site 2, initiator methionine 1, chain 1, site 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
1QO5	X-RAY DIFFRACTION	2.5
8D44	ELECTRON MICROSCOPY	2.8
1XDL	X-RAY DIFFRACTION	3
1XDM	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P05062-F1	96.12	0.93

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (3): 188 (proton acceptor); 230 (schiff-base intermediate with dihydroxyacetone-p); 364 (necessary for preference for fructose 1,6-bisphosphate over fructose 1-phosphate)

Ligand- & substrate-binding residues (3): 43; 272–274; 304

Post-translational modifications (14): 36, 39, 89, 119, 121, 132, 272, 276, 299, 301, 309, 317, 2, 13

Mutagenesis-validated functional residues (7):

Position	Phenotype
43	loss of enzymatic activity. retains the ability to interact with g6pd.
46	decreases enzymatic activity. retains the ability to interact with g6pd.
108	decreases enzymatic activity. retains the ability to interact with g6pd.
147	loss of enzymatic activity. impairs the interaction with g6pd.
149	loss of enzymatic activity. impairs the interaction with g6pd.
230	loss of enzymatic activity. impairs the interaction with g6pd.
304	decreases enzymatic activity. impairs the interaction with g6pd.

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-5657560	Hereditary fructose intolerance
R-HSA-70171	Glycolysis
R-HSA-70263	Gluconeogenesis
R-HSA-70350	Fructose catabolism
R-HSA-1430728	Metabolism
R-HSA-1643685	Disease
R-HSA-5652084	Fructose metabolism
R-HSA-5663084	Diseases of carbohydrate metabolism
R-HSA-5668914	Diseases of metabolism
R-HSA-70326	Glucose metabolism
R-HSA-71387	Metabolism of carbohydrates and carbohydrate derivatives

MSigDB gene sets: 310 (showing top): GOBP_NUCLEOSIDE_DIPHOSPHATE_METABOLIC_PROCESS, YAGI_AML_WITH_INV_16_TRANSLOCATION, PID_HNF3B_PATHWAY, GOBP_NADPPLUS_METABOLIC_PROCESS, GNF2_HPN, GOBP_CARBOHYDRATE_DERIVATIVE_CATABOLIC_PROCESS, GOBP_MONOSACCHARIDE_CATABOLIC_PROCESS, GOBP_ORGANOPHOSPHATE_METABOLIC_PROCESS, KEGG_GLYCOLYSIS_GLUCONEOGENESIS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOCC_MICROTUBULE_ORGANIZING_CENTER, GOBP_CARBOHYDRATE_DERIVATIVE_METABOLIC_PROCESS, GOBP_GLUCOSE_6_PHOSPHATE_METABOLIC_PROCESS, GOBP_NUCLEOBASE_CONTAINING_SMALL_MOLECULE_METABOLIC_PROCESS, GOBP_GENERATION_OF_PRECURSOR_METABOLITES_AND_ENERGY

GO Biological Process (8): fructose metabolic process (GO:0006000), gluconeogenesis (GO:0006094), glycolytic process (GO:0006096), fructose 1,6-bisphosphate metabolic process (GO:0030388), obsolete fructose catabolic process to hydroxyacetone phosphate and glyceraldehyde-3-phosphate (GO:0061624), vacuolar proton-transporting V-type ATPase complex assembly (GO:0070072), negative regulation of pentose-phosphate shunt (GO:1905856), fructose catabolic process (GO:0006001)

GO Molecular Function (9): fructose-bisphosphate aldolase activity (GO:0004332), cytoskeletal protein binding (GO:0008092), identical protein binding (GO:0042802), ATPase binding (GO:0051117), molecular adaptor activity (GO:0060090), fructose-1-phosphate aldolase activity (GO:0061609), fructose binding (GO:0070061), protein binding (GO:0005515), lyase activity (GO:0016829)

