HOGA1

Summary

HOGA1 (4-hydroxy-2-oxoglutarate aldolase 1, HGNC:25155) is a protein-coding gene on chromosome 10q24.2, encoding 4-hydroxy-2-oxoglutarate aldolase, mitochondrial (Q86XE5). Catalyzes the final step in the metabolic pathway of hydroxyproline.

The authors of PMID:20797690 cloned this gene while searching for genes in a region of chromosome 10 linked to primary hyperoxalurea type III. They noted that even though the encoded protein has been described as a mitochondrial dihydrodipicolinate synthase-like enzyme, it shares little homology with E. coli dihydrodipicolinate synthase (Dhdps), particularly in the putative substrate-binding region. Moreover, neither lysine biosynthesis nor sialic acid metabolism, for which Dhdps is responsible, occurs in vertebrate mitochondria. They propose that this gene encodes mitochondrial 4-hydroxyl-2-oxoglutarate aldolase (EC 4.1.3.16), which catalyzes the final step in the metabolic pathway of hydroxyproline, releasing glyoxylate and pyruvate. This gene is predominantly expressed in the liver and kidney, and mutations in this gene are found in patients with primary hyperoxalurea type III. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.

Source: NCBI Gene 112817 — RefSeq curated summary.

At a glance

• Gene–disease (curated): primary hyperoxaluria type 3 (Definitive, ClinGen)
• GWAS associations: 2
• Clinical variants (ClinVar): 586 total — 43 pathogenic, 73 likely-pathogenic
• Phenotypes (HPO): 11
• Druggable target: yes
• MANE Select transcript: NM_138413

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25155
Approved symbol	HOGA1
Name	4-hydroxy-2-oxoglutarate aldolase 1
Location	10q24.2
Locus type	gene with protein product
Status	Approved
Aliases	FLJ37472, DHDPS2, NPL2
Ensembl gene	ENSG00000241935
Ensembl biotype	protein_coding
OMIM	613597
Entrez	112817

Gene structure

Transcript identifiers

Ensembl transcripts: 6 — 5 protein_coding, 1 retained_intron

ENST00000370642, ENST00000370646, ENST00000370647, ENST00000465608, ENST00000880786, ENST00000970078

RefSeq mRNA: 2 — MANE Select: NM_138413 NM_001134670, NM_138413

CCDS: CCDS44469, CCDS7467

Canonical transcript exons

ENST00000370646 — 7 exons

Exon	Start	End
ENSE00001240387	97599089	97599216
ENSE00001334916	97600067	97600163
ENSE00001334917	97599680	97599814
ENSE00001453222	97611510	97612802
ENSE00003566736	97601857	97601990
ENSE00003586831	97598775	97598903
ENSE00003846745	97584389	97584914

Expression profiles

Bgee: expression breadth ubiquitous, 164 present calls, max score 97.85.

FANTOM5 (CAGE): breadth broad, TPM avg 1.4693 / max 58.1089, expressed in 497 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
106447	0.9054	393
106446	0.2520	121
106449	0.2394	33
106448	0.0725	31

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
kidney epithelium	UBERON:0004819	97.85	gold quality
right lobe of liver	UBERON:0001114	93.08	gold quality
adult mammalian kidney	UBERON:0000082	91.54	gold quality
metanephros cortex	UBERON:0010533	91.17	gold quality
liver	UBERON:0002107	90.93	gold quality
renal medulla	UBERON:0000362	90.85	gold quality
kidney	UBERON:0002113	89.28	gold quality
apex of heart	UBERON:0002098	88.29	gold quality
heart left ventricle	UBERON:0002084	85.32	gold quality
cardiac ventricle	UBERON:0002082	84.30	gold quality
adult organism	UBERON:0007023	84.08	gold quality
cortex of kidney	UBERON:0001225	84.04	gold quality
right adrenal gland cortex	UBERON:0035827	81.70	gold quality
metanephros	UBERON:0000081	81.25	gold quality
body of pancreas	UBERON:0001150	81.02	gold quality
right adrenal gland	UBERON:0001233	80.19	gold quality
heart	UBERON:0000948	78.99	gold quality
left adrenal gland	UBERON:0001234	78.61	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	78.57	gold quality
right atrium auricular region	UBERON:0006631	78.43	gold quality
left adrenal gland cortex	UBERON:0035825	78.09	gold quality
popliteal artery	UBERON:0002250	77.03	gold quality
tibial artery	UBERON:0007610	77.00	gold quality
cardiac atrium	UBERON:0002081	76.50	gold quality
adrenal cortex	UBERON:0001235	76.16	gold quality
aorta	UBERON:0000947	75.58	gold quality
spinal cord	UBERON:0002240	75.51	gold quality
adrenal gland	UBERON:0002369	74.89	gold quality
right hemisphere of cerebellum	UBERON:0014890	74.84	gold quality
hindlimb stylopod muscle	UBERON:0004252	74.76	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.08

