Hypophosphatemic nephrolithiasis/osteoporosis 1

Summary

Hypophosphatemic nephrolithiasis/osteoporosis 1 (MONDO:0012850) is a disease caused by SLC34A1 (GenCC Strong), with 3 cohort genes.

At a glance

• Causal gene: SLC34A1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 210

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypophosphatemic nephrolithiasis/osteoporosis 1
Mondo ID	MONDO:0012850
MeSH	C567363
OMIM	612286
DOID	DOID:0080077
UMLS	C2676786
MedGen	436776
GARD	0018346
Is cancer (heuristic)	no

Also known as: hypophosphatemic nephrolithiasis/osteoporosis type 1 · nephrolithiasis/osteoporosis, hypophosphatemic, 1 · nephrolithiasis/osteoporosis, hypophosphatemic, type 1 · NPHLOP1

Data availability: 210 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › nephrolithiasis/osteoporosis, hypophosphatemic › hypophosphatemic nephrolithiasis/osteoporosis 1

Related subtypes (1): hypophosphatemic nephrolithiasis/osteoporosis 2

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

210 retrieved; paginated sample, class counts are floors:

121 uncertain significance, 31 conflicting classifications of pathogenicity, 14 likely benign, 11 benign, 11 likely pathogenic, 11 benign/likely benign, 7 pathogenic, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1179157	GRCh37/hg19 5q35.3(chr5:176812675-176813587)	SLC34A1	Pathogenic	no assertion criteria provided
12931	NM_003052.5(SLC34A1):c.142_143delinsTT (p.Ala48Phe)	SLC34A1	Pathogenic	no assertion criteria provided
1457675	NM_003052.5(SLC34A1):c.241dup (p.Glu81fs)	SLC34A1	Pathogenic	criteria provided, multiple submitters, no conflicts
234926	NM_003052.5(SLC34A1):c.644+1G>A	SLC34A1	Pathogenic	criteria provided, multiple submitters, no conflicts
2681783	NM_003052.5(SLC34A1):c.644+2T>G	SLC34A1	Pathogenic	criteria provided, single submitter
3592101	NM_003052.5(SLC34A1):c.189_190del (p.Cys64fs)	SLC34A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3592112	NM_003052.5(SLC34A1):c.557_558del (p.Pro186fs)	SLC34A1	Pathogenic	criteria provided, single submitter
422006	NM_003052.5(SLC34A1):c.73C>T (p.Arg25Ter)	SLC34A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
433538	NM_003052.5(SLC34A1):c.934C>T (p.Gln312Ter)	SLC34A1	Pathogenic	criteria provided, single submitter
929955	NM_003052.5(SLC34A1):c.745C>T (p.Arg249Ter)	SLC34A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
975094	NM_003052.5(SLC34A1):c.454_480dup (p.Val152_Val160dup)	SLC34A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
234927	NM_003052.5(SLC34A1):c.458G>T (p.Gly153Val)	SLC34A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2690703	NM_003052.5(SLC34A1):c.1484G>A (p.Arg495His)	SLC34A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3068343	NM_003052.5(SLC34A1):c.189del (p.Cys64fs)	SLC34A1	Likely pathogenic	criteria provided, single submitter
3347516	NM_003052.5(SLC34A1):c.778_809delinsAGC (p.Gly260fs)	SLC34A1	Likely pathogenic	criteria provided, single submitter
3592103	NM_003052.5(SLC34A1):c.247G>T (p.Glu83Ter)	SLC34A1	Likely pathogenic	criteria provided, single submitter
3592124	NM_003052.5(SLC34A1):c.876_877del (p.Gly292_Asp293insTer)	SLC34A1	Likely pathogenic	criteria provided, single submitter
3592125	NM_003052.5(SLC34A1):c.897_898del (p.His299fs)	SLC34A1	Likely pathogenic	criteria provided, single submitter
3592135	NM_003052.5(SLC34A1):c.1008C>A (p.Cys336Ter)	SLC34A1	Likely pathogenic	criteria provided, single submitter
4074269	NM_003052.5(SLC34A1):c.1174+1G>A	SLC34A1	Likely pathogenic	criteria provided, single submitter
4526810	NM_003052.5(SLC34A1):c.1739C>T (p.Pro580Leu)	SLC34A1	Likely pathogenic	criteria provided, single submitter
4526811	NM_003052.5(SLC34A1):c.1879del (p.Arg627fs)	SLC34A1	Likely pathogenic	criteria provided, single submitter
1061290	NM_003052.5(SLC34A1):c.1223T>A (p.Val408Glu)	SLC34A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1076059	NM_003052.5(SLC34A1):c.244G>T (p.Glu82Ter)	SLC34A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1108868	NM_003052.5(SLC34A1):c.1449G>A (p.Ser483=)	SLC34A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
12933	NM_003052.5(SLC34A1):c.460_480dup (p.Ile154_Val160dup)	SLC34A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1510792	NM_003052.5(SLC34A1):c.56G>A (p.Arg19His)	SLC34A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1553272	NM_003052.5(SLC34A1):c.937-8T>A	SLC34A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1679240	NM_003052.5(SLC34A1):c.937-2A>C	SLC34A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1906663	NM_003052.5(SLC34A1):c.537G>A (p.Leu179=)	SLC34A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 6 · 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
SLC34A1	Strong	Autosomal dominant	hypophosphatemic nephrolithiasis/osteoporosis 1	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC34A1	Orphanet:157215	Hereditary hypophosphatemic rickets with hypercalciuria
SLC34A1	Orphanet:244305	Dominant hypophosphatemia with nephrolithiasis or osteoporosis
SLC34A1	Orphanet:300547	Autosomal recessive infantile hypercalcemia
SLC34A1	Orphanet:3337	Primary Fanconi renotubular syndrome
SLC5A2	Orphanet:69076	Familial renal glucosuria
SLC34A3	Orphanet:157215	Hereditary hypophosphatemic rickets with hypercalciuria

