GRHPR

Summary

GRHPR (glyoxylate and hydroxypyruvate reductase, HGNC:4570) is a protein-coding gene on chromosome 9p13.2, encoding Glyoxylate reductase/hydroxypyruvate reductase (Q9UBQ7). Enzyme with hydroxy-pyruvate reductase, glyoxylate reductase and D-glycerate dehydrogenase enzymatic activities.

This gene encodes an enzyme with hydroxypyruvate reductase, glyoxylate reductase, and D-glycerate dehydrogenase enzymatic activities. The enzyme has widespread tissue expression and has a role in metabolism. Type II hyperoxaluria is caused by mutations in this gene.

Source: NCBI Gene 9380 — RefSeq curated summary.

At a glance

• Gene–disease (curated): primary hyperoxaluria type 2 (Definitive, GenCC)
• GWAS associations: 5
• Clinical variants (ClinVar): 643 total — 60 pathogenic, 82 likely-pathogenic
• Phenotypes (HPO): 15
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_012203

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4570
Approved symbol	GRHPR
Name	glyoxylate and hydroxypyruvate reductase
Location	9p13.2
Locus type	gene with protein product
Status	Approved
Aliases	PH2
Ensembl gene	ENSG00000137106
Ensembl biotype	protein_coding
OMIM	604296
Entrez	9380

Gene structure

Transcript identifiers

Ensembl transcripts: 26 — 16 protein_coding, 6 protein_coding_CDS_not_defined, 3 retained_intron, 1 nonsense_mediated_decay

ENST00000318158, ENST00000377824, ENST00000460882, ENST00000480596, ENST00000482603, ENST00000487399, ENST00000491488, ENST00000493368, ENST00000494290, ENST00000497693, ENST00000512404, ENST00000607784, ENST00000874641, ENST00000874642, ENST00000874643, ENST00000874644, ENST00000874645, ENST00000874646, ENST00000874647, ENST00000874648, ENST00000874649, ENST00000874650, ENST00000926738, ENST00000926739, ENST00000926740, ENST00000926741

RefSeq mRNA: 1 — MANE Select: NM_012203 NM_012203

CCDS: CCDS6609

Canonical transcript exons

ENST00000318158 — 9 exons

Exon	Start	End
ENSE00001934486	37422696	37422833
ENSE00001952551	37436661	37436990
ENSE00003484133	37430511	37430646
ENSE00003646434	37432008	37432138
ENSE00003695745	37424845	37424975
ENSE00003695972	37429732	37429836
ENSE00003698670	37425922	37425994
ENSE00003698807	37426538	37426654
ENSE00003701615	37428484	37428572

Expression profiles

Bgee: expression breadth ubiquitous, 292 present calls, max score 99.13.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 84.2267 / max 608.9334, expressed in 1826 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
96732	84.1771	1826
96731	0.0496	17

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lobe of liver	UBERON:0001114	99.13	gold quality
liver	UBERON:0002107	98.64	gold quality
right adrenal gland	UBERON:0001233	98.57	gold quality
left adrenal gland	UBERON:0001234	98.48	gold quality
left adrenal gland cortex	UBERON:0035825	98.44	gold quality
right adrenal gland cortex	UBERON:0035827	98.44	gold quality
adrenal cortex	UBERON:0001235	98.23	gold quality
adrenal gland	UBERON:0002369	98.18	gold quality
tendon of biceps brachii	UBERON:0008188	98.16	gold quality
adult mammalian kidney	UBERON:0000082	97.82	gold quality
adrenal tissue	UBERON:0018303	97.77	gold quality
hindlimb stylopod muscle	UBERON:0004252	97.56	gold quality
apex of heart	UBERON:0002098	97.43	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	97.42	gold quality
metanephros cortex	UBERON:0010533	97.04	gold quality
right atrium auricular region	UBERON:0006631	97.03	gold quality
gastrocnemius	UBERON:0001388	97.01	gold quality
muscle of leg	UBERON:0001383	96.85	gold quality
heart left ventricle	UBERON:0002084	96.79	gold quality
medial globus pallidus	UBERON:0002477	96.76	gold quality
spinal cord	UBERON:0002240	96.72	gold quality
lower esophagus	UBERON:0013473	96.70	gold quality
lower esophagus muscularis layer	UBERON:0035833	96.70	gold quality
left ovary	UBERON:0002119	96.68	gold quality
tibial nerve	UBERON:0001323	96.63	gold quality
cardiac ventricle	UBERON:0002082	96.62	gold quality
right ovary	UBERON:0002118	96.56	gold quality
left uterine tube	UBERON:0001303	96.53	gold quality
cardiac atrium	UBERON:0002081	96.53	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	96.52	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-10553	yes	32.87
E-MTAB-6524	no	229.58
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PPARA

miRNA regulators (miRDB)