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

47 targeting HOGA1, 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-3613-3P	100.00	76.36	7965
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-379-3P	99.69	69.60	1524
HSA-MIR-411-3P	99.69	69.63	1524
HSA-MIR-802	99.61	67.70	1254
HSA-MIR-7106-5P	99.53	67.47	3574
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-143-3P	99.49	69.05	1457
HSA-MIR-4770	99.49	69.09	1451
HSA-MIR-6740-3P	99.48	68.49	1392
HSA-MIR-6839-3P	99.39	68.86	1301
HSA-MIR-4652-3P	99.33	70.02	2742
HSA-MIR-128-1-5P	99.33	60.46	332
HSA-MIR-128-2-5P	99.33	60.83	311
HSA-MIR-6088	99.29	68.45	1284
HSA-MIR-6734-3P	99.15	66.27	1627
HSA-MIR-6799-5P	99.14	65.72	2093
HSA-MIR-485-5P	99.10	64.78	1889
HSA-MIR-6884-5P	99.10	64.50	1987
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-4478	99.07	65.16	2320
HSA-MIR-936	98.87	70.51	1124
HSA-MIR-7977	98.65	66.18	2590
HSA-MIR-6728-3P	98.63	67.63	1534

Literature-anchored findings (GeneRIF, showing 16)

• DHDPSL is the gene encoding 4-hydroxy-2-oxoglutarate aldolase, catalyzing the final step in the metabolic pathway of hydroxyproline. (PMID:20797690)
• Detection of HOGA1 variants in idiopathic calcium oxalate urolithiasis also suggests HOGA1 may be a predisposing factor for this condition (PMID:21896830)
• hHOGA utilizes a type I aldolase reaction mechanism, but employs novel residue interactions for substrate binding (PMID:21998747)
• Two crystal forms of DHDPSL were obtained, both of which diffracted X-rays to approximately 2.0 A resolution (PMID:22232173)
• seven different mutations were identified in primary hyperoxaluria type 3 (PMID:22391140)
• Our results strongly suggest HOGA1 as a major cause of PH, indicate a greater genetic heterogeneity of hyperoxaluria, and point to a favorable outcome of type III in the context of PH despite incomplete or absent biochemical remission (PMID:22781098)
• Among the seven patients identified with HOGA1 mutations the median onset of clinical symptoms was 1.8 years. Five patients initially presented with urolithiasis, and two other patients presented with urinary tract infection. (PMID:25972204)
• Results show that HOGA1 harboring mutations found in primary hyperoxaluria is thermally unstable and targeted for proteolytic degradation leading to an absolute loss of function. (PMID:27096395)
• Study found that primary hyperoxaluria type 3 (PH3) was significantly diagnosed in Chinese children with urolithiasis. Nine novel HOGA1 mutations were identified in association with PH3, which provide a first-line investigation in Chinese PH3 patients. The eGFR was normal in all children with PH3. This finding contrasts with the early impairment of renal function in PH1 and PH2. (PMID:31123811)
• Potential mutation hot spot region (c.834_834+1) in the Chinese population and two novel mutations were found. (PMID:31401635)
• Biophysical and structural studies showed that pyruvate was a competitive inhibitor of HOGA1 with an inhibition constant in the micromolar range. (PMID:31696211)
• Mutations in HOGA1 do Not Confer a Dominant Phenotype Manifesting as Kidney Stone Disease. (PMID:33350326)
• Extended genetic analysis of exome sequencing for primary hyperoxaluria in pediatric urolithiasis patients with hyperoxaluria. (PMID:34995728)
• HOGA1 gene pathogenic variants in primary hyperoxaluria type III: Spectrum of pathogenic sequence variants, and phenotypic association. (PMID:36259736)
• Kidney cysts in patients with HOGA1 variants. (PMID:36928260)
• HOGA1 variants in Chinese patients with primary hyperoxaluria type 3: genetic features and genotype-phenotype relationships. (PMID:37318624)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	hoga1	ENSDARG00000018944
mus_musculus	Hoga1	ENSMUSG00000025176
rattus_norvegicus	Hoga1	ENSRNOG00000029501

Paralogs (1): NPL (ENSG00000135838)

Protein

Protein identifiers

4-hydroxy-2-oxoglutarate aldolase, mitochondrial — Q86XE5 (reviewed: Q86XE5)

Alternative names: Dihydrodipicolinate synthase-like, Probable 2-keto-4-hydroxyglutarate aldolase, Protein 569272

All UniProt accessions (2): Q86XE5, H7BY76

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the final step in the metabolic pathway of hydroxyproline.

