Hypercalcemia, infantile, 2

Summary

Hypercalcemia, infantile, 2 (MONDO:0014851) is a disease caused by SLC34A1 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: SLC34A1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 184

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypercalcemia, infantile, 2
Mondo ID	MONDO:0014851
OMIM	616963
DOID	DOID:0061135
UMLS	C4310473
MedGen	934441
GARD	0018435
Is cancer (heuristic)	no

Also known as: autosomal recessive infantile hypercalcemia caused by mutation in SLC34A1 · HCINF2 · hypercalcemia, infantile 2 · hypercalcemia, infantile, 2 · hypercalcemia, infantile, type 2 · SLC34A1 autosomal recessive infantile hypercalcemia

Data availability: 184 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › mineral metabolism disease › calcium metabolic disease › hypercalcemia disease › hypercalcemia, infantile › hypercalcemia, infantile, 2

Related subtypes (1): hypercalcemia, infantile, 1

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

184 retrieved; paginated sample, class counts are floors:

106 uncertain significance, 31 conflicting classifications of pathogenicity, 13 likely pathogenic, 10 likely benign, 9 pathogenic, 6 pathogenic/likely pathogenic, 6 benign/likely benign, 3 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1179157	GRCh37/hg19 5q35.3(chr5:176812675-176813587)	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
234928	NM_003052.5(SLC34A1):c.1006+1G>A	SLC34A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
234929	NM_003052.5(SLC34A1):c.1006T>G (p.Cys336Gly)	SLC34A1	Pathogenic	no assertion criteria provided
234930	NM_003052.5(SLC34A1):c.458G>C (p.Gly153Ala)	SLC34A1	Pathogenic	criteria provided, single submitter
2444055	NM_003052.5(SLC34A1):c.527_528del (p.Ser176fs)	SLC34A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3359162	NM_003052.5(SLC34A1):c.533T>A (p.Leu178Ter)	SLC34A1	Pathogenic	no assertion criteria provided
3376790	NM_003052.5(SLC34A1):c.1188del (p.Phe397fs)	SLC34A1	Pathogenic	criteria provided, single submitter
3381884	NM_003052.5(SLC34A1):c.627del (p.Asp209fs)	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
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
3347516	NM_003052.5(SLC34A1):c.778_809delinsAGC (p.Gly260fs)	SLC34A1	Likely pathogenic	criteria provided, single submitter
3381883	NM_003052.5(SLC34A1):c.581G>A (p.Gly194Asp)	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
3780621	NM_003052.5(SLC34A1):c.1463G>A (p.Trp488Ter)	SLC34A1	Likely pathogenic	criteria provided, single submitter
4074269	NM_003052.5(SLC34A1):c.1174+1G>A	SLC34A1	Likely pathogenic	criteria provided, single submitter
438694	NM_003052.5(SLC34A1):c.713A>C (p.Glu238Ala)	SLC34A1	Likely pathogenic	no assertion criteria provided
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
1028069	NM_003052.5(SLC34A1):c.532+2T>C	SLC34A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1061290	NM_003052.5(SLC34A1):c.1223T>A (p.Val408Glu)	SLC34A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 4 · 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 recessive	hypercalcemia, infantile, 2	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

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
SLC34A1	HGNC:11019	ENSG00000131183	Q06495	Sodium-dependent phosphate transport protein 2A	gencc,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.

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)
SLC34A1	Other/Unknown	no		Na/Pi_transpt

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
adult mammalian kidney	1
kidney epithelium	1
nephron tubule	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC34A1	3,362

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SLC34A1	Q06495	72.24

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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 SLC34A1 causes hypophosphatemic nephrolithiasis/osteoporosis 1 (NPHLOP1)	1	5710.0×	5e-04	SLC34A1
Type II Na+/Pi cotransporters	1	2855.0×	5e-04	SLC34A1
Surfactant metabolism	1	368.4×	0.003	SLC34A1

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
indole metabolic process	1	8426.0×	9e-04	SLC34A1
gentamycin metabolic process	1	8426.0×	9e-04	SLC34A1
arsenate ion transmembrane transport	1	8426.0×	9e-04	SLC34A1
positive regulation of phosphate transmembrane transport	1	8426.0×	9e-04	SLC34A1
cellular response to phosphate starvation	1	4213.0×	0.001	SLC34A1
cellular response to metal ion	1	4213.0×	0.001	SLC34A1
positive regulation of sodium-dependent phosphate transport	1	4213.0×	0.001	SLC34A1
cellular response to staurosporine	1	3370.4×	0.001	SLC34A1
positive regulation of membrane potential	1	2808.7×	0.001	SLC34A1
tricarboxylic acid metabolic process	1	2808.7×	0.001	SLC34A1
response to mercury ion	1	2407.4×	0.001	SLC34A1
response to potassium ion	1	2106.5×	0.001	SLC34A1
response to thyroid hormone	1	2106.5×	0.001	SLC34A1
dentinogenesis	1	2106.5×	0.001	SLC34A1
phosphate ion transport	1	1872.4×	0.001	SLC34A1
sodium-dependent phosphate transport	1	1872.4×	0.001	SLC34A1
intracellular phosphate ion homeostasis	1	1532.0×	0.001	SLC34A1
response to magnesium ion	1	1404.3×	0.001	SLC34A1
cellular response to parathyroid hormone stimulus	1	1404.3×	0.001	SLC34A1
phosphate ion transmembrane transport	1	1203.7×	0.001	SLC34A1
glycoprotein metabolic process	1	1123.5×	0.001	SLC34A1
response to growth hormone	1	1123.5×	0.001	SLC34A1
response to peptide	1	1123.5×	0.001	SLC34A1
response to vitamin A	1	1053.2×	0.001	SLC34A1
phosphate ion homeostasis	1	1053.2×	0.001	SLC34A1
response to lead ion	1	936.2×	0.001	SLC34A1
response to cadmium ion	1	732.7×	0.002	SLC34A1
sodium ion import across plasma membrane	1	624.1×	0.002	SLC34A1
ossification	1	227.7×	0.005	SLC34A1
response to estradiol	1	198.3×	0.005	SLC34A1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC34A1	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SODIUM PHOSPHATE, DIBASIC, ANHYDROUS	4	SLC34A1
POTASSIUM PHOSPHATE, MONOBASIC	4	SLC34A1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SLC34A1	8	Binding:7, Functional: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

2 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

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SLC34A1
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.