16 targeting GRHPR, 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-4455	100.00	65.48	1587
HSA-MIR-3919	99.87	69.45	2489
HSA-MIR-130B-5P	99.83	68.50	1888
HSA-MIR-944	99.82	70.85	3042
HSA-MIR-4756-3P	99.62	66.30	1319
HSA-MIR-3123	99.47	67.15	2693
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-4504	99.10	69.14	1328
HSA-MIR-760	98.81	66.65	1392
HSA-MIR-4501	98.72	67.19	921
HSA-MIR-4669	97.94	62.71	224
HSA-MIR-3074-3P	97.83	67.26	922
HSA-MIR-3657	96.33	66.29	608
HSA-MIR-6753-5P	94.70	64.08	470
HSA-MIR-6722-5P	93.60	64.28	59

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 7)

• substrate specificity of human glyoxylate reductase (PMID:16756993)
• the GRHPR gene may have a role in primary hyperoxaluria type 2 in a Japanese patient [case report] (PMID:17510093)
• Our findings suggest that the GRHPR defect in noncancerous tissues may represent an independent predictor of poor survival for hepatocellular carcinoma patients after curative resection (PMID:23486161)
• GRHPR directly interacts with SVCT1. (PMID:23599041)
• GRHPR was genotyped in Japanese patients with PH2 and all GRHPR mutations described to date were reviewed in terms of geographic and ethnic association (PMID:24116921)
• Glyoxylate reductase/hydroxypyruvate reductase regulates the free d-aspartate level in mammalian cells. (PMID:34289161)
• Glyoxylate reductase: Definitive identification in human liver mitochondria, its importance for the compartment-specific detoxification of glyoxylate. (PMID:38200664)

Cross-species orthologs

9 orthologs

Organism	Symbol	Gene ID
danio_rerio	grhpra	ENSDARG00000068264
mus_musculus	Grhpr	ENSMUSG00000035637
rattus_norvegicus	Grhpr	ENSRNOG00000012794
drosophila_melanogaster	CtBP	FBGN0020496
drosophila_melanogaster	CG9331	FBGN0032889
drosophila_melanogaster	CG1236	FBGN0037370
drosophila_melanogaster	CG31673	FBGN0051673
drosophila_melanogaster	CG31674	FBGN0051674
caenorhabditis_elegans		WBGENE00006424

Paralogs (3): PHGDH (ENSG00000092621), CTBP1 (ENSG00000159692), CTBP2 (ENSG00000175029)

Protein

Protein identifiers

Glyoxylate reductase/hydroxypyruvate reductase — Q9UBQ7 (reviewed: Q9UBQ7)

All UniProt accessions (3): A0A384N605, Q9UBQ7, U3KQ56

UniProt curated annotations — full annotation on UniProt →

Function. Enzyme with hydroxy-pyruvate reductase, glyoxylate reductase and D-glycerate dehydrogenase enzymatic activities. Reduces hydroxypyruvate to D-glycerate, glyoxylate to glycolate, oxidizes D-glycerate to hydroxypyruvate.

Subunit / interactions. Homodimer.

Tissue specificity. Ubiquitous. Most abundantly expressed in the liver.

Disease relevance. Hyperoxaluria primary 2 (HP2) [MIM:260000] A disorder characterized by elevated urinary excretion of oxalate and L-glycerate, progressive tissue accumulation of insoluble calcium oxalate, nephrolithiasis, nephrocalcinosis, and end-stage renal disease. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the D-isomer specific 2-hydroxyacid dehydrogenase family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UBQ7-1	1	yes
Q9UBQ7-2	2

RefSeq proteins (1): NP_036335* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR006139	D-isomer_2_OHA_DH_cat_dom	Domain
IPR006140	D-isomer_DH_NAD-bd	Domain
IPR029753	D-isomer_DH_CS	Conserved_site
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily
IPR050223	D-isomer_2-hydroxyacid_DH	Family

Pfam: PF00389, PF02826

Enzyme classification (BRENDA):

• EC 1.1.1.26 — glyoxylate reductase (BRENDA: 17 organisms, 38 substrates, 13 inhibitors, 31 Km, 19 kcat entries)
• EC 1.1.1.79 — glyoxylate reductase (NADP+) (BRENDA: 24 organisms, 131 substrates, 53 inhibitors, 116 Km, 71 kcat entries)
• EC 1.1.1.81 — hydroxypyruvate reductase (BRENDA: 30 organisms, 73 substrates, 65 inhibitors, 82 Km, 39 kcat entries)

