Hereditary hypophosphatemic rickets with hypercalciuria

Summary

Hereditary hypophosphatemic rickets with hypercalciuria (MONDO:0009431) is a disease caused by SLC34A3 (GenCC Definitive), with 1 cohort gene and 2 clinical trials.

At a glance

• Prevalence: <1 / 1 000 000 (Europe)
• Causal gene: SLC34A3 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 325
• Phenotypes (HPO): 21
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

21 HPO clinical features (Orphanet curated; top 21 by frequency):

HPO ID	Term	Frequency
HP:0002148	Hypophosphatemia	Very frequent (80-99%)
HP:0002150	Hypercalciuria	Very frequent (80-99%)
HP:0003109	Hyperphosphaturia	Very frequent (80-99%)
HP:0004912	Hypophosphatemic rickets	Very frequent (80-99%)
HP:0010639	Elevated alkaline phosphatase of bone origin	Very frequent (80-99%)
HP:0031415	High serum calcitriol	Very frequent (80-99%)
HP:0031425	Increased circulating beta-C-terminal telopeptide level	Very frequent (80-99%)
HP:0031428	Increased circulating osteocalcin level	Very frequent (80-99%)
HP:0031817	Decreased circulating parathyroid hormone level	Very frequent (80-99%)
HP:0000787	Nephrolithiasis	Frequent (30-79%)
HP:0000924	Abnormality of the skeletal system	Frequent (30-79%)
HP:0001510	Growth delay	Frequent (30-79%)
HP:0002653	Bone pain	Frequent (30-79%)
HP:0002749	Osteomalacia	Frequent (30-79%)
HP:0004349	Reduced bone mineral density	Frequent (30-79%)
HP:0012408	Medullary nephrocalcinosis	Frequent (30-79%)
HP:0000897	Rachitic rosary	Occasional (5-29%)
HP:0002515	Waddling gait	Occasional (5-29%)
HP:0002756	Pathologic fracture	Occasional (5-29%)
HP:0002979	Bowing of the legs	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary hypophosphatemic rickets with hypercalciuria
Mondo ID	MONDO:0009431
MeSH	C562793
OMIM	241530
Orphanet	157215
DOID	DOID:0050947
NCIT	C131450
SNOMED CT	237891005
UMLS	C1853271
MedGen	501133
GARD	0016977
Is cancer (heuristic)	no

Also known as: HHRH · hypercalciuric hypophosphatemic rickets · hypophosphatemic hypercalciuric rickets · hypophosphatemic rickets with hypercalciuria · hypophosphatemic rickets with hypercalciuria, hereditary

Data availability: 325 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary hypophosphatemic rickets › hereditary hypophosphatemic rickets with hypercalciuria

Related subtypes (3): autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, X-linked hypophosphatemic rickets

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

325 retrieved; paginated sample, class counts are floors:

189 uncertain significance, 38 conflicting classifications of pathogenicity, 30 likely pathogenic, 19 pathogenic/likely pathogenic, 18 likely benign, 14 benign/likely benign, 13 pathogenic, 4 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1008911	NM_001177316.2(SLC34A3):c.3G>A (p.Met1Ile)	SLC34A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1066383	NM_001177316.2(SLC34A3):c.1335+2T>A	SLC34A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073253	NM_001177316.2(SLC34A3):c.671del (p.Leu224fs)	SLC34A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1179153	NM_001177316.2(SLC34A3):c.1242C>A (p.Tyr414Ter)	SLC34A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1332756	NM_001177316.2(SLC34A3):c.1336-11_1336-1del	SLC34A3	Pathogenic	criteria provided, single submitter
1422510	NM_001177316.2(SLC34A3):c.1008_1009dup (p.Gly337fs)	SLC34A3	Pathogenic	criteria provided, multiple submitters, no conflicts
1426	NM_001177316.2(SLC34A3):c.908del (p.Pro303fs)	SLC34A3	Pathogenic	criteria provided, single submitter
1428	NM_001177316.2(SLC34A3):c.1238C>A (p.Ala413Glu)	SLC34A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1430	NM_001177316.2(SLC34A3):c.228del (p.Cys77fs)	SLC34A3	Pathogenic	no assertion criteria provided
1431	NM_001177316.2(SLC34A3):c.586G>A (p.Gly196Arg)	SLC34A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1432	NM_001177316.2(SLC34A3):c.1402C>T (p.Arg468Trp)	SLC34A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1433	NM_001177316.2(SLC34A3):c.925+20_926-48del	SLC34A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1435	NM_001177316.2(SLC34A3):c.1093+41_1094-15del	SLC34A3	Pathogenic	no assertion criteria provided
1459128	NM_001177316.2(SLC34A3):c.1046_1047del (p.Val349fs)	SLC34A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686208	NM_001177316.2(SLC34A3):c.1217G>T (p.Gly406Val)	SLC34A3	Pathogenic	criteria provided, single submitter
1916375	NM_001177316.2(SLC34A3):c.734dup (p.Leu246fs)	SLC34A3	Pathogenic	criteria provided, multiple submitters, no conflicts
198610	NM_001177316.2(SLC34A3):c.575C>T (p.Ser192Leu)	SLC34A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2008084	NM_001177316.2(SLC34A3):c.1093+2T>C	SLC34A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2627449	NM_001177316.2(SLC34A3):c.1247del (p.Leu416fs)	SLC34A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3020355	NM_001177316.2(SLC34A3):c.2T>C (p.Met1Thr)	SLC34A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3254619	NM_001177316.2(SLC34A3):c.1622G>A (p.Trp541Ter)	SLC34A3	Pathogenic	criteria provided, single submitter
3596882	NM_001177316.2(SLC34A3):c.448+2T>C	SLC34A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4074275	NC_000009.11:g.(?140125385)(140131007_?)del	SLC34A3	Pathogenic	criteria provided, single submitter
423400	NM_001177316.2(SLC34A3):c.1623G>A (p.Trp541Ter)	SLC34A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
438692	NM_001177316.2(SLC34A3):c.1556dup (p.Pro520fs)	SLC34A3	Pathogenic	no assertion criteria provided
444094	NM_001177316.2(SLC34A3):c.575C>G (p.Ser192Trp)	SLC34A3	Pathogenic	criteria provided, single submitter
444095	NM_001177316.2(SLC34A3):c.1561dup (p.Leu521fs)	SLC34A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
444096	NM_001177316.2(SLC34A3):c.1639_1652del (p.Arg547fs)	SLC34A3	Pathogenic	criteria provided, single submitter
445687	NM_001177316.2(SLC34A3):c.448+1G>A	SLC34A3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4526815	NM_001177316.2(SLC34A3):c.135G>A (p.Trp45Ter)	SLC34A3	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
SLC34A3	Definitive	Semidominant	hereditary hypophosphatemic rickets with hypercalciuria	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC34A3	Orphanet:157215	Hereditary hypophosphatemic rickets with hypercalciuria

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
SLC34A3	HGNC:20305	ENSG00000198569	Q8N130	Sodium-dependent phosphate transport protein 2C	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC34A3	Other/Unknown	no		Na/Pi_transpt

Expression context

Cohort genes with no expression data: 0.

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
adult mammalian kidney	1
lower esophagus mucosa	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
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
SLC34A3	3,023

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC34A3	Q8N130	75.86

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Defective SLC34A3 causes Hereditary hypophosphatemic rickets with hypercalciuria (HHRH)	1	11420.0×	2e-04	SLC34A3
Type II Na+/Pi cotransporters	1	2855.0×	4e-04	SLC34A3

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
phosphate ion transport	1	1872.4×	9e-04	SLC34A3
sodium-dependent phosphate transport	1	1872.4×	9e-04	SLC34A3
intracellular phosphate ion homeostasis	1	1532.0×	9e-04	SLC34A3
sodium ion transport	1	271.8×	0.004	SLC34A3

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
SLC34A3	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC34A3	1	Binding:1

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	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: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
EARLY_PHASE1	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03771105	EARLY_PHASE1	RECRUITING	The Impact of Phosphate Metabolism on Healthy Aging
NCT06065852	Not specified	RECRUITING	National Registry of Rare Kidney Diseases