Subunit / interactions. Homotetramer.

Subcellular location. Mitochondrion.

Disease relevance. Hyperoxaluria primary 3 (HP3) [MIM:613616] A disorder phenotypically similar to hyperoxaluria type 1 and type 2. It is characterized by increase in urinary oxalate excretion and mild glycolic aciduria. Clinical manifestations include calcium oxalate urolithiasis, hematuria, pain, and/or urinary tract infection. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by divalent cations.

Similarity. Belongs to the DapA family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q86XE5-1	1	yes
Q86XE5-3	2

RefSeq proteins (2): NP_001128142, NP_612422* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002220	DapA-like	Family
IPR013785	Aldolase_TIM	Homologous_superfamily
IPR020625	Schiff_base-form_aldolases_AS	Active_site

Pfam: PF00701

Enzyme classification (BRENDA):

• EC 4.1.3.16 — 4-Hydroxy-2-oxoglutarate aldolase (BRENDA: 5 organisms, 49 substrates, 51 inhibitors, 34 Km, 15 kcat entries)

Substrate kinetics (BRENDA)

16 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
4-HYDROXY-2-OXOGLUTARATE	0.008–0.281	14
L-4-HYDROXY-2-OXOGLUTARATE	0.024–71	3
4-HYDROXY-ALPHA-KETOGLUTARATE	0.1–1.33	2
D-4-HYDROXY-2-OXOGLUTARATE	0.031–0.11	2
PYRUVATE	10–25	2
(D)-4-HYDROXY-ALPHA-KETOGLUTARATE	0.14	1
2-KETO-4-HYDROXYBUTYRATE	3.1	1
3-(4-HYDROXYPHENYL)PYRUVATE	7.7	1
3-(4-IMIDAZOLE)PYRUVATE	7.4	1
ACETALDEHYDE	10	1
GLYOXYLATE	0.43	1
OXALOACETATE	30	1
PYRUVALDEHYDE	5.1	1
PYRUVIC ACID ETHYL ESTER	2.8	1
PYRUVIC ACID METHYL ESTER	3.2	1

Catalyzed reactions (Rhea), 2 shown:

• (4R)-4-hydroxy-2-oxoglutarate = glyoxylate + pyruvate (RHEA:30687)
• (4S)-4-hydroxy-2-oxoglutarate = glyoxylate + pyruvate (RHEA:35639)

UniProt features (48 total): helix 17, mutagenesis site 9, strand 8, sequence variant 3, binding site 3, turn 3, transit peptide 1, chain 1, active site 1, site 1, splice variant 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
3S5O	X-RAY DIFFRACTION	1.97
3S5N	X-RAY DIFFRACTION	2.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86XE5-F1	92.75	0.90

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 (2): 196 (schiff-base intermediate with substrate); 168 (involved in proton transfer during cleavage)

Ligand- & substrate-binding residues (3): 77–78; 198; 222

Mutagenesis-validated functional residues (9):

Position	Phenotype
77	2-fold decrease in kcat and a nearly 8-fold increase in km.
77	significant loss of activity.
78	6-fold increase in km.
78	25-fold increase in km.
140	no change in activity.
168	no enzymatic activity.
196	no enzymatic activity.
198	2.5-fold decrease in kcat and 4.2 fold increase in km.
198	7-fold increase in km.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-389661	Glyoxylate metabolism and glycine degradation

MSigDB gene sets: 95 (showing top): GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_MODIFIED_AMINO_ACID_CATABOLIC_PROCESS, GOBP_ALDEHYDE_CATABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, GOBP_ORGANIC_ACID_BIOSYNTHETIC_PROCESS, SHEPARD_BMYB_MORPHOLINO_DN, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, AGGCACT_MIR5153P, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS, ACEVEDO_LIVER_TUMOR_VS_NORMAL_ADJACENT_TISSUE_DN, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, GOBP_GLYOXYLATE_METABOLIC_PROCESS, GOBP_MONOCARBOXYLIC_ACID_BIOSYNTHETIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_CATABOLIC_PROCESS

GO Biological Process (5): glyoxylate catabolic process (GO:0009436), trans-4-hydroxy-L-proline catabolic process (GO:0019470), oxalate metabolic process (GO:0033609), pyruvate biosynthetic process (GO:0042866), glyoxylate metabolic process (GO:0046487)