Substrate kinetics (BRENDA)

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

Substrate	Km (mM)	Measurements
GLYOXYLATE	0.0045–16	45
NADPH	0.0009–0.0648	38
HYDROXYPYRUVATE	0.0038–40	27
NADH	0.0061–0.24	14
GLYOXYLATE	0.0045–18.011	13
NADH	0.013–2.42	12
NADPH	0.0105–0.22	12
SUCCINIC SEMIALDEHYDE	0.87–8.96	9
3-HYDROXYPYRUVATE	0.057–9.35	8
GLYOXYLATE	3–80	7
HYDROXYPYRUVATE	0.058–1.4	6
NADH	0.0058–0.1	5
NADPH	0.0026–0.408	4
PHENYLPYRUVATE	3.7–6.58	4
HYDROXYPYRUVATE	0.8–6.8	3

Catalyzed reactions (Rhea), 3 shown:

• glycolate + NADP(+) = glyoxylate + NADPH + H(+) (RHEA:10992)
• (R)-glycerate + NAD(+) = 3-hydroxypyruvate + NADH + H(+) (RHEA:17905)
• (R)-glycerate + NADP(+) = 3-hydroxypyruvate + NADPH + H(+) (RHEA:18657)

UniProt features (51 total): strand 15, helix 15, binding site 9, modified residue 3, splice variant 3, turn 2, chain 1, active site 1, site 1, sequence variant 1

Structure

Experimental structures (PDB)

4 structures.

PDB	Method	Resolution (Å)
2GCG	X-RAY DIFFRACTION	2.2
2H1S	X-RAY DIFFRACTION	2.45
2Q50	X-RAY DIFFRACTION	2.45
2WWR	X-RAY DIFFRACTION	2.82

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBQ7-F1	96.80	0.98

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): 293 (proton donor); 274 (raises pka of active site his)

Ligand- & substrate-binding residues (9): 295; 83–84; 162–164; 185–188; 217; 243; 245; 269; 293–296

Post-translational modifications (3): 36, 272, 298

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

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

MSigDB gene sets: 188 (showing top): MODULE_151, DITTMER_PTHLH_TARGETS_UP, DACOSTA_UV_RESPONSE_VIA_ERCC3_UP, GOBP_MONOCARBOXYLIC_ACID_METABOLIC_PROCESS, SHEPARD_BMYB_MORPHOLINO_DN, GOBP_DICARBOXYLIC_ACID_METABOLIC_PROCESS, chr9p13, GOBP_GLYOXYLATE_METABOLIC_PROCESS, JAZAG_TGFB1_SIGNALING_VIA_SMAD4_UP, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOBP_ALDEHYDE_METABOLIC_PROCESS, FLECHNER_BIOPSY_KIDNEY_TRANSPLANT_REJECTED_VS_OK_DN, MULLIGHAN_NPM1_SIGNATURE_3_DN, GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_CH_OH_GROUP_OF_DONORS, DEURIG_T_CELL_PROLYMPHOCYTIC_LEUKEMIA_UP

GO Biological Process (3): carboxylic acid metabolic process (GO:0019752), dicarboxylic acid metabolic process (GO:0043648), glyoxylate metabolic process (GO:0046487)

GO Molecular Function (12): hydroxypyruvate reductase (NADH) activity (GO:0008465), hydroxypyruvate reductase [NAD(P)H] activity (GO:0016618), glyoxylate reductase (NADPH) activity (GO:0030267), carboxylic acid binding (GO:0031406), protein homodimerization activity (GO:0042803), NAD binding (GO:0051287), NADPH binding (GO:0070402), hydroxypyruvate reductase (NADPH) activity (GO:0120509), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor (GO:0016616), NADP binding (GO:0050661)

GO Cellular Component (6): cytoplasm (GO:0005737), mitochondrion (GO:0005739), peroxisomal matrix (GO:0005782), cytosol (GO:0005829), extracellular exosome (GO:0070062), catalytic complex (GO:1902494)

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
hydroxypyruvate reductase [NAD(P)H] activity	2
anion binding	2
adenyl nucleotide binding	2
cellular anatomical structure	2
cytoplasm	2
oxoacid metabolic process	1
carboxylic acid metabolic process	1
aldehyde metabolic process	1
monocarboxylic acid metabolic process	1
oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor	1
glyoxylate reductase activity	1
organic acid binding	1
identical protein binding	1
protein dimerization activity	1
NADP binding	1
binding	1
catalytic activity	1
oxidoreductase activity, acting on CH-OH group of donors	1
intracellular anatomical structure	1
intracellular membrane-bounded organelle	1
peroxisome	1
microbody lumen	1
extracellular vesicle	1
protein-containing complex	1