GO Cellular Component (6): microtubule organizing center (GO:0005815), cytosol (GO:0005829), centriolar satellite (GO:0034451), extracellular exosome (GO:0070062), cytoplasm (GO:0005737), cytoskeleton (GO:0005856)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Glucose metabolism	2
Metabolism of carbohydrates and carbohydrate derivatives	2
Diseases of carbohydrate metabolism	1
Fructose metabolism	1
Diseases of metabolism	1
Disease	1
Metabolism	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
aldehyde-lyase activity	2
protein binding	2
binding	2
hexose metabolic process	1
glucose metabolic process	1
hexose biosynthetic process	1
phosphoglycerate kinase activity	1
phosphoglycerate mutase activity	1
phosphopyruvate hydratase activity	1
pyruvate kinase activity	1
pyruvate metabolic process	1
generation of precursor metabolites and energy	1
aerobic respiration	1
carbohydrate catabolic process	1
pyridine nucleotide catabolic process	1
glyceraldehyde-3-phosphate dehydrogenase [NAD(P)+] (phosphorylating) activity	1
ADP catabolic process	1
ATP metabolic process	1
nicotinamide nucleotide metabolic process	1
organophosphate metabolic process	1
carbohydrate derivative metabolic process	1
proton-transporting V-type ATPase complex assembly	1
pentose-phosphate shunt	1
regulation of pentose-phosphate shunt	1
negative regulation of purine nucleotide metabolic process	1
fructose metabolic process	1
hexose catabolic process	1
enzyme binding	1
molecular_function	1
monosaccharide binding	1
catalytic activity	1
microtubule cytoskeleton	1
cytoplasm	1
centrosome	1
extracellular vesicle	1
intracellular anatomical structure	1
intracellular membraneless organelle	1

Protein interactions and networks

STRING

1940 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
ALDOB	GAPDH	P00354	911
ALDOB	PKLR	P11973	834
ALDOB	TMOD1	P28289	824
ALDOB	PFKL	P17858	796
ALDOB	BAAT	Q14032	780
ALDOB	PFKP	Q01813	733
ALDOB	PFKM	P08237	724
ALDOB	AMPD2	Q01433	724
ALDOB	AMPD3	Q01432	718
ALDOB	GPI	P06744	707
ALDOB	SLC2A2	P11168	682
ALDOB	AMPD1	P23109	669
ALDOB	KHK	P50053	660
ALDOB	TPI1	P00938	655
ALDOB	XPA	P23025	650

IntAct

49 interactions, top by confidence:

A	B	Type	Score
ALDOB	ALDOA	psi-mi:“MI:0915”(physical association)	0.550
ALDOB	ALDOA	psi-mi:“MI:0914”(association)	0.550
ALDOA	ALDOB	psi-mi:“MI:0914”(association)	0.550
BBS1	ALDOB	psi-mi:“MI:0915”(physical association)	0.540
ALDOB	BBS4	psi-mi:“MI:0915”(physical association)	0.540
ALDOB	BBS2	psi-mi:“MI:0915”(physical association)	0.540
BBS7	ALDOB	psi-mi:“MI:0915”(physical association)	0.540
ALDOB	BBS1	psi-mi:“MI:0915”(physical association)	0.540
ALDOB	BBS7	psi-mi:“MI:0915”(physical association)	0.540
BBS1	ALDOB	psi-mi:“MI:0403”(colocalization)	0.540
ALDOB	BBS2	psi-mi:“MI:0403”(colocalization)	0.540
ALDOB	BBS4	psi-mi:“MI:0403”(colocalization)	0.540
ALDOB	BBS7	psi-mi:“MI:0403”(colocalization)	0.540
Slc12a1	ALDOB	psi-mi:“MI:0915”(physical association)	0.440
Slc12a1	ALDOB	psi-mi:“MI:0403”(colocalization)	0.440
ALDOB	ALDOB	psi-mi:“MI:0915”(physical association)	0.400
ALDOB	MUC20	psi-mi:“MI:0915”(physical association)	0.370
HIVEP1	ALDOB	psi-mi:“MI:0915”(physical association)	0.370
ALDOB	TXN2	psi-mi:“MI:0915”(physical association)	0.370
ALDOB	AGXT2	psi-mi:“MI:0915”(physical association)	0.370
ALDOB	BMPR1A	psi-mi:“MI:0915”(physical association)	0.370
ALDOB	BUB1	psi-mi:“MI:0915”(physical association)	0.370
ALDOB	CDKN2A	psi-mi:“MI:0915”(physical association)	0.370
CTNNA1	ALDOB	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (47): ALDOB (Co-fractionation), ALDOB (Co-fractionation), ALDOB (Two-hybrid), ALDOB (Two-hybrid), ALDOB (Two-hybrid), ALDOB (Two-hybrid), ALDOB (Two-hybrid), ALDOB (Two-hybrid), ALDOB (Two-hybrid), ALDOB (Two-hybrid), ALDOB (Two-hybrid), ALDOB (Two-hybrid), ALDOB (Two-hybrid), ALDOB (Two-hybrid), ALDOB (Two-hybrid)