GO Molecular Function (6): (R,S)-4-hydroxy-2-oxoglutarate aldolase activity (GO:0008700), protein homodimerization activity (GO:0042803), (4S)-4-hydroxy-2-oxoglutarate aldolase activity (GO:0106009), protein binding (GO:0005515), lyase activity (GO:0016829), oxo-acid-lyase activity (GO:0016833)

GO Cellular Component (3): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
oxo-acid-lyase activity	2
aldehyde catabolic process	1
glyoxylate metabolic process	1
monocarboxylic acid catabolic process	1
modified amino acid catabolic process	1
L-amino acid catabolic process	1
non-proteinogenic amino acid catabolic process	1
dicarboxylic acid metabolic process	1
pyruvate metabolic process	1
monocarboxylic acid biosynthetic process	1
aldehyde metabolic process	1
monocarboxylic acid metabolic process	1
identical protein binding	1
protein dimerization activity	1
binding	1
catalytic activity	1
carbon-carbon lyase activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
mitochondrion	1
intracellular organelle lumen	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1078 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HOGA1	GRHPR	Q9UBQ7	983
HOGA1	AGXT	P21549	957
HOGA1	MTRFR	Q9H3J6	826
HOGA1	MRPS16	Q9Y3D3	812
HOGA1	TUFM	P49411	792
HOGA1	TSFM	P43897	770
HOGA1	MRPS22	P82650	764
HOGA1	GFM1	Q96RP9	718
HOGA1	PHC3	Q8NDX5	713
HOGA1	OGDH	Q02218	668
HOGA1	PRODH2	Q9UF12	611
HOGA1	SPMIP1	A0A1B0GUX0	590
HOGA1	AIFM1	O95831	578
HOGA1	MRPL58	Q14197	540
HOGA1	SLC7A9	P82251	490

IntAct

30 interactions, top by confidence:

A	B	Type	Score
HOGA1	USP47	psi-mi:“MI:0915”(physical association)	0.640
HOGA1	CIMAP1A	psi-mi:“MI:0915”(physical association)	0.560
HOGA1	STARD7	psi-mi:“MI:0915”(physical association)	0.500
HOGA1	STARD7	psi-mi:“MI:0914”(association)	0.500
SPRYD4	ATP5MG	psi-mi:“MI:0914”(association)	0.500
COQ4	COQ9	psi-mi:“MI:0914”(association)	0.500
LRRK2	HOGA1	psi-mi:“MI:0407”(direct interaction)	0.440
HOGA1	MESD	psi-mi:“MI:0915”(physical association)	0.400
ABHD11	NME4	psi-mi:“MI:0914”(association)	0.350
ADCK5	ATP5F1B	psi-mi:“MI:0914”(association)	0.350
NIT1	NDUFS6	psi-mi:“MI:0914”(association)	0.350
ADCK5	AKR1B10	psi-mi:“MI:0914”(association)	0.350
COQ2	NME6	psi-mi:“MI:0914”(association)	0.350
HOGA1	NME6	psi-mi:“MI:0914”(association)	0.350
SPRYD4	ALDH1L1	psi-mi:“MI:0914”(association)	0.350
BOLA3	NDUFAB1	psi-mi:“MI:0914”(association)	0.350
HOGA1	C1QBP	psi-mi:“MI:0914”(association)	0.350
NIT1	PMPCB	psi-mi:“MI:0914”(association)	0.350
	AP3B1	psi-mi:“MI:0914”(association)	0.350
ITLN2	IGLC7	psi-mi:“MI:0914”(association)	0.350
FNDC11	HSPA8	psi-mi:“MI:0914”(association)	0.350
HOGA1	AKR7A3	psi-mi:“MI:0914”(association)	0.350
FECH	POTEF	psi-mi:“MI:0914”(association)	0.350
CIMAP1A	HOGA1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (27): USP47 (Affinity Capture-MS), LYRM7 (Affinity Capture-MS), HOGA1 (Affinity Capture-MS), HOGA1 (Affinity Capture-MS), HOGA1 (Affinity Capture-MS), HOGA1 (Affinity Capture-MS), HOGA1 (Affinity Capture-MS), HOGA1 (Affinity Capture-MS), HOGA1 (Affinity Capture-MS), ECH1 (Affinity Capture-MS), C1QBP (Affinity Capture-MS), WBSCR16 (Affinity Capture-MS), USP47 (Affinity Capture-MS), HOGA1 (Synthetic Lethality), HOGA1 (Two-hybrid)