Protein interactions and networks

STRING

2634 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
GRHPR	HOGA1	Q86XE5	983
GRHPR	AGXT	P21549	979
GRHPR	OGDH	Q02218	824
GRHPR	TMTC1	Q8IUR5	768
GRHPR	PHC3	Q8NDX5	597
GRHPR	HAO1	Q9UJM8	590
GRHPR	PRODH2	Q9UF12	588
GRHPR	SLC26A1	Q9H2B4	575
GRHPR	GLYCTK	Q8IVS8	554
GRHPR	SHMT2	P34897	516
GRHPR	SLC7A9	P82251	494
GRHPR	GLDC	P23378	472
GRHPR	SLC3A1	Q07837	471
GRHPR	SLC2A1	P11166	466
GRHPR	HYI	Q5T013	463

IntAct

35 interactions, top by confidence:

A	B	Type	Score
GTF2F1	GTF2F2	psi-mi:“MI:0914”(association)	0.870
PYGO2	BCL9	psi-mi:“MI:0914”(association)	0.690
GRHPR	SLC23A1	psi-mi:“MI:0915”(physical association)	0.630
GRHPR	SLC23A1	psi-mi:“MI:0403”(colocalization)	0.630
TFDP1	E2F3	psi-mi:“MI:0914”(association)	0.530
CDC14B	GRHPR	psi-mi:“MI:0915”(physical association)	0.400
SLBP	GRHPR	psi-mi:“MI:0915”(physical association)	0.400
	TK2	psi-mi:“MI:0915”(physical association)	0.400
GRHPR	PCNA	psi-mi:“MI:0915”(physical association)	0.370
GRHPR	FOS	psi-mi:“MI:0915”(physical association)	0.370
PTH2R	GRHPR	psi-mi:“MI:0915”(physical association)	0.370
GRHPR	CDC7	psi-mi:“MI:0915”(physical association)	0.370
GRHPR	GLS2	psi-mi:“MI:0915”(physical association)	0.370
APBB1	SSPOP	psi-mi:“MI:0914”(association)	0.350
SH2D3C	ANXA2P2	psi-mi:“MI:0914”(association)	0.350
PRDM7	SNRPD2	psi-mi:“MI:0914”(association)	0.350
PRDM9	CDC14C	psi-mi:“MI:0914”(association)	0.350
SFMBT2	DCD	psi-mi:“MI:0914”(association)	0.350
ATG16L1	ESYT2	psi-mi:“MI:0914”(association)	0.350
FECH	POTEF	psi-mi:“MI:0914”(association)	0.350
AZU1	UBA6	psi-mi:“MI:0914”(association)	0.350
DDX28	UBA6	psi-mi:“MI:0914”(association)	0.350
ITM2C	UBA6	psi-mi:“MI:0914”(association)	0.350
MRPL49	UBA6	psi-mi:“MI:0914”(association)	0.350
NPPB	ACOT7	psi-mi:“MI:0914”(association)	0.350
PEX7	UBA6	psi-mi:“MI:0914”(association)	0.350

BioGRID (116): GRHPR (Affinity Capture-RNA), GRHPR (Affinity Capture-RNA), AKR1B1 (Co-fractionation), ETFA (Co-fractionation), ETFB (Co-fractionation), GRHPR (Co-fractionation), GRHPR (Co-fractionation), GRHPR (Co-fractionation), GRHPR (Co-fractionation), GRHPR (Co-fractionation), GRHPR (Co-fractionation), GRHPR (Co-fractionation), GRHPR (Co-fractionation), GRHPR (Co-fractionation), GRHPR (Co-fractionation)

ESM2 similar proteins: A2XNR6, A5A6P1, A5GFY8, B0X4N8, D4AAT7, O04130, O08651, O43175, O49485, O65361, P13803, P13804, P32232, P35520, P37142, P40939, P49079, P49080, P54887, P54888, Q16T79, Q29554, Q2QS13, Q3LXA3, Q42806, Q42942, Q4KLZ6, Q59A32, Q5EAD2, Q5R7M2, Q5RC31, Q60HD7, Q61753, Q64428, Q64737, Q67U69, Q75LJ3, Q8AWD2, Q91Z53, Q941T1

Diamond homologs: A1AH96, A1JT62, A1RYE4, A4TGN1, A4W577, A5CAL1, A6TFG7, A7FPA2, A7MKR1, A7ZTA0, A8A609, A8ARD9, A8G7S7, A9MUT4, A9R4G6, B1IZP1, B1JH01, B1L765, B1LJB3, B1X8G8, B2K7F1, B2U573, B2VCD1, B4SWJ5, B4T938, B4TZ41, B5BHT3, B5EX58, B5FLC2, B5R4N3, B5RGN1, B5XMZ4, B5YVK6, B6I3C3, B6YWH0, B7L6W9, B7LTG7, B7M3H6, B7MER0, B7N1K7

SIGNOR signaling

0 interactions.