ESM2 similar proteins: A5A6I5, B5DGM7, F4KGQ0, O65581, O65735, P00883, P00884, P04075, P05062, P05063, P05064, P05065, P07341, P07764, P08440, P09117, P09972, P14223, P17784, P22197, P29356, P46256, P46257, P46563, P49577, P52210, P53442, P53445, P53446, P53447, P53448, P54216, P79226, Q10A30, Q27744, Q3T0S5, Q4KMC8, Q5N725, Q5NVR5, Q5R1X4

Diamond homologs: A5A6I5, B5DGM7, F4KGQ0, O65581, O65735, P00883, P00884, P04075, P05062, P05063, P05064, P05065, P07341, P07752, P07764, P08440, P09117, P09972, P14223, P16096, P17784, P22197, P29356, P46256, P46257, P46563, P49577, P52210, P53442, P53445, P53446, P53447, P53448, P53449, P54216, P79226, P86979, P91759, Q01516, Q01517

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
DBP	“up-regulates quantity by expression”	ALDOB	“transcriptional regulation”
HNF1A	“up-regulates quantity by expression”	ALDOB	“transcriptional regulation”
PPARGC1A	“up-regulates quantity by expression”	ALDOB	“transcriptional regulation”
NCOA1	“up-regulates quantity by expression”	ALDOB	“transcriptional regulation”
ALDOB	“up-regulates quantity”	“D-glyceraldehyde 3-phosphate(2-)”	“chemical modification”
ALDOB	“up-regulates quantity”	“glycerone phosphate(2-)”	“chemical modification”
ALDOB	“down-regulates quantity”	“beta-D-fructofuranose 1,6-bisphosphate(4-)”	“chemical modification”
ALDOB	“down-regulates quantity”	“beta-D-fructofuranose 1-phosphate(2-)”	“chemical modification”
ALDOB	“up-regulates quantity”	D-glyceraldehyde	“chemical modification”

Disease & clinical

Clinical variants and AI predictions

ClinVar

609 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	50
Likely pathogenic	73
Uncertain significance	158
Likely benign	242
Benign	21

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1065849	NM_000035.4(ALDOB):c.331C>T (p.Gln111Ter)	Pathogenic
1065850	NM_000035.4(ALDOB):c.403T>C (p.Cys135Arg)	Pathogenic
1065855	NM_000035.4(ALDOB):c.770T>C (p.Leu257Pro)	Pathogenic
1065867	NM_000035.4(ALDOB):c.841_842del (p.Thr281fs)	Pathogenic
1065871	NM_000035.4(ALDOB):c.761dup (p.Thr255fs)	Pathogenic
1065878	NM_000035.4(ALDOB):c.799+2T>A	Pathogenic
1069392	NM_000035.4(ALDOB):c.607C>T (p.Gln203Ter)	Pathogenic
1071688	NM_000035.4(ALDOB):c.325-1G>T	Pathogenic
1073061	NC_000009.11:g.(?104188817)(104193189_?)del	Pathogenic
1073062	NC_000009.11:g.(?104188827)(104193169_?)del	Pathogenic
1379379	NM_000035.4(ALDOB):c.227dup (p.Val77fs)	Pathogenic
1438416	NM_000035.4(ALDOB):c.149_155dup (p.Glu53fs)	Pathogenic
1451325	NM_000035.4(ALDOB):c.255C>G (p.Tyr85Ter)	Pathogenic
1454003	NM_000035.4(ALDOB):c.34C>T (p.Gln12Ter)	Pathogenic
1454872	NM_000035.4(ALDOB):c.360del (p.Asn120fs)	Pathogenic
1456001	NM_000035.4(ALDOB):c.427del (p.Val143fs)	Pathogenic
1675307	NM_000035.4(ALDOB):c.812T>C (p.Leu271Ser)	Pathogenic
188782	NM_000035.4(ALDOB):c.612T>A (p.Tyr204Ter)	Pathogenic
188861	NM_000035.4(ALDOB):c.360_363del (p.Asn120fs)	Pathogenic
1954703	NM_000035.4(ALDOB):c.539del (p.Gln180fs)	Pathogenic
2016414	NM_000035.4(ALDOB):c.642C>A (p.Tyr214Ter)	Pathogenic
2094555	NM_000035.4(ALDOB):c.999+2T>C	Pathogenic
218380	NM_000035.4(ALDOB):c.324+1G>A	Pathogenic
218381	NM_000035.4(ALDOB):c.865del (p.Leu289fs)	Pathogenic
2422164	NC_000009.11:g.(?104124710)(104500261_?)del	Pathogenic
2429130	NC_000009.11:g.(104187910_104188836)_(104193180_104197990)del	Pathogenic
2579206	GRCh38/hg38 9q31.1(chr9:101426458-101431155)x0	Pathogenic
2675466	NM_000035.4(ALDOB):c.538C>T (p.Gln180Ter)	Pathogenic
2707586	NM_000035.4(ALDOB):c.136del (p.Arg46fs)	Pathogenic
2758683	NM_000035.4(ALDOB):c.235del (p.Leu79fs)	Pathogenic