ESM2 similar proteins: A0PJR5, A2C0Z2, A4SGK0, A5VSZ7, A6UCL8, A6WXC3, A7HTW0, A9BEF8, A9HL57, A9JS71, A9M9B7, B0CJD4, B2S8T2, B3PPF4, B5ZSI8, B9JBU0, C0RFS3, C3MHX3, F1R6N4, O75521, O87873, P52045, Q11DU2, Q1MB43, Q21LR0, Q28C91, Q2K3L0, Q2T4M6, Q2VZG7, Q3MIE0, Q46GP3, Q50130, Q57AM5, Q5HZQ8, Q5M8W9, Q5NPY2, Q5XIC0, Q6NL24, Q6NY77, Q78JN3

Diamond homologs: A0A0A2JW93, A0AIN8, A0LV15, A3CN43, A3CVI7, A4VU96, A4W0I7, A4WNS1, A4XSW1, A5FZS7, A5GHT4, A5V3L9, A6Y9S5, A7HX36, A7ZDQ5, A8AXI2, A8DRH7, A8LKQ5, A9HIW2, A9KFS0, A9NDT3, B0BPI4, B1LTD9, B2FL61, B2GC11, B3GXP5, B4SRX7, B6JGA4, B8GN57, B8ZRR3, C1CRD6, C4L2D2, P0CL20, P58207, P75682, Q03K16, Q04KR9, Q07607, Q0AI27, Q0BYG4

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	43
Likely pathogenic	73
Uncertain significance	170
Likely benign	208
Benign	21

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070213	NM_138413.4(HOGA1):c.70del (p.Val24fs)	Pathogenic
1346647	NM_138413.4(HOGA1):c.660G>C (p.Leu220Phe)	Pathogenic
1361551	NM_138413.4(HOGA1):c.420C>G (p.Tyr140Ter)	Pathogenic
1423670	NM_138413.4(HOGA1):c.573del (p.Asn191fs)	Pathogenic
1424866	NM_138413.4(HOGA1):c.397del (p.Ala133fs)	Pathogenic
1451724	NM_138413.4(HOGA1):c.700G>T (p.Gly234Ter)	Pathogenic
1452928	NM_138413.4(HOGA1):c.3G>T (p.Met1Ile)	Pathogenic
1456334	NM_138413.4(HOGA1):c.904del (p.Cys302fs)	Pathogenic
1459497	NC_000010.10:g.(?99359814)(99359930_?)del	Pathogenic
204268	NM_138413.4(HOGA1):c.117C>A (p.Tyr39Ter)	Pathogenic
204269	NM_138413.4(HOGA1):c.208C>T (p.Arg70Ter)	Pathogenic
204271	NM_138413.4(HOGA1):c.346C>T (p.Gln116Ter)	Pathogenic
204274	NM_138413.4(HOGA1):c.728C>A (p.Ala243Asp)	Pathogenic
204279	NM_138413.4(HOGA1):c.907C>T (p.Arg303Cys)	Pathogenic
204285	NM_138413.4(HOGA1):c.700+5G>T	Pathogenic
204287	NM_138413.4(HOGA1):c.158del (p.Asp53fs)	Pathogenic
2057925	NM_138413.4(HOGA1):c.903del (p.Cys302fs)	Pathogenic
2117688	NM_138413.4(HOGA1):c.179del (p.Asn60fs)	Pathogenic
2427238	NC_000010.10:g.(?99344451)(99344681_?)del	Pathogenic
2427239	NC_000010.10:g.(?99358512)(99361767_?)del	Pathogenic
2664097	NM_138413.4(HOGA1):c.926T>C (p.Leu309Pro)	Pathogenic
2664379	NM_138413.4(HOGA1):c.3G>A (p.Met1Ile)	Pathogenic
2664380	NM_138413.4(HOGA1):c.186_187del (p.His62fs)	Pathogenic
2664383	NM_138413.4(HOGA1):c.238G>T (p.Glu80Ter)	Pathogenic
2664401	NM_138413.4(HOGA1):c.85G>T (p.Glu29Ter)	Pathogenic
2664402	NM_138413.4(HOGA1):c.754C>T (p.Gln252Ter)	Pathogenic
2664410	NM_138413.4(HOGA1):c.881G>A (p.Trp294Ter)	Pathogenic
2664412	NM_138413.4(HOGA1):c.940G>T (p.Glu314Ter)	Pathogenic
2671866	NM_138413.4(HOGA1):c.769_770del (p.Cys257fs)	Pathogenic
2783196	NM_138413.4(HOGA1):c.236del (p.Gly79fs)	Pathogenic

SpliceAI

1667 predictions. Top by Δscore:

