Primary hyperoxaluria type 1

Summary

Primary hyperoxaluria type 1 (MONDO:0009823) is a disease caused by AGXT (GenCC Definitive), with 1 cohort gene and 19 clinical trials. Top therapeutic interventions include lumasiran, nedosiran sodium, and stiripentol.

At a glance

• Prevalence: 1-9 / 1 000 000 (Netherlands) [Orphanet-validated]
• Causal gene: AGXT (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 551
• Phenotypes (HPO): 19
• Clinical trials: 19

Clinical features

Epidemiology

Prevalence records

6 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	<1 / 1 000 000	0.015	Netherlands	Validated
Annual incidence	1-9 / 1 000 000	0.83	France	Validated
Point prevalence	1-9 / 1 000 000	0.29	Netherlands	Validated
Point prevalence	1-9 / 1 000 000	0.2	Switzerland	Validated
Point prevalence	1-9 / 1 000 000	0.1	France	Validated
Prevalence at birth	1-9 / 100 000	1	Switzerland	Validated

Signs & symptoms

Clinical features (HPO)

19 HPO clinical features (Orphanet curated; top 19 by frequency):

HPO ID	Term	Frequency
HP:0000121	Nephrocalcinosis	Very frequent (80-99%)
HP:0000787	Nephrolithiasis	Very frequent (80-99%)
HP:0001903	Anemia	Very frequent (80-99%)
HP:0001942	Metabolic acidosis	Very frequent (80-99%)
HP:0003159	Hyperoxaluria	Very frequent (80-99%)
HP:0003761	Calcinosis	Very frequent (80-99%)
HP:0011021	Abnormality of circulating enzyme level	Very frequent (80-99%)
HP:0100518	Dysuria	Frequent (30-79%)
HP:0000790	Hematuria	Frequent (30-79%)
HP:0001508	Failure to thrive	Frequent (30-79%)
HP:0012213	Decreased glomerular filtration rate	Frequent (30-79%)
HP:0000010	Recurrent urinary tract infections	Occasional (5-29%)
HP:0000805	Enuresis	Occasional (5-29%)
HP:0000924	Abnormality of the skeletal system	Occasional (5-29%)
HP:0003774	Stage 5 chronic kidney disease	Occasional (5-29%)
HP:0000164	Abnormality of the dentition	Very rare (<1-4%)
HP:0001297	Stroke	Very rare (<1-4%)
HP:0001939	Abnormality of metabolism/homeostasis	Very rare (<1-4%)
HP:0002621	Atherosclerosis	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	primary hyperoxaluria type 1
Mondo ID	MONDO:0009823
MeSH	C536414
OMIM	259900
Orphanet	93598
DOID	DOID:0111670
ICD-11	692812009
NCIT	C123212
SNOMED CT	65520001
UMLS	C0268164
MedGen	75658
GARD	0002835
Is cancer (heuristic)	no

Also known as: AGXT primary hyperoxaluria · glycolic aciduria · HP1 · hyperoxaluria, primary, type I · peroxisomal alanine glyoxylate aminotransferase deficiency · peroxisomal alanine-glyoxylate aminotransferase deficiency · PH1 · primary hyperoxaluria caused by mutation in AGXT · primary hyperoxaluria type 1 · primary hyperoxaluria type I · serine pyruvate aminotransferase deficiency

Data availability: 551 ClinVar variants · 6 GenCC gene-disease records · 7 cell lines.