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC34A1	HGNC:11019	ENSG00000131183	Q06495	Sodium-dependent phosphate transport protein 2A	gencc,clinvar
SLC5A2	HGNC:11037	ENSG00000140675	P31639	Sodium/glucose cotransporter 2	clinvar
SLC34A3	HGNC:20305	ENSG00000198569	Q8N130	Sodium-dependent phosphate transport protein 2C	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC34A1	Sodium-dependent phosphate transport protein 2A	Involved in actively transporting phosphate into cells via Na(+) cotransport in the renal brush border membrane.
SLC5A2	Sodium/glucose cotransporter 2	Electrogenic Na(+)-coupled sugar symporter that actively transports D-glucose at the plasma membrane, with a Na(+) to sugar coupling ratio of 1:1.
SLC34A3	Sodium-dependent phosphate transport protein 2C	Involved in actively transporting phosphate into cells via Na(+) cotransport in the renal brush border membrane.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.0

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
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC34A1	Other/Unknown	no		Na/Pi_transpt
SLC5A2	Other/Unknown	no		Na/solute_symporter, Na/solute_symporter_CS, Na/Glc_symporter_sf
SLC34A3	Other/Unknown	no		Na/Pi_transpt

Expression context

Cohort genes with no expression data: 0.

2 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adult mammalian kidney	3
nephron tubule	2
kidney epithelium	1
male germ line stem cell (sensu Vertebrata) in testis	1
lower esophagus mucosa	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC34A1	52	tissue_specific	marker	nephron tubule, adult mammalian kidney, kidney epithelium
SLC5A2	171	tissue_specific	marker	nephron tubule, adult mammalian kidney, male germ line stem cell (sensu Vertebrata) in testis
SLC34A3	147	tissue_specific	yes	lower esophagus mucosa, right uterine tube, adult mammalian kidney

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC34A1	3,362
SLC34A3	3,023
SLC5A2	1,572

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SLC5A2	P31639	12

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC34A3	Q8N130	75.86
SLC34A1	Q06495	72.24

