Nephrolithiasis, calcium oxalate

Summary

Nephrolithiasis, calcium oxalate (MONDO:0957318) is a disease with 6 cohort genes and 5 clinical trials. Top therapeutic interventions include tolvaptan and glycolic acid.

At a glance

• Cohort genes: 6
• ClinVar variants: 77
• Clinical trials: 5

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	nephrolithiasis, calcium oxalate
Mondo ID	MONDO:0957318
OMIM	167030
UMLS	C1833683
MedGen	318935
Is cancer (heuristic)	no

Data availability: 77 ClinVar variants.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › urinary system disorder › kidney disorder › nephrolithiasis › nephrolithiasis, calcium oxalate

Related subtypes (2): acute urate nephropathy, nephrolithiasis, X-linked recessive, with renal failure

Subtypes (2): nephrolithiasis susceptibility caused by SLC26A1, nephrolithiasis, calcium oxalate, 2, with or without nephrocalcinosis

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

77 retrieved; paginated sample, class counts are floors:

26 association, 15 uncertain significance, 13 likely benign, 9 conflicting classifications of pathogenicity, 8 benign/likely benign, 4 benign, 1 pathogenic, 1 benign/likely benign; other

ClinVar	Variant (HGVS)	Gene	Classification	Review
1801328	NM_022042.4(SLC26A1):c.824T>C (p.Leu275Pro)	IDUA	Pathogenic	no assertion criteria provided
1136337	NM_022042.4(SLC26A1):c.153G>C (p.Gln51His)	IDUA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1425196	NM_022042.4(SLC26A1):c.1385G>A (p.Arg462Gln)	IDUA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1450147	NM_022042.4(SLC26A1):c.1531G>A (p.Ala511Thr)	IDUA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
242374	NM_022042.4(SLC26A1):c.554C>T (p.Thr185Met)	IDUA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
242375	NM_022042.4(SLC26A1):c.1073C>T (p.Ser358Leu)	IDUA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
64577	NM_022042.4(SLC26A1):c.1043T>C (p.Leu348Pro)	IDUA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
64588	NM_022042.4(SLC26A1):c.1906G>T (p.Asp636Tyr)	IDUA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
720732	NM_000203.5(IDUA):c.299+988C>T	IDUA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
961738	NM_022042.4(SLC26A1):c.763G>A (p.Gly255Ser)	IDUA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
126865	NM_001622.4(AHSG):c.574-298T>G	AHSG	association	no assertion criteria provided
126866	NM_001622.4(AHSG):c.574-149A>G	AHSG	association	no assertion criteria provided
126864	NM_199173.4(BGLAP):c.*304G>A	BGLAP	association	no assertion criteria provided
126867	NM_000610.4(CD44):c.67+11205G>A	CD44	association	no assertion criteria provided
126868	NM_000610.4(CD44):c.67+14128T>C	CD44	association	no assertion criteria provided
126869	NM_000610.4(CD44):c.68-18471G>A	CD44	association	no assertion criteria provided
126870	NM_000610.4(CD44):c.68-13570A>T	CD44	association	no assertion criteria provided
126871	NM_000610.4(CD44):c.68-9931G>A	CD44	association	no assertion criteria provided
126872	NM_000610.4(CD44):c.68-6677C>G	CD44	association	no assertion criteria provided
126873	NM_000610.4(CD44):c.68-5908G>A	CD44	association	no assertion criteria provided
126874	NM_000610.4(CD44):c.68-5843A>G	CD44	association	no assertion criteria provided
126875	NM_000610.4(CD44):c.68-5493C>T	CD44	association	no assertion criteria provided
126876	NM_000610.4(CD44):c.234-905G>A	CD44	association	no assertion criteria provided
126877	NM_000610.4(CD44):c.923-767T>A	CD44	association	no assertion criteria provided
126878	NM_000610.4(CD44):c.2024+779A>G	CD44	association	no assertion criteria provided
126880	NM_017545.2(HAO1):c.*697T>C	HAO1	association	no assertion criteria provided
126881	NM_017545.3(HAO1):c.814-2945A>G	HAO1	association	no assertion criteria provided
126882	NM_017545.3(HAO1):c.814-4211G>A	HAO1	association	no assertion criteria provided
126883	NM_017545.3(HAO1):c.721+1617G>C	HAO1	association	no assertion criteria provided
126884	NM_017545.3(HAO1):c.545+1171T>C	HAO1	association	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AHSG	Orphanet:2850	Alopecia-intellectual disability syndrome
IDUA	Orphanet:93473	Hurler syndrome
IDUA	Orphanet:93474	Scheie syndrome
IDUA	Orphanet:93476	Hurler-Scheie syndrome