Disease & clinical

Cancer significance

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	60
Likely pathogenic	82
Uncertain significance	136
Likely benign	268
Benign	25

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1069571	NC_000009.11:g.(?37425909)(37426661_?)del	Pathogenic
1074076	NM_012203.2(GRHPR):c.23_26dup (p.Phe10fs)	Pathogenic
1075299	NM_012203.2(GRHPR):c.361dup (p.Thr121fs)	Pathogenic
1075315	NM_012203.2(GRHPR):c.347_350delinsACCCTAGGAGGGCAAAGACCGCGGTGTGGAGACTGTGGGTGTGGGGAAGTGCATCCAAGGCCCTGGGTTCTCCAGCCCTGCCACAACCTTGCTCTGTGACCTCCAGCAAGACCCTGCCCCTTCTGGGCGTGTGCGTAGTATGAGGGAGGACCTAGCTCAGTGCCAAGCCCCAGCAGGATGTCTTTCCTCAACCGCAGCCACGGGTCTCAGCCCATGGAAGAATAAACCTCCCCCTGTGAGGCTGTTGTGACAGTTTTGAGAAAAGGTTCAGACTCAGAGGCTGCTACTTACCA (p.Val116_Ser117delinsAspProArgArgAlaLysThrAlaValTrpArgLeuTrpValTrpGlySerAlaSerLysAlaLeuGlySerProAlaLeuProGlnProCysSerValThrSerSerLysThrLeuProLeuLeuGlyValCysValValTer)	Pathogenic
1353654	NM_012203.2(GRHPR):c.532_533del (p.Gln178fs)	Pathogenic
1416063	NM_012203.2(GRHPR):c.532dup (p.Gln178fs)	Pathogenic
1442008	NM_012203.2(GRHPR):c.274G>T (p.Glu92Ter)	Pathogenic
1455478	NC_000009.11:g.(?37422738)(37424982_?)del	Pathogenic
1457953	NC_000009.11:g.(?37436648)(37436789_?)del	Pathogenic
1460348	NM_012203.2(GRHPR):c.107C>A (p.Ser36Ter)	Pathogenic
162020	NM_012203.2(GRHPR):c.866_867del (p.Val289fs)	Pathogenic
162021	NM_012203.2(GRHPR):c.248_249del (p.Val83fs)	Pathogenic
2008195	NM_012203.2(GRHPR):c.423G>A (p.Trp141Ter)	Pathogenic
204232	NM_012203.2(GRHPR):c.203T>C (p.Leu68Pro)	Pathogenic
204233	NM_012203.2(GRHPR):c.287G>T (p.Arg96Leu)	Pathogenic
204235	NM_012203.2(GRHPR):c.494G>A (p.Gly165Asp)	Pathogenic
204240	NM_012203.2(GRHPR):c.965T>C (p.Met322Thr)	Pathogenic
204241	NM_012203.2(GRHPR):c.84-2A>G	Pathogenic
204245	NM_012203.2(GRHPR):c.45del (p.Ala17fs)	Pathogenic
204247	NM_012203.2(GRHPR):c.288-2_288del	Pathogenic
204249	NM_012203.2(GRHPR):c.375del (p.Leu126fs)	Pathogenic
204253	NM_012203.2(GRHPR):c.694del (p.Gln232fs)	Pathogenic
2061787	NM_012203.2(GRHPR):c.916del (p.Ser306fs)	Pathogenic
2110730	NM_012203.2(GRHPR):c.729del (p.Ser244fs)	Pathogenic
2173845	NM_012203.2(GRHPR):c.932_935dup (p.Asn312fs)	Pathogenic
2416508	NM_012203.2(GRHPR):c.734+1del	Pathogenic
2425774	NC_000009.11:g.(?37425909)(37429843_?)del	Pathogenic
2425775	NC_000009.11:g.(?37428471)(37429843_?)del	Pathogenic
2664098	NM_012203.2(GRHPR):c.109_118delinsCAC (p.Asp37fs)	Pathogenic
2664100	NM_012203.2:c.215_493del	Pathogenic