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 1

Related subtypes (2): primary hyperoxaluria type 2, 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

551 retrieved; paginated sample, class counts are floors:

158 pathogenic, 134 uncertain significance, 87 likely pathogenic, 56 pathogenic/likely pathogenic, 42 conflicting classifications of pathogenicity, 34 likely benign, 26 benign, 14 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
204181	NM_000030.2(AGXT):c.[299_307dup;308G>A]		Pathogenic	no assertion criteria provided
204202	NM_000030.2(AGXT):c.[829_830insA;830C>A]		Pathogenic	no assertion criteria provided
2681193	NM_000030.3(AGXT):c.[32C>T;836T>C]		Pathogenic	criteria provided, single submitter
1330294	NM_000030.3(AGXT):c.642del (p.Pro215fs)	AGXT	Pathogenic	criteria provided, single submitter
1378865	NM_000030.3(AGXT):c.215A>T (p.Asn72Ile)	AGXT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
140583	NM_000030.3(AGXT):c.33dup (p.Lys12fs)	AGXT	Pathogenic	criteria provided, multiple submitters, no conflicts
140584	NM_000030.3(AGXT):c.560C>T (p.Ser187Phe)	AGXT	Pathogenic	criteria provided, multiple submitters, no conflicts
1456950	NM_000030.3(AGXT):c.942+1G>A	AGXT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1879839	NM_000030.3(AGXT):c.596-1G>A	AGXT	Pathogenic	criteria provided, single submitter
188738	NM_000030.3(AGXT):c.481G>T (p.Gly161Cys)	AGXT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188774	NM_000030.3(AGXT):c.777-1G>C	AGXT	Pathogenic	criteria provided, multiple submitters, no conflicts
188775	NM_000030.3(AGXT):c.33del (p.Lys12fs)	AGXT	Pathogenic	criteria provided, multiple submitters, no conflicts
188866	NM_000030.3(AGXT):c.302T>C (p.Leu101Pro)	AGXT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188891	NM_000030.3(AGXT):c.322T>C (p.Trp108Arg)	AGXT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188898	NM_000030.3(AGXT):c.752G>A (p.Trp251Ter)	AGXT	Pathogenic	criteria provided, single submitter
188957	NM_000030.3(AGXT):c.106C>T (p.Arg36Cys)	AGXT	Pathogenic	criteria provided, multiple submitters, no conflicts
188979	NM_000030.3(AGXT):c.653C>T (p.Ser218Leu)	AGXT	Pathogenic	criteria provided, multiple submitters, no conflicts
188985	NM_000030.3(AGXT):c.122G>T (p.Gly41Val)	AGXT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188986	NM_000030.3(AGXT):c.1049G>A (p.Gly350Asp)	AGXT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189021	NM_000030.3(AGXT):c.346G>A (p.Gly116Arg)	AGXT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189035	NM_000030.3(AGXT):c.737G>A (p.Trp246Ter)	AGXT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189161	NM_000030.3(AGXT):c.976del (p.Val326fs)	AGXT	Pathogenic	criteria provided, multiple submitters, no conflicts
2029609	NM_000030.3(AGXT):c.490C>T (p.Gln164Ter)	AGXT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
204065	NM_000030.3(AGXT):c.2T>C (p.Met1Thr)	AGXT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
204066	NM_000030.3(AGXT):c.3G>T (p.Met1Ile)	AGXT	Pathogenic	no assertion criteria provided
204068	NM_000030.3(AGXT):c.28C>T (p.Pro10Ser)	AGXT	Pathogenic	no assertion criteria provided
204069	NM_000030.3(AGXT):c.32C>G (p.Pro11Arg)	AGXT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
204070	NM_000030.3(AGXT):c.74T>G (p.Leu25Arg)	AGXT	Pathogenic	no assertion criteria provided
204071	NM_000030.3(AGXT):c.77T>C (p.Leu26Pro)	AGXT	Pathogenic	no assertion criteria provided
204072	NM_000030.3(AGXT):c.107G>A (p.Arg36His)	AGXT	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · 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
AGXT	Definitive	Autosomal recessive	primary hyperoxaluria type 1	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AGXT	Orphanet:93598	Primary hyperoxaluria type 1

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
AGXT	HGNC:341	ENSG00000172482	P21549	Alanine–glyoxylate aminotransferase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
AGXT	Alanine–glyoxylate aminotransferase	Peroxisomal aminotransferase that catalyzes the transamination of glyoxylate to glycine and contributes to the glyoxylate detoxification.