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BGLAP	HGNC:1043	ENSG00000242252	P02818	Osteocalcin	clinvar
SLC26A1	HGNC:10993	ENSG00000145217	Q9H2B4	Sulfate anion transporter 1	clinvar
CD44	HGNC:1681	ENSG00000026508	P16070	CD44 antigen	clinvar
AHSG	HGNC:349	ENSG00000145192	P02765	Alpha-2-HS-glycoprotein	clinvar
HAO1	HGNC:4809	ENSG00000101323	Q9UJM8	2-Hydroxyacid oxidase 1	clinvar
IDUA	HGNC:5391	ENSG00000127415	P35475	Alpha-L-iduronidase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BGLAP	Osteocalcin	The carboxylated form is one of the main organic components of the bone matrix, which constitutes 1-2% of the total bone protein.
SLC26A1	Sulfate anion transporter 1	Sodium-independent sulfate anion transporter.
CD44	CD44 antigen	Cell-surface receptor that plays a role in cell-cell interactions, cell adhesion and migration, helping them to sense and respond to changes in the tissue microenvironment.
AHSG	Alpha-2-HS-glycoprotein	Promotes endocytosis, possesses opsonic properties and influences the mineral phase of bone.
HAO1	2-Hydroxyacid oxidase 1	Broad substrate specificity (S)-2-hydroxy-acid oxidase that preferentially oxidizes glycolate.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.5

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
Transporter	1	13.0×	0.299
Antibody/Immunoglobulin	1	4.9×	0.377
Enzyme (other)	1	2.0×	0.543
Other/Unknown	3	0.9×	0.758

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BGLAP	Other/Unknown	no		GLA_domain, Osteocalcin/MGP, GLA-like_dom_SF
SLC26A1	Transporter	yes		SLC26A/SulP_fam, STAS_dom, SLC26A/SulP_dom
CD44	Other/Unknown	no		Link_dom, CD44_antigen, C-type_lectin-like/link_sf
AHSG	Other/Unknown	no		Cystatin_dom, Prot_inh_fetuin_CS, Cystatin_Fetuin_A
HAO1	Enzyme (other)	yes	1.1.3.15	FMN-dep_DH, FMN_hydac_DH_AS, Alpha-hydoxy_acid_DH_FMN
IDUA	Antibody/Immunoglobulin	yes	3.2.1.76	Glyco_hydro_39, Ig-like_fold, GH_hydrolase_sf

Expression context

Cohort genes with no expression data: 0.

3 cohort genes 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	3
right lobe of liver	3
right hemisphere of cerebellum	2
liver	2
primordial germ cell in gonad	1
left adrenal gland cortex	1
right adrenal gland cortex	1
mammalian vulva	1
parotid gland	1
stromal cell of endometrium	1
cerebellar cortex	1
cerebellar hemisphere	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BGLAP	130	broad	yes	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, right hemisphere of cerebellum
SLC26A1	156	tissue_specific	yes	right adrenal gland cortex, left adrenal gland cortex, right lobe of liver
CD44	294	ubiquitous	marker	parotid gland, stromal cell of endometrium, mammalian vulva
AHSG	125	tissue_specific	marker	liver, right lobe of liver, male germ line stem cell (sensu Vertebrata) in testis
HAO1	28	tissue_specific	yes	right lobe of liver, liver, male germ line stem cell (sensu Vertebrata) in testis
IDUA	209	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CD44	6,810
AHSG	3,426
HAO1	2,955
BGLAP	1,988
IDUA	1,927
SLC26A1	1,454

Structural data

PDB: 4 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HAO1	Q9UJM8	21
IDUA	P35475	11
BGLAP	P02818	8
CD44	P16070	6

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC26A1	Q9H2B4	83.13
AHSG	P02765	77.59

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 40. Enrichment computed across 6 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
MPS I - Hurler syndrome (HS-GAG degradation)	1	1903.3×	0.007	IDUA
MPS I - Hurler syndrome (CS/DS degradation)	1	1903.3×	0.007	IDUA
Glycosaminoglycan metabolism	2	73.2×	0.007	SLC26A1, CD44
Metabolism of carbohydrates and carbohydrate derivatives	2	40.1×	0.010	SLC26A1, CD44
Transport and metabolism of PAPS	1	271.9×	0.023	SLC26A1
Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus	1	211.5×	0.023	BGLAP
Inorganic anion exchange by SLC26 transporters	1	211.5×	0.023	SLC26A1
Gamma-carboxylation of protein precursors	1	190.3×	0.023	BGLAP
Removal of aminoterminal propeptides from gamma-carboxylated proteins	1	190.3×	0.023	BGLAP
Hyaluronan metabolism	1	158.6×	0.025	CD44
Glyoxylate metabolism and glycine degradation	1	126.9×	0.026	HAO1
Developmental Lineage of Mammary Stem Cells	1	126.9×	0.026	CD44
Hyaluronan degradation	1	119.0×	0.026	CD44
CS/DS degradation	1	90.6×	0.028	IDUA
Developmental Lineage of Mammary Gland Myoepithelial Cells	1	90.6×	0.028	CD44
Cytosolic sulfonation of small molecules	1	86.5×	0.028	SLC26A1
HS-GAG degradation	1	82.8×	0.028	IDUA
RUNX2 regulates osteoblast differentiation	1	76.1×	0.028	BGLAP
Developmental Lineage of Mammary Gland Luminal Epithelial Cells	1	76.1×	0.028	CD44
Phase II - Conjugation of compounds	1	46.4×	0.043	SLC26A1
Neutrophil degranulation	2	7.7×	0.048	CD44, AHSG
Peroxisomal protein import	1	28.8×	0.062	HAO1
Integrin cell surface interactions	1	22.4×	0.071	CD44
Biological oxidations	1	21.6×	0.071	SLC26A1
R-HSA-425393	1	21.6×	0.071	SLC26A1
Interferon gamma signaling	1	20.9×	0.071	CD44
Interferon Signaling	1	20.0×	0.071	CD44
Degradation of the extracellular matrix	1	19.6×	0.071	CD44
Post-translational protein phosphorylation	1	16.7×	0.081	AHSG
Cell surface interactions at the vascular wall	1	15.9×	0.082	CD44