SpliceAI

2035 predictions. Top by Δscore:

Variant	Effect	Δscore
9:37422804:GG:G	donor_gain	1.0000
9:37422805:GG:G	donor_gain	1.0000
9:37422832:GA:G	donor_gain	1.0000
9:37422834:G:GG	donor_gain	1.0000
9:37422861:G:GT	donor_gain	1.0000
9:37424840:CGCA:C	acceptor_loss	1.0000
9:37424843:A:AG	acceptor_gain	1.0000
9:37424843:AGCT:A	acceptor_gain	1.0000
9:37424843:AGCTG:A	acceptor_loss	1.0000
9:37424844:G:A	acceptor_loss	1.0000
9:37424844:G:GA	acceptor_gain	1.0000
9:37424844:GCT:G	acceptor_gain	1.0000
9:37424844:GCTG:G	acceptor_gain	1.0000
9:37424844:GCTGT:G	acceptor_gain	1.0000
9:37425992:GCG:G	donor_gain	1.0000
9:37425995:G:GG	donor_gain	1.0000
9:37426536:A:AG	acceptor_gain	1.0000
9:37426537:G:GG	acceptor_gain	1.0000
9:37430509:A:AG	acceptor_gain	1.0000
9:37430510:G:GG	acceptor_gain	1.0000
9:37430510:GT:G	acceptor_gain	1.0000
9:37422792:GA:G	donor_gain	0.9900
9:37424844:GC:G	acceptor_gain	0.9900
9:37424959:G:GT	donor_gain	0.9900
9:37424973:C:T	donor_gain	0.9900
9:37424973:CAG:C	donor_loss	0.9900
9:37424974:AGG:A	donor_loss	0.9900
9:37424976:G:GA	donor_loss	0.9900
9:37424977:T:G	donor_loss	0.9900
9:37425916:CAACA:C	acceptor_loss	0.9900

AlphaMissense

2118 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
9:37425942:A:C	S79R	0.997
9:37425944:C:A	S79R	0.997
9:37425944:C:G	S79R	0.997
9:37430638:C:A	N242K	0.996
9:37430638:C:G	N242K	0.996
9:37430646:G:T	R245M	0.996
9:37430642:A:C	S244R	0.995
9:37430644:C:A	S244R	0.995
9:37430644:C:G	S244R	0.995
9:37432070:C:A	A266D	0.994
9:37436681:A:C	S296R	0.994
9:37436683:T:A	S296R	0.994
9:37436683:T:G	S296R	0.994
9:37430646:G:C	R245T	0.992
9:37426584:G:C	A112P	0.991
9:37426603:T:C	L118P	0.991
9:37426620:C:A	R124S	0.991
9:37426621:G:C	R124P	0.991
9:37428558:G:A	G160E	0.991
9:37428491:T:A	W138R	0.990
9:37428491:T:C	W138R	0.990
9:37428546:T:A	V156D	0.990
9:37430631:T:C	F240S	0.990
9:37436672:C:G	H293D	0.990
9:37436700:G:C	R302P	0.990
9:37426585:C:A	A112D	0.989
9:37426635:G:C	A129P	0.989
9:37429732:G:A	G165D	0.989
9:37429753:T:C	L172P	0.989
9:37436674:C:A	H293Q	0.989

dbSNP variants (sampled 300 via entrez): RS1000023061 (9:37434563 A>G), RS1000066238 (9:37433626 T>C), RS1000094694 (9:37435711 A>G), RS1000177976 (9:37421920 C>T), RS1000183440 (9:37439548 T>C), RS1000397445 (9:37433411 T>C,G), RS1000459654 (9:37434764 A>C), RS1000999524 (9:37423328 C>G,T), RS1001015505 (9:37434856 A>G), RS1001218782 (9:37423667 G>T), RS1001466433 (9:37435030 T>C), RS1001825442 (9:37425055 C>T), RS1002409750 (9:37428889 A>C), RS1002639791 (9:37421211 C>T), RS1002856982 (9:37433120 C>G,T)

Disease associations

OMIM: gene MIM:604296 | disease phenotypes: MIM:260000, MIM:259900, MIM:616719

GenCC curated gene-disease

Disease	Classification	Inheritance
primary hyperoxaluria type 2	Definitive	Autosomal recessive

Mondo (5): primary hyperoxaluria type 2 (MONDO:0009824), primary hyperoxaluria (MONDO:0002474), nephrocalcinosis (MONDO:0001567), nephrolithiasis (MONDO:0008171), acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome (MONDO:0014744)