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 3 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Type II Na+/Pi cotransporters	2	1903.3×	3e-06	SLC34A1, SLC34A3
Defective SLC34A3 causes Hereditary hypophosphatemic rickets with hypercalciuria (HHRH)	1	3806.7×	1e-03	SLC34A3
Defective SLC5A2 causes renal glucosuria (GLYS1)	1	3806.7×	1e-03	SLC5A2
Defective SLC34A1 causes hypophosphatemic nephrolithiasis/osteoporosis 1 (NPHLOP1)	1	1903.3×	0.001	SLC34A1
Cellular hexose transport	1	181.3×	0.012	SLC5A2
Surfactant metabolism	1	122.8×	0.015	SLC34A1
SLC transporter disorders	1	68.0×	0.023	SLC5A2
Disorders of transmembrane transporters	1	46.4×	0.029	SLC5A2
SLC-mediated transmembrane transport	1	19.7×	0.061	SLC5A2
Transport of small molecules	1	8.4×	0.126	SLC5A2
Disease	1	4.4×	0.212	SLC5A2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
phosphate ion transport	2	1248.3×	1e-05	SLC34A1, SLC34A3
sodium-dependent phosphate transport	2	1248.3×	1e-05	SLC34A1, SLC34A3
intracellular phosphate ion homeostasis	2	1021.3×	1e-05	SLC34A1, SLC34A3
sodium ion import across plasma membrane	2	416.1×	7e-05	SLC34A1, SLC5A2
sodium ion transport	2	181.2×	3e-04	SLC5A2, SLC34A3
alpha-glucoside transport	1	2808.7×	0.001	SLC5A2
indole metabolic process	1	2808.7×	0.001	SLC34A1
gentamycin metabolic process	1	2808.7×	0.001	SLC34A1
arsenate ion transmembrane transport	1	2808.7×	0.001	SLC34A1
positive regulation of phosphate transmembrane transport	1	2808.7×	0.001	SLC34A1
renal D-glucose absorption	1	1872.4×	0.002	SLC5A2
cellular response to phosphate starvation	1	1404.3×	0.002	SLC34A1
cellular response to metal ion	1	1404.3×	0.002	SLC34A1
positive regulation of sodium-dependent phosphate transport	1	1404.3×	0.002	SLC34A1
cellular response to staurosporine	1	1123.5×	0.002	SLC34A1
positive regulation of membrane potential	1	936.2×	0.002	SLC34A1
tricarboxylic acid metabolic process	1	936.2×	0.002	SLC34A1
D-glucose import across plasma membrane	1	936.2×	0.002	SLC5A2
response to mercury ion	1	802.5×	0.002	SLC34A1
response to potassium ion	1	702.2×	0.002	SLC34A1
response to thyroid hormone	1	702.2×	0.002	SLC34A1
dentinogenesis	1	702.2×	0.002	SLC34A1
hexose transmembrane transport	1	468.1×	0.003	SLC5A2
response to magnesium ion	1	468.1×	0.003	SLC34A1
cellular response to parathyroid hormone stimulus	1	468.1×	0.003	SLC34A1
phosphate ion transmembrane transport	1	401.2×	0.003	SLC34A1
glycoprotein metabolic process	1	374.5×	0.003	SLC34A1
response to growth hormone	1	374.5×	0.003	SLC34A1
response to peptide	1	374.5×	0.003	SLC34A1
response to vitamin A	1	351.1×	0.003	SLC34A1

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 1

Druggability breadth: 3 of 3 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
SLC34A1	SODIUM PHOSPHATE, DIBASIC, ANHYDROUS
SLC5A2	ERTUGLIFLOZIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC5A2	16	4
SLC34A1	2	4
SLC34A3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SODIUM PHOSPHATE, DIBASIC, ANHYDROUS	4	SLC34A1
POTASSIUM PHOSPHATE, MONOBASIC	4	SLC34A1
ERTUGLIFLOZIN	4	SLC5A2
BEXAGLIFLOZIN	4	SLC5A2
IPRAGLIFLOZIN	4	SLC5A2
CANAGLIFLOZIN ANHYDROUS	4	SLC5A2
TOFOGLIFLOZIN	4	SLC5A2
EMPAGLIFLOZIN	4	SLC5A2
TOFOGLIFLOZIN ANHYDROUS	4	SLC5A2
SOTAGLIFLOZIN	4	SLC5A2
DAPAGLIFLOZIN	4	SLC5A2
ENAVOGLIFLOZIN	3	SLC5A2
HENAGLIFLOZIN	3	SLC5A2
LUSEOGLIFLOZIN	2	SLC5A2
REMOGLIFLOZIN ETABONATE	2	SLC5A2
YM-543 FREE ACID	2	SLC5A2
LICOGLIFLOZIN	2	SLC5A2
SERGLIFLOZIN ETABONATE	2	SLC5A2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC5A2	160	Binding:157, Functional:2, ADMET:1
SLC34A1	8	Binding:7, Functional:1
SLC34A3	1	Binding:1

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
SLC5A2	160

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

18 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.

Compound	Max phase	Cohort target (bioactivity)
SODIUM PHOSPHATE, DIBASIC, ANHYDROUS	4	SLC34A1
POTASSIUM PHOSPHATE, MONOBASIC	4	SLC34A1
ERTUGLIFLOZIN	4	SLC5A2
BEXAGLIFLOZIN	4	SLC5A2
IPRAGLIFLOZIN	4	SLC5A2
CANAGLIFLOZIN ANHYDROUS	4	SLC5A2
TOFOGLIFLOZIN	4	SLC5A2
EMPAGLIFLOZIN	4	SLC5A2
TOFOGLIFLOZIN ANHYDROUS	4	SLC5A2
SOTAGLIFLOZIN	4	SLC5A2
DAPAGLIFLOZIN	4	SLC5A2
ENAVOGLIFLOZIN	3	SLC5A2
HENAGLIFLOZIN	3	SLC5A2
LUSEOGLIFLOZIN	2	SLC5A2
REMOGLIFLOZIN ETABONATE	2	SLC5A2
YM-543 FREE ACID	2	SLC5A2
LICOGLIFLOZIN	2	SLC5A2
SERGLIFLOZIN ETABONATE	2	SLC5A2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	SLC34A1, SLC5A2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SLC34A3

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)
SLC34A3	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.