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of bone mineralization	2	244.2×	0.002	BGLAP, AHSG
disaccharide metabolic process	1	2808.7×	0.004	IDUA
glycine biosynthetic process	1	2808.7×	0.004	HAO1
heparin proteoglycan catabolic process	1	2808.7×	0.004	IDUA
response to hydroxyisoflavone	1	2808.7×	0.004	BGLAP
glycolate catabolic process	1	2808.7×	0.004	HAO1
negative regulation of bone development	1	1404.3×	0.007	BGLAP
response to vitamin K	1	936.2×	0.007	BGLAP
monocyte aggregation	1	936.2×	0.007	CD44
positive regulation of monocyte aggregation	1	936.2×	0.007	CD44
regulation of lamellipodium morphogenesis	1	936.2×	0.007	CD44
skeletal system development	2	41.9×	0.007	BGLAP, AHSG
pinocytosis	1	702.2×	0.007	AHSG
dermatan sulfate proteoglycan catabolic process	1	702.2×	0.007	IDUA
response to macrophage colony-stimulating factor	1	702.2×	0.007	BGLAP
regulation of testosterone biosynthetic process	1	561.7×	0.008	BGLAP
response to gravity	1	468.1×	0.009	BGLAP
fatty acid alpha-oxidation	1	401.2×	0.009	HAO1
glycosaminoglycan catabolic process	1	401.2×	0.009	IDUA
oxalate transport	1	401.2×	0.009	SLC26A1
cellular response to zinc ion starvation	1	401.2×	0.009	BGLAP
positive regulation of neurotransmitter secretion	1	312.1×	0.010	BGLAP
heparan sulfate proteoglycan catabolic process	1	312.1×	0.010	IDUA
regulation of bone resorption	1	255.3×	0.011	BGLAP
regulation of osteoclast differentiation	1	255.3×	0.011	BGLAP
cellular response to vitamin D	1	255.3×	0.011	BGLAP
regulation of cellular response to insulin stimulus	1	255.3×	0.011	BGLAP
positive regulation of heterotypic cell-cell adhesion	1	216.1×	0.012	CD44
sulfate transmembrane transport	1	200.6×	0.013	SLC26A1
negative regulation of DNA damage response, signal transduction by p53 class mediator	1	187.2×	0.013	CD44

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 6

Druggability breadth: 4 of 6 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
BGLAP	0	0
SLC26A1	0	0
CD44	0	0
AHSG	0	0
HAO1	0	0
IDUA	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
HAO1	30	Binding:30
IDUA	15	Binding:15
CD44	9	Binding:9
AHSG	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
HAO1	1.1.3.15	(S)-2-hydroxy-acid oxidase
IDUA	3.2.1.76	L-iduronidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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	2	HAO1, IDUA
D	Druggable family + AlphaFold only, no drug	1	SLC26A1
E	Difficult family or no structure, no drug	3	BGLAP, CD44, AHSG

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
BGLAP	0	—
SLC26A1	0	—
CD44	9	—
AHSG	2	—
HAO1	30	—
IDUA	15	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE1/PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00381849	PHASE1/PHASE2	COMPLETED	Use of an Herbal Preparation to Prevent and Dissolve Kidney Stones
NCT02096965	PHASE1	COMPLETED	Use of Tolvaptan to Reduce Urinary Supersaturation: a Pilot Proof of Principle Study
NCT06330246	Not specified	RECRUITING	O. Formigenes Colonization in Calcium Oxalate Kidney Stone Disease
NCT06331546	Not specified	RECRUITING	Gut Oxalate Absorption in Calcium Oxalate Stone Disease
NCT06989320	Not specified	RECRUITING	Endogenous Oxalate Synthesis in Idiopathic Calcium Oxalate Kidney Stone Disease

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
TOLVAPTAN	4	1
GLYCOLIC ACID	2	1
CHEMBL4303142	0	1