Orphanet (3): Primary hyperoxaluria (Orphanet:416), Primary hyperoxaluria type 2 (Orphanet:93599), Acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome (Orphanet:466794)

HPO phenotypes

15 total (15 of 15 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000010	Recurrent urinary tract infections
HP:0000083	Renal insufficiency
HP:0000121	Nephrocalcinosis
HP:0000787	Nephrolithiasis
HP:0000790	Hematuria
HP:0001942	Metabolic acidosis
HP:0003159	Hyperoxaluria
HP:0003593	Infantile onset
HP:0006000	Ureteral obstruction
HP:0008672	Calcium oxalate nephrolithiasis
HP:0011280	Abnormality of urine calcium concentration
HP:0012100	Abnormal circulating creatinine concentration
HP:6000638	Reduced hepatic glyoxylate reductase activity
HP:6000670	Elevated urinary L-glycerate level

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST007565_180	Morning person	4.000000e-17
GCST007576_252	Chronotype	4.000000e-17
GCST008103_35	Bipolar disorder	8.000000e-08
GCST009088_3	Severe bacterial meningitis	7.000000e-07
GCST011350_17	C-reactive protein levels	9.000000e-10

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0008328	chronotype measurement
EFO:0004458	C-reactive protein measurement

MeSH disease descriptors (4)