Variant	Effect	Δscore
10:97598902:GT:G	donor_gain	1.0000
10:97599083:T:TA	acceptor_gain	1.0000
10:97599084:GGCA:G	acceptor_loss	1.0000
10:97599085:GCA:G	acceptor_loss	1.0000
10:97599085:GCAG:G	acceptor_loss	1.0000
10:97599087:A:AG	acceptor_gain	1.0000
10:97599087:A:T	acceptor_loss	1.0000
10:97599088:G:GA	acceptor_gain	1.0000
10:97599088:GC:G	acceptor_gain	1.0000
10:97599088:GCC:G	acceptor_gain	1.0000
10:97599088:GCCA:G	acceptor_gain	1.0000
10:97599705:T:TA	acceptor_gain	1.0000
10:97599812:GAT:G	donor_gain	1.0000
10:97599815:G:GG	donor_gain	1.0000
10:97602196:T:G	donor_gain	1.0000
10:97602196:T:TG	donor_gain	1.0000
10:97584912:GAG:G	donor_gain	0.9900
10:97584915:G:GA	donor_loss	0.9900
10:97584916:T:G	donor_loss	0.9900
10:97598904:G:GG	donor_gain	0.9900
10:97599084:G:A	acceptor_gain	0.9900
10:97599088:GCCAC:G	acceptor_gain	0.9900
10:97599214:AAG:A	donor_loss	0.9900
10:97599216:GG:G	donor_loss	0.9900
10:97599217:G:C	donor_loss	0.9900
10:97599218:T:A	donor_loss	0.9900
10:97599717:GT:G	acceptor_gain	0.9900
10:97599808:TGGTG:T	donor_gain	0.9900
10:97599810:GTGAT:G	donor_gain	0.9900
10:97599811:TGATG:T	donor_loss	0.9900

AlphaMissense

2123 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:97611542:G:C	K289N	0.996
10:97611542:G:T	K289N	0.996
10:97599799:G:C	K196N	0.995
10:97599799:G:T	K196N	0.995
10:97599683:G:C	A158P	0.992
10:97599803:A:C	S198R	0.992
10:97599805:C:A	S198R	0.992
10:97599805:C:G	S198R	0.992
10:97599684:C:A	A158D	0.991
10:97599205:C:G	H153D	0.990
10:97599681:T:A	V157D	0.990
10:97601971:T:C	L272P	0.990
10:97611582:C:A	R303S	0.990
10:97600151:A:C	S230R	0.989
10:97600153:C:A	S230R	0.989
10:97600153:C:G	S230R	0.989
10:97599792:G:A	G194D	0.986
10:97611541:A:C	K289T	0.986
10:97584839:T:C	F46L	0.985
10:97584841:C:A	F46L	0.985
10:97584841:C:G	F46L	0.985
10:97599768:T:A	L186H	0.985
10:97598802:A:T	E80V	0.984
10:97600112:T:C	F217L	0.984
10:97600114:T:A	F217L	0.984
10:97600114:T:G	F217L	0.984
10:97601866:G:A	G237E	0.984
10:97584840:T:C	F46S	0.983
10:97584914:G:C	G71R	0.983
10:97598789:G:C	G76R	0.983

dbSNP variants (sampled 300 via entrez): RS1000038934 (10:97602534 G>C,T), RS1000186778 (10:97609616 C>G,T), RS1000194610 (10:97591148 T>A), RS1000294126 (10:97611764 G>A,C,T), RS1000409112 (10:97605742 G>C), RS1000581146 (10:97587313 A>C), RS1000632142 (10:97586993 C>T), RS1000706512 (10:97600301 G>A,T), RS1000741474 (10:97607116 A>G), RS1000793026 (10:97592404 C>T), RS1000838610 (10:97583872 C>T), RS1000885933 (10:97598635 T>C), RS1001094697 (10:97601242 G>A), RS1001148192 (10:97595493 C>A,T), RS1001283390 (10:97591781 C>T)

Disease associations

OMIM: gene MIM:613597 | disease phenotypes: MIM:613616

GenCC curated gene-disease

Disease	Classification	Inheritance
primary hyperoxaluria type 3	Definitive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
primary hyperoxaluria type 3	Definitive	AR

Mondo (1): primary hyperoxaluria type 3 (MONDO:0013327)

Orphanet (2): Primary hyperoxaluria (Orphanet:416), Primary hyperoxaluria type 3 (Orphanet:93600)