SpliceAI

821 predictions. Top by Δscore:

Variant	Effect	Δscore
9:101425448:CTTAC:C	donor_loss	1.0000
9:101425451:A:AC	donor_gain	1.0000
9:101425452:C:CC	donor_gain	1.0000
9:101425525:T:TA	donor_gain	1.0000
9:101425625:GACC:G	acceptor_loss	1.0000
9:101425629:T:C	acceptor_loss	1.0000
9:101426551:TTA:T	donor_loss	1.0000
9:101426552:TA:T	donor_loss	1.0000
9:101426553:A:AC	donor_gain	1.0000
9:101426553:AC:A	donor_gain	1.0000
9:101426553:ACCTT:A	donor_gain	1.0000
9:101426554:C:CC	donor_gain	1.0000
9:101426554:CC:C	donor_gain	1.0000
9:101426554:CCT:C	donor_gain	1.0000
9:101426554:CCTT:C	donor_gain	1.0000
9:101426554:CCTTC:C	donor_gain	1.0000
9:101426634:CCATT:C	acceptor_gain	1.0000
9:101426635:CATT:C	acceptor_gain	1.0000
9:101426635:CATTC:C	acceptor_gain	1.0000
9:101426636:ATT:A	acceptor_gain	1.0000
9:101426637:TT:T	acceptor_gain	1.0000
9:101426638:TC:T	acceptor_loss	1.0000
9:101426639:C:CC	acceptor_gain	1.0000
9:101426639:CTAA:C	acceptor_loss	1.0000
9:101426640:T:G	acceptor_loss	1.0000
9:101426654:A:T	acceptor_gain	1.0000
9:101427449:A:AC	donor_gain	1.0000
9:101427450:C:CC	donor_gain	1.0000
9:101427450:CT:C	donor_gain	1.0000
9:101427478:GCACC:G	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000018906 (9:101426432 T>A), RS1001021018 (9:101427719 G>A,C), RS1001109094 (9:101420778 A>G), RS1001251762 (9:101433581 T>G), RS1001325875 (9:101425349 G>A), RS1001347484 (9:101431801 A>C), RS1001352301 (9:101425230 C>T), RS1001716587 (9:101431527 G>A), RS1001811141 (9:101429684 C>G,T), RS1001897418 (9:101420664 A>G), RS1002038217 (9:101435666 C>T), RS1002101023 (9:101437339 C>T), RS1002321370 (9:101432880 C>A,T), RS1002328554 (9:101420900 A>G), RS1002336445 (9:101426849 G>T)

Disease associations

OMIM: gene MIM:612724 | disease phenotypes: MIM:229600, MIM:232200

GenCC curated gene-disease

Disease	Classification	Inheritance
hereditary fructose intolerance	Definitive	Autosomal recessive
complex neurodevelopmental disorder	Limited	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hereditary fructose intolerance	Definitive	AR

Mondo (3): hereditary fructose intolerance (MONDO:0009249), disorder of glycogen metabolism (MONDO:0002412), complex neurodevelopmental disorder (MONDO:0100038)

Orphanet (2): Hereditary fructose intolerance (Orphanet:469), Glycogen storage disease (Orphanet:79201)

HPO phenotypes

44 total (30 of 44 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000114	Proximal tubulopathy
HP:0000518	Cataract
HP:0000952	Jaundice
HP:0001069	Episodic hyperhidrosis
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001254	Lethargy
HP:0001259	Coma
HP:0001394	Cirrhosis
HP:0001397	Hepatic steatosis
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001942	Metabolic acidosis
HP:0001943	Hypoglycemia
HP:0002013	Vomiting
HP:0002014	Diarrhea
HP:0002018	Nausea
HP:0002019	Constipation
HP:0002027	Abdominal pain
HP:0002049	Proximal renal tubular acidosis
HP:0002148	Hypophosphatemia
HP:0002149	Hyperuricemia
HP:0002239	Gastrointestinal hemorrhage
HP:0002240	Hepatomegaly
HP:0002904	Hyperbilirubinemia
HP:0002910	Elevated circulating hepatic transaminase concentration
HP:0002918	Hypermagnesemia
HP:0003076	Glycosuria