Descriptor	Name	Tree numbers
D006960	Hyperoxaluria, Primary	C12.050.351.968.419.313.500; C12.200.777.419.313.500; C12.950.419.313.500; C16.320.565.202.460; C18.452.648.202.460
D009397	Nephrocalcinosis	C12.050.351.968.419.590; C12.200.777.419.590; C12.950.419.590; C18.452.174.130.560
D053040	Nephrolithiasis	C12.050.351.968.419.600; C12.050.351.968.967.249; C12.200.777.419.600; C12.200.777.967.249; C12.950.419.600; C12.950.967.249
C536415	Primary hyperoxaluria type 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295972 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression, increases expression	3
sodium arsenite	increases abundance, decreases expression, affects cotreatment	2
Smoke	decreases expression	2
Cyclosporine	decreases expression	2
bisphenol F	increases expression	1
triphenyl phosphate	affects expression	1
sodium arsenate	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
manganese chloride	affects cotreatment, decreases expression, increases abundance	1
aflatoxin B2	increases methylation	1
di-n-butylphosphoric acid	affects expression	1
K 7174	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
nutlin 3	affects cotreatment, increases secretion	1
ICG 001	increases expression	1
bisphenol B	increases expression	1
2-amino-14,16-dimethyloctadecan-3-ol	decreases expression	1
bisphenol S	increases expression	1
LDN 193189	affects cotreatment, increases expression	1
bisphenol AF	increases expression	1
Acetaminophen	decreases expression	1
Arsenic	affects cotreatment, decreases expression, increases abundance	1
Benzo(a)pyrene	decreases expression	1
Cadmium	decreases expression	1
Caffeine	increases phosphorylation	1
Dactinomycin	affects cotreatment, increases secretion	1
Isoniazid	increases expression	1
Ivermectin	decreases expression	1
Lead	decreases expression	1
Manganese	affects cotreatment, decreases expression, increases abundance	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118680	Binding	Binding affinity to GRHPR in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B2Y7	Abcam HEK293T GRHPR KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00765128	PHASE4	COMPLETED	Intravenous Ketorolac for Postoperative Pain in Percutaneous Nephrolithotomy
NCT01295879	PHASE4	COMPLETED	Vitamin D Repletion in Stone Formers With Hypercalciuria
NCT01329042	PHASE4	COMPLETED	Efficacy of Potassium Sodium Hydrogen Citrate Therapy on Renal Stone Recurrence and/or Residual Fragments After Shockwave Lithotripsy and Percutaneous Nephrolithotomy in Calcium Oxalate Urolithiasis
NCT01452880	PHASE4	COMPLETED	Remifentanil in Extracorporeal Shock Wave Lithotripsy
NCT01675362	PHASE4	COMPLETED	Are There Protective Effects of Antioxidants, Calcium Channel Blocker and Angiotensin Receptor Blocker Against Extracorporeal Shockwaves Lithotripsy Induced Renal Injury?
NCT02011737	PHASE4	UNKNOWN	Naftopidil 75mg for Improving Clearance of Urinary Stones
NCT02095665	PHASE4	COMPLETED	Ureteral Stent-related Pain and Mirabegron (SPAM) Trial
NCT02375295	PHASE4	UNKNOWN	Struvite Stones Antibiotic Study
NCT02384200	PHASE4	COMPLETED	A Randomized Trial of Preoperative Prophylactic Antibiotics Prior to Kidney Stone Surgery (Percutaneous Nephrolithotomy [PCNL])
NCT02430168	PHASE4	UNKNOWN	Comparison of RIRS Versus PCNL Methods, According to Postoperative Pain and Analgesic Demand in 2 to 4 cm Renal Stones
NCT02430883	PHASE4	UNKNOWN	Is There Any Relation Between Pain and Stone Location in Retrograde Intrarenal Surgery?
NCT02443909	PHASE4	UNKNOWN	Comparison of Safety and Efficiency of 20w and 30w Holmium Laser Device in Management of 2-3 cm Diameter Kidney Stones With Retrograde Intrarenal Surgery
NCT02451319	PHASE4	UNKNOWN	Comparison of Safety and Efficiency of 20w 30w Holmium Laser Device in Treatment of 1-2 cm Diameter Kidney Stones With RIRS
NCT02489656	PHASE4	UNKNOWN	Quality of Life in Patients With Double Loop Ureteral Stent (JJ Silicone Hydrogel Study)
NCT02818140	PHASE4	COMPLETED	Ultrasound-guided Transmuscular Quadratus Lumborum Block for Percutaneous Nephrolithotomy
NCT02966236	PHASE4	UNKNOWN	Impact of Tranexamic Acid Use in Percutaneous Nephrolithotomy
NCT03035812	PHASE4	COMPLETED	Alkalinization by Urologists & Nephrologists
NCT03229889	PHASE4	COMPLETED	Trial of Tadalafil, Tamsulosin and Combination for Access Sheath Deployment
NCT03332056	PHASE4	COMPLETED	The Use of Belladonna and Opium Suppository in the Treatment of Postoperative Stent Pain
NCT03549611	PHASE4	WITHDRAWN	Pre-induction Analgesia: Multimodel Regimen vs Aceteminophen for Post Ureteroscopy Pain
NCT03692715	PHASE4	COMPLETED	Antibiotic Prophylaxis Before Shock Wave Lithotripsy
NCT03872843	PHASE4	COMPLETED	Opioid Free Management After Ureteroscopy
NCT03888144	PHASE4	COMPLETED	Study of Ketorolac Versus Opioid for Pain After Endoscopy
NCT04095975	PHASE4	COMPLETED	Effectiveness of Urinary Alkalinizing Agents on Kidney Stone Risk
NCT04663269	PHASE4	TERMINATED	Regional Erector Spinae Analgesic Block vs Standard of Care Undergoing Percutaneous Nephrolithotomy
NCT05082142	PHASE4	COMPLETED	Tranexamic Acid to Improve Same-day Discharge Rates After Holmium Laser Enucleation of the Prostate (HoLEP)
NCT05365477	PHASE4	COMPLETED	Empiric Versus Selective Prevention Strategies for Kidney Stone Disease
NCT05414669	PHASE4	COMPLETED	Allopurinol Effect on MDA,NO,KIM-1 Urine Levels, RI and Renal Elastography in Kidney Stone Patients Post ESWL
NCT05924165	PHASE4	COMPLETED	Narcotic-Free Percutaneous Nephrolithotomy
NCT06124066	PHASE4	COMPLETED	THE EFFECTS OF MIRABEGRON AND TAMSULOSIN FOR PATIENTS WITH URETERAL STENTS
NCT06966635	PHASE4	RECRUITING	Exploratory Study on the Treatment of Gout With Potassium Citrate Sustained-release Tablets
NCT07124299	PHASE4	RECRUITING	Alpha-Blockers Prior to Ureteral Access Sheath Placement in Flexible Ureteroscopy: A Randomized Prospective Study
NCT07225764	PHASE4	RECRUITING	CaOx Stone Prevention
NCT07512297	PHASE4	NOT_YET_RECRUITING	Pain Control During ESWL Using Non-Opioid Analgesics
NCT07582341	PHASE4	COMPLETED	Combined Intravenous and Irrigation Tranexamic Acid During Percutaneous Nephrolithotomy
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
NCT03116685	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Oxabact in Patients With Primary Hyperoxaluria
NCT03905694	PHASE3	COMPLETED	A Study of Lumasiran in Infants and Young Children With Primary Hyperoxaluria Type 1
NCT03938272	PHASE3	TERMINATED	An Extension Study to Evaluate the Long-term Efficacy and Safety of Oxabact in Patients With Primary Hyperoxaluria