HPO phenotypes

11 total (11 of 11 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000121	Nephrocalcinosis
HP:0000790	Hematuria
HP:0003110	Abnormality of urine homeostasis
HP:0003159	Hyperoxaluria
HP:0008672	Calcium oxalate nephrolithiasis
HP:0012211	Abnormal renal physiology
HP:0012531	Pain
HP:0100515	Pollakisuria
HP:0100518	Dysuria
HP:6001009	Increased urine 4-hydroxy-2-oxoglutarate level

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST001391_4	Metabolite levels	1.000000e-12
GCST003501_11	Asparaginase-induced acute pancreatitis in acute lymphoblastic leukemia (onset time)	1.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004725	metabolite measurement
EFO:1001507	asparaginase-induced acute pancreatitis

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5996 (SINGLE PROTEIN)

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

Binding affinities (BindingDB)

20 measured of 20 human assays (20 total across all organisms); most potent 20 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
(3aR,5R,6S,7R,7aR)-5- ((cyclopentylamino)methyl)-2- (methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazole-6,7-diol	KI	0.6 nM	US-9718854: Selective glycosidase inhibitors and uses thereof
(3aR,5R,6S,7R,7aR)-5- ((cyclopropylamino)methyl)-2- (methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazole-6,7-diol	KI	1.3 nM	US-9718854: Selective glycosidase inhibitors and uses thereof
(3aR,5R,6S,7R,7aR)-5- ((cyclobutylamino)methyl)-2- (methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazole-6,7-diol	KI	1.4 nM	US-9718854: Selective glycosidase inhibitors and uses thereof
((3aR,5R,6S,7R,7aR)-6,7-dihydroxy- 2-(methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-5-yl)methyl diethylcarbamate	KI	2.7 nM	US-9718854: Selective glycosidase inhibitors and uses thereof
(3aR,5R,6S,7R,7aR)-2- (methylamino)-5- ((methylamino)methyl)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazole- 6,7-diol	KI	2.8 nM	US-9718854: Selective glycosidase inhibitors and uses thereof
(3aR,5R,6S,7R,7aR)-5-(((2- hydroxyethyl)amino)methyl)-2- (methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazole-6,7-diol	KI	3 nM	US-9718854: Selective glycosidase inhibitors and uses thereof
(3aR,5R,6S,7R,7aR)-5-(((2- methoxyethyl)amino)methyl)-2- (methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazole-6,7-diol	KI	3.3 nM	US-9718854: Selective glycosidase inhibitors and uses thereof
(3aR,5R,6S,7R,7aR)-5- ((ethylamino)methyl)-2- (methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazole-6,7-diol	KI	3.7 nM	US-9718854: Selective glycosidase inhibitors and uses thereof
(3aR,5R,6S,7R,7aR)-5- ((allylamino)methyl)-2- (methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazole-6,7-diol	KI	3.8 nM	US-9718854: Selective glycosidase inhibitors and uses thereof
(3aR,5R,6S,7R,7aR)-2-(ethylamino)- 5-((isopropylamino)methyl)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazole- 6,7-diol	KI	5.4 nM	US-9718854: Selective glycosidase inhibitors and uses thereof
2-((((3aR,5R,6S,7R,7aR)-6,7- dihydroxy-2-(methylamino)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazol- 5-yl)methyl)amino)acetonitrile	KI	5.4 nM	US-9718854: Selective glycosidase inhibitors and uses thereof
(3aR,5R,6S,7R,7aR)-2-(ethylamino)- 5-((methylamino)methyl)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazole- 6,7-diol	KI	5.6 nM	US-9718854: Selective glycosidase inhibitors and uses thereof
(3aR,5R,6S,7R,7aR)-5- ((cyclopropylamino)methyl)-2- (dimethylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazole-6,7-diol	KI	6 nM	US-9718854: Selective glycosidase inhibitors and uses thereof
(3aR,5R,6S,7R,7aR)-5-(((3- hydroxypropyl)amino)methyl)-2- (methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazole-6,7-diol	KI	6 nM	US-9718854: Selective glycosidase inhibitors and uses thereof
(3aR,5R,6S,7R,7aR)-2- (methylamino)-5-(((tetrahydro-2H- pyran-4-yl)amino)methyl)-5,6,7,7a- tetrahydro-3aH-pyrano[3,2-d]thiazole- 6,7-diol	KI	6.5 nM	US-9718854: Selective glycosidase inhibitors and uses thereof
(3aR,5R,6S,7R,7aR)-5-(((1H-pyrazol- 3-yl)amino)methyl)-2-(methylamino)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazole-6,7-diol	KI	6.8 nM	US-9718854: Selective glycosidase inhibitors and uses thereof
(3aR,5R,6S,7R,7aR)-5- ((cyclohexylamino)methyl)-2- (methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazole-6,7-diol	KI	9.3 nM	US-9718854: Selective glycosidase inhibitors and uses thereof
((3aR,5R,6S,7R,7aR)-6,7-dihydroxy- 2-(methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazol-5-yl)methyl dimethylcarbamate	KI	9.9 nM	US-9718854: Selective glycosidase inhibitors and uses thereof
(3aR,5R,6S,7R,7aR)-5 (aminomethyl)-2-(ethylamino)- 5,6,7,7a-tetrahydro-3aH-pyrano[3,2- d]thiazole-6,7-diol	KI	11 nM	US-9718854: Selective glycosidase inhibitors and uses thereof
(3aR,5R,6S,7R,7aR)-5-(((4- fluorobenzyl)oxy)methyl)-2- (methylamino)-5,6,7,7a-tetrahydro- 3aH-pyrano[3,2-d]thiazole-6,7-diol	KI	25 nM	US-9718854: Selective glycosidase inhibitors and uses thereof

