Primary hyperoxaluria type 2

Summary

Primary hyperoxaluria type 2 (MONDO:0009824) is a disease caused by GRHPR (GenCC Definitive), with 1 cohort gene and 5 clinical trials. Top therapeutic interventions include nedosiran sodium, stiripentol, and nedosiran.

At a glance

• Prevalence: (Worldwide) [Orphanet-validated]
• Causal gene: GRHPR (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 291
• Phenotypes (HPO): 6
• Clinical trials: 5

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		10	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

6 HPO clinical features (Orphanet curated; top 6 by frequency):

HPO ID	Term	Frequency
HP:0000121	Nephrocalcinosis	Very frequent (80-99%)
HP:0000787	Nephrolithiasis	Very frequent (80-99%)
HP:0003159	Hyperoxaluria	Very frequent (80-99%)
HP:0000010	Recurrent urinary tract infections	Frequent (30-79%)
HP:0006000	Ureteral obstruction	Frequent (30-79%)
HP:0000083	Renal insufficiency	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	primary hyperoxaluria type 2
Mondo ID	MONDO:0009824
MeSH	C536415
OMIM	260000
Orphanet	93599
DOID	DOID:0111671
ICD-11	347920969
NCIT	C123213
SNOMED CT	40951006
UMLS	C0268165
MedGen	120616
GARD	0002836
Is cancer (heuristic)	no

Also known as: D-glycerate dehydrogenase deficiency · GRHPR primary hyperoxaluria · HP2 · hyperoxaluria, primary, type II · L-glyceric aciduria · primary hyperoxaluria caused by mutation in GRHPR · primary hyperoxaluria type 2 · primary hyperoxaluria type II

Data availability: 291 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn carbohydrate metabolic disorder › primary hyperoxaluria › primary hyperoxaluria type 2

Related subtypes (2): primary hyperoxaluria type 1, primary hyperoxaluria type 3

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

291 retrieved; paginated sample, class counts are floors:

80 uncertain significance, 79 likely pathogenic, 34 pathogenic, 30 pathogenic/likely pathogenic, 24 conflicting classifications of pathogenicity, 23 likely benign, 11 benign, 10 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
204246	NM_012203.1(GRHPR):c.[84-8_84-5delCCCC;84-13_84-12delCC]		Pathogenic	no assertion criteria provided
204248	Multiple alleles		Pathogenic	no assertion criteria provided
2664425	Multiple alleles		Pathogenic	criteria provided, single submitter
1069746	NM_012203.2(GRHPR):c.589del (p.Ala197fs)	GRHPR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179173	NM_012203.2(GRHPR):c.865+1G>T	GRHPR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1447096	NM_012203.2(GRHPR):c.277del (p.Ile93fs)	GRHPR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
162020	NM_012203.2(GRHPR):c.866_867del (p.Val289fs)	GRHPR	Pathogenic	criteria provided, multiple submitters, no conflicts
162021	NM_012203.2(GRHPR):c.248_249del (p.Val83fs)	GRHPR	Pathogenic	no assertion criteria provided
162022	NM_012203.2(GRHPR):c.904C>T (p.Arg302Cys)	GRHPR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1726382	NM_012203.2(GRHPR):c.496C>T (p.Gln166Ter)	GRHPR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
204231	NM_012203.2(GRHPR):c.102G>A (p.Trp34Ter)	GRHPR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
204232	NM_012203.2(GRHPR):c.203T>C (p.Leu68Pro)	GRHPR	Pathogenic	no assertion criteria provided
204233	NM_012203.2(GRHPR):c.287G>T (p.Arg96Leu)	GRHPR	Pathogenic	no assertion criteria provided
204235	NM_012203.2(GRHPR):c.494G>A (p.Gly165Asp)	GRHPR	Pathogenic	criteria provided, multiple submitters, no conflicts
204240	NM_012203.2(GRHPR):c.965T>C (p.Met322Thr)	GRHPR	Pathogenic	no assertion criteria provided
204241	NM_012203.2(GRHPR):c.84-2A>G	GRHPR	Pathogenic	criteria provided, multiple submitters, no conflicts
204243	NM_012203.2(GRHPR):c.493+2T>A	GRHPR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
204244	NM_012203.2(GRHPR):c.735-1G>A	GRHPR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
204245	NM_012203.2(GRHPR):c.45del (p.Ala17fs)	GRHPR	Pathogenic	no assertion criteria provided
204247	NM_012203.2(GRHPR):c.288-2_288del	GRHPR	Pathogenic	no assertion criteria provided
204249	NM_012203.2(GRHPR):c.375del (p.Leu126fs)	GRHPR	Pathogenic	criteria provided, single submitter
204250	NM_012203.2(GRHPR):c.404+3_404+6del	GRHPR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
204251	NM_012203.2(GRHPR):c.540del (p.Leu181fs)	GRHPR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
204252	NM_012203.2(GRHPR):c.608_609del (p.Pro203fs)	GRHPR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
204253	NM_012203.2(GRHPR):c.694del (p.Gln232fs)	GRHPR	Pathogenic	criteria provided, multiple submitters, no conflicts
2067052	NM_012203.2(GRHPR):c.626C>T (p.Ser209Phe)	GRHPR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2078185	NM_012203.2(GRHPR):c.100del (p.Trp34fs)	GRHPR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2088287	NM_012203.2(GRHPR):c.516_532dup (p.Gln178fs)	GRHPR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2101269	NM_012203.2(GRHPR):c.102_112del (p.Trp34_Glu38delinsTer)	GRHPR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2664098	NM_012203.2(GRHPR):c.109_118delinsCAC (p.Asp37fs)	GRHPR	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
GRHPR	Definitive	Autosomal recessive	primary hyperoxaluria type 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GRHPR	Orphanet:93599	Primary hyperoxaluria type 2