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)
AGXT	Enzyme (other)	yes	2.6.1.44	Aminotrans_V_dom, PyrdxlP-dep_Trfase_major, PyrdxlP-dep_Trfase_small

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
endometrium epithelium	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AGXT	125	tissue_specific	marker	right lobe of liver, liver, endometrium epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AGXT	2,648

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AGXT	P21549	17

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. 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×	0.007	AGXT
Protein localization	1	190.3×	0.010	AGXT
Peroxisomal protein import	1	173.0×	0.010	AGXT
Metabolism of amino acids and derivatives	1	67.6×	0.018	AGXT
Metabolism	1	11.6×	0.086	AGXT

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
obsolete glycine biosynthetic process, by transamination of glyoxylate	1	5617.3×	4e-04	AGXT
oxalic acid secretion	1	5617.3×	4e-04	AGXT
glyoxylate catabolic process	1	4213.0×	4e-04	AGXT
L-cysteine catabolic process	1	4213.0×	4e-04	AGXT
L-alanine catabolic process	1	4213.0×	4e-04	AGXT
glyoxylate metabolic process	1	2808.7×	5e-04	AGXT
L-serine metabolic process	1	1685.2×	7e-04	AGXT
Notch signaling pathway	1	141.6×	0.007	AGXT

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
AGXT	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
AGXT	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AGXT	2.6.1.44, 2.6.1.51	alanine-glyoxylate transaminase, serine-pyruvate transaminase

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	AGXT
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)
AGXT	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 19.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	6
PHASE3	5
Not specified	5
PHASE1/PHASE2	2
PHASE1	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
NCT03681184	PHASE3	COMPLETED	A Study to Evaluate Lumasiran in Children and Adults With Primary Hyperoxaluria Type 1
NCT03905694	PHASE3	COMPLETED	A Study of Lumasiran in Infants and Young Children With Primary Hyperoxaluria Type 1
NCT04152200	PHASE3	COMPLETED	A Study to Evaluate Lumasiran in Patients With Advanced Primary Hyperoxaluria Type 1
NCT04580420	PHASE2	RECRUITING	Safety & Efficacy of DCR-PHXC in Patients With PH1 and ESRD
NCT06839235	PHASE1/PHASE2	RECRUITING	Phase 1/2 Study of ABO-101 in Primary Hyperoxaluria Type 1 (redePHine)
NCT07587021	PHASE2	NOT_YET_RECRUITING	Study of YOLT-203 in Children and Adults With Primary Hyperoxaluria Type 1 (PH1)
NCT01281878	PHASE2	COMPLETED	Trial on Treatment of Patients With Primary Hyperoxaluria Type I With Pyridoxal-phosphate
NCT02706886	PHASE1/PHASE2	COMPLETED	Study of Lumasiran in Healthy Adults and Patients With Primary Hyperoxaluria Type 1
NCT03350451	PHASE2	COMPLETED	An Extension Study of an Investigational Drug, Lumasiran (ALN-GO1), in Participants With Primary Hyperoxaluria Type 1
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
NCT02795325	PHASE1	TERMINATED	A Study of DCR-PH1 in Patients With Primary Hyperoxaluria Type 1 (PH1)
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT04982393	Not specified	ACTIVE_NOT_RECRUITING	BONAPH1DE, A Prospective Observational Study of Patients With Primary Hyperoxaluria Type 1 (PH1)
NCT02830009	Not specified	COMPLETED	IDENTIFICATION OF A MULTI-ANALYTE PROFILE FOR PRIMARY HYPEROXALURIA AND COMPARISON WITH HEALTHY SIBLINGS AND IDIOPATHIC HYPERCALCIURIA
NCT03067142	Not specified	COMPLETED	Proteomics of Primary Hyperoxaluria Type 1
NCT05993416	Not specified	NO_LONGER_AVAILABLE	Treatment of Primary Hyperoxaluria Type 1 With Nedosiran

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
LUMASIRAN	4	5
NEDOSIRAN SODIUM	4	3
STIRIPENTOL	4	1
NEDOSIRAN	2	2