ChEMBL bioactivities

20 potent at pChembl≥5 of 20 total, top 20 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
9.22	Ki	0.6	nM	CHEMBL5978535
8.89	Ki	1.3	nM	CHEMBL5786372
8.85	Ki	1.4	nM	CHEMBL6063279
8.57	Ki	2.7	nM	CHEMBL5896489
8.55	Ki	2.8	nM	CHEMBL5795406
8.52	Ki	3	nM	CHEMBL6005801
8.48	Ki	3.3	nM	CHEMBL5865117
8.43	Ki	3.7	nM	CHEMBL6026848
8.42	Ki	3.8	nM	CHEMBL6043605
8.27	Ki	5.4	nM	CHEMBL5764830
8.27	Ki	5.4	nM	CHEMBL5771884
8.25	Ki	5.6	nM	CHEMBL5840416
8.22	Ki	6	nM	CHEMBL6032422
8.22	Ki	6	nM	CHEMBL5874425
8.19	Ki	6.5	nM	CHEMBL5854899
8.17	Ki	6.8	nM	CHEMBL6003048
8.03	Ki	9.3	nM	CHEMBL6059376
8.00	Ki	9.9	nM	CHEMBL5871563
7.96	Ki	11	nM	CHEMBL5942672
7.60	Ki	25	nM	CHEMBL5838445

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Aflatoxin B1	decreases expression, decreases methylation, increases methylation	4
Benzo(a)pyrene	decreases expression, decreases methylation	3
Tetrachlorodibenzodioxin	affects expression, increases expression	3
Cyclosporine	decreases expression	3
GSK-J4	increases expression	1
sotorasib	affects cotreatment, increases expression	1
methyleugenol	decreases expression	1
bisphenol A	decreases expression	1
sulforaphane	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	increases expression	1
perfluorooctane sulfonic acid	decreases expression	1
entinostat	increases expression	1
jinfukang	affects cotreatment, increases expression	1
trametinib	increases expression, affects cotreatment	1
NVP-BKM120	affects cotreatment, increases expression	1
Sunitinib	decreases expression	1
Troglitazone	decreases expression	1
Leflunomide	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Cisplatin	affects cotreatment, increases expression	1
Estradiol	affects cotreatment, decreases expression	1
Niclosamide	increases expression	1
Fenofibrate	decreases expression	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	affects expression	1
Okadaic Acid	decreases expression	1

ChEMBL screening assays

5 unique, capped per target: 5 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5731045	Binding	Fluorescence based hOGA assay: Enzymatic reactions were carried out in a reaction containing 50 mM NaH2PO4, 100 mM NaCl and 0.1% BSA (pH 7.0) using 2 mM 4-Methylumbelliferyl N-acetyl-β-D-glucosaminide dihydrate (Sigma M2133) dissolved in dd	Selective glycosidase inhibitors and uses thereof

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04042402	PHASE3	ACTIVE_NOT_RECRUITING	Long Term Extension Study in Patients With Primary Hyperoxaluria
NCT06465472	PHASE3	NOT_YET_RECRUITING	Evaluation of the Efficacy and Safety of Stiripentol in Patients 6 Years and Older With Primary Hyperoxaluria Type 1, 2 or 3
NCT05001269	PHASE2	COMPLETED	Nedosiran in Pediatric Patients From Birth to 11 Years of Age With PH and Relatively Intact Renal Function
NCT04555486	PHASE1	COMPLETED	Study to Evaluate Safety, Tolerability, PK and PD of DCR-PHXC in PH Type 3 Patients
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT04542590	Not specified	COMPLETED	Natural History of Patients With PH3 and a History of Stone Events