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GRHPR	HGNC:4570	ENSG00000137106	Q9UBQ7	Glyoxylate reductase/hydroxypyruvate reductase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GRHPR	Glyoxylate reductase/hydroxypyruvate reductase	Enzyme with hydroxy-pyruvate reductase, glyoxylate reductase and D-glycerate dehydrogenase enzymatic activities.

Protein-family classification

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

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GRHPR	Enzyme (other)	yes	1.1.1.26	D-isomer_2_OHA_DH_cat_dom, D-isomer_DH_NAD-bd, D-isomer_DH_CS

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
liver	1
right adrenal gland	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GRHPR	292	ubiquitous	marker	right lobe of liver, liver, right adrenal gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GRHPR	2,785

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GRHPR	Q9UBQ7	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Glyoxylate metabolism and glycine degradation	1	761.3×	0.001	GRHPR

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
dicarboxylic acid metabolic process	1	8426.0×	4e-04	GRHPR
carboxylic acid metabolic process	1	2808.7×	4e-04	GRHPR
glyoxylate metabolic process	1	2808.7×	4e-04	GRHPR

Therapeutics

Drug target analysis

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

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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GRHPR	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
GRHPR	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GRHPR	1.1.1.26, 1.1.1.79, 1.1.1.81	glyoxylate reductase, glyoxylate reductase (NADP+), hydroxypyruvate reductase

Pharmacogenomics

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

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

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

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

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

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GRHPR	2	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	2
PHASE2	2
Not specified	1

Top trials by phase / activity

NCT	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
NCT03847909	PHASE2	COMPLETED	A Study to Evaluate DCR-PHXC in Children and Adults With Primary Hyperoxaluria Type 1 and Primary Hyperoxaluria Type 2
NCT05001269	PHASE2	COMPLETED	Nedosiran in Pediatric Patients From Birth to 11 Years of Age With PH and Relatively Intact Renal Function
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
NEDOSIRAN SODIUM	4	2
STIRIPENTOL	4	1
NEDOSIRAN	2	1