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001276_8	Liver enzyme levels (alkaline phosphatase)	1.000000e-09
GCST002619_2	Age-related cataracts	2.000000e-06
GCST006016_33	Serum alkaline phosphatase levels	4.000000e-26
GCST011353_53	Serum alkaline phosphatase levels	4.000000e-30
GCST90011900_209	Serum alkaline phosphatase levels	1.000000e-67
GCST90013406_31	Liver enzyme levels (alkaline phosphatase)	9.000000e-58

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004533	alkaline phosphatase measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D006008	Glycogen Storage Disease	C16.320.565.202.449; C18.452.648.202.449

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

51 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, affects cotreatment, affects expression, decreases expression, increases methylation	4
sodium arsenite	decreases expression, increases expression	3
Acetaminophen	affects cotreatment, decreases expression	3
Tetrachlorodibenzodioxin	affects cotreatment, decreases expression	3
deoxynivalenol	affects cotreatment, affects expression, increases expression	2
Clozapine	decreases expression, increases expression	2
Tobacco Smoke Pollution	increases expression	2
Zearalenone	affects cotreatment, affects expression, increases expression	2
Cyclosporine	decreases expression	2
Aflatoxin B1	affects expression, decreases expression, decreases methylation	2
aristolochic acid I	increases expression	1
methyleugenol	decreases expression	1
6-hydroxy-5-((p- sulfophenyl)azo)-2-naphthalenesulfonic acid disodium salt	decreases expression, affects cotreatment	1
benzo(b)fluoranthene	affects cotreatment, affects expression	1
fluoranthene	affects cotreatment, affects expression	1
ferric citrate	decreases reaction, increases expression	1
1,2,5,6-dibenzanthracene	affects cotreatment, affects expression	1
1-methylphenanthrene	affects cotreatment, affects expression	1
dibenzo(a,l)pyrene	affects cotreatment, affects expression	1
perfluorooctane sulfonic acid	decreases expression	1
tebuconazole	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
2-palmitoylglycerol	increases expression	1
obeticholic acid	decreases expression	1
belinostat	decreases expression	1
Rosiglitazone	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Troglitazone	decreases expression	1
Bosentan	decreases expression	1
Alcohols	decreases reaction, increases expression	1

Cellosaurus cell lines

6 cell lines: 4 cancer cell line, 1 induced pluripotent stem cell, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_D2I3	Abcam Raji ALDOB KO	Cancer cell line	Male
CVCL_D6I0	FDCHi015-A	Induced pluripotent stem cell	Female
CVCL_D9W9	Ubigene HK-2 ALDOB KO	Transformed cell line	Male
CVCL_E1L2	HyCyte Hep-G2 KO-hALDOB	Cancer cell line	Male
CVCL_UQ14	Abcam Jurkat ALDOB KO	Cancer cell line	Male
CVCL_WQ98	Abcam K-562 ALDOB KO	Cancer cell line	Female

Clinical trials (associated diseases)

41 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT02782741	PHASE3	COMPLETED	Study to Compare the Efficacy and Safety of Enzyme Replacement Therapies Avalglucosidase Alfa and Alglucosidase Alfa Administered Every Other Week in Patients With Late-onset Pompe Disease Who Have Not Been Previously Treated for Pompe Disease
NCT04808505	PHASE3	RECRUITING	A Study to Evaluate the Safety, Efficacy, PK, PD and Immunogenicity of Cipaglucosidase Alfa/Miglustat in IOPD Subjects Aged 0 to <18
NCT00765414	PHASE2	COMPLETED	Extension Study of Long-term Safety and Efficacy of Myozyme for a Single Patient With Pompe Disease Who Were Previously Enrolled in Genzyme Sponsored ERT Studies.
NCT02032524	PHASE2	COMPLETED	Avalglucosidase Alfa Extension Study
NCT03019406	PHASE2	ACTIVE_NOT_RECRUITING	A Study to Assess Safety and Efficacy of Avalglucosidase Alfa Administered Every Other Week in Pediatric Patients With Infantile-onset Pompe Disease Previously Treated With Alglucosidase Alfa
NCT06130228	PHASE2	UNKNOWN	Nutritional Therapy in Late-onset Pompe Disease
NCT06310681	Not specified	COMPLETED	Pilot Testing of a Co-adapted Group Programme for Parents/Carers of Children With Complex Neurodisability
NCT07303049	Not specified	NOT_YET_RECRUITING	Cognitive Benefit of Intensive Rehabilitation Using Rhythmic Music Training in Children With Complex Neurodevelopmental Disorder
NCT01185210	Not specified	UNKNOWN	Investigation of Alanine in Fructose Intolerance: A Dose Ranging Study
NCT01705171	Not specified	COMPLETED	Is the Expression of the GLUT5 Specific Fructose Transport Protein Abnormal in Patients With Fructose Intolerance?
NCT02085889	Not specified	UNKNOWN	Fructose and Lactose Intolerance and Malabsorption in Functional Gastrointestinal Disorders
NCT02979106	Not specified	COMPLETED	Metabolic Consequences of Heterozygous Hereditary Fructose Intolerance
NCT03261856	Not specified	COMPLETED	Clinical Utility of Breath Tests in GI
NCT03545581	Not specified	COMPLETED	Fructose Supplementation in Carriers for Hereditary Fructose Intolerance
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT04022434	Not specified	UNKNOWN	Investigation of Supplemental L-alanine in the Management of Dietary Fructose Intolerance
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT06044389	Not specified	UNKNOWN	Observational Study on the Safety and Efficacy of the Medical Product Fructosin.
NCT05095727	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	A Study of mRNA-3745 in Adult and Pediatric Participants With Glycogen Storage Disease Type 1a (GSD1a)
NCT00001342	Not specified	COMPLETED	Study of Glycogen Storage Disease and Associated Disorders
NCT00566878	Not specified	COMPLETED	Pompe Lactation Sub-Registry
NCT01461304	Not specified	NO_LONGER_AVAILABLE	Compassionate Use of Triheptanoin (C7) for Inherited Disorders of Energy Metabolism
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT02057731	Not specified	COMPLETED	Study of Glycogen Storage Disease Expression in Carriers
NCT02176096	Not specified	COMPLETED	Comparison of the Effect of a Novel Starch (Glycosade) Versus Gastrostomy Tube-Dextrose Infusion on Overnight Euglycaemia Control in Children With Glycogen Storage Disease Type I: Open Label Demonstration Trial
NCT02318966	Not specified	COMPLETED	Glycosade v UCCS in the Dietary Management of Hepatic GSD
NCT02338817	Not specified	TERMINATED	Clinical Evaluation of a Non-Invasive Hypoglycemia Detector in a Glycogen Storage Disease Population
NCT02385162	Not specified	WITHDRAWN	Biomarker for Glycogen Storage Diseases (BioGlycogen)
NCT03255213	Not specified	COMPLETED	Lingual Muscle Training in Late-Onset Pompe Disease (LOPD)
NCT03564561	Not specified	RECRUITING	Natural History of Pompe Disease
NCT04292938	Not specified	COMPLETED	McArdle Disease Treatment by Ketogenic Diet
NCT04399694	Not specified	COMPLETED	Identification and Characterization of Novel Non-Coding Variants That Contribute to Genetic Disorders
NCT04929002	Not specified	ACTIVE_NOT_RECRUITING	Carbon-13 Magnetic Resonance Spectroscopy in Glycogen Storage Diseases
NCT05199246	Not specified	COMPLETED	Assessment of Safety and Acute Effects of a Lower-limb Powered Dermoskeleton in Patients With Neuromuscular Disorders
NCT05200702	Not specified	COMPLETED	Assessment of Safety and Acute Effects of a Knee-hip Powered Soft Exoskeleton in Patients With Neuromuscular Disorders
NCT06396546	Not specified	RECRUITING	‘Glycogen Storage Diseases (GSDs) in Indian Children- Establishing an Indian GSD (I-GSD) Registry’
NCT06795152	Not specified	RECRUITING	Rare Glycogen Storage Diseases Natural History Study
NCT06813443	Not specified	RECRUITING	Characterization of Patients With Cardiomyopathy to Identify Critical Patients Candidates for Cardiac Transplantation
NCT07136844	Not specified	RECRUITING	Gait Analysis Parameter and Upper Limb Evaluation in Adult Patients With Neurological or Metabolic Pathology
NCT07336394	Not specified	RECRUITING	Precision Diagnosis and Risk Stratification of Rare Cardiomyopathies Based on Novel Cardiac Magnetic Resonance Techniques