Hypercalcemia, infantile, 1

Summary

Hypercalcemia, infantile, 1 (MONDO:0020739) is a disease caused by CYP24A1 (GenCC Strong), with 2 cohort genes.

At a glance

• Causal gene: CYP24A1 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 238

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypercalcemia, infantile, 1
Mondo ID	MONDO:0020739
OMIM	143880
DOID	DOID:0061136
GARD	0018434
Is cancer (heuristic)	no

Also known as: autosomal recessive infantile hypercalcemia 1 · HCINF1 · hypercalcemia, infantile, 1

Data availability: 238 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, 1

Related subtypes (1): hypercalcemia, infantile, 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

238 retrieved; paginated sample, class counts are floors:

132 uncertain significance, 22 conflicting classifications of pathogenicity, 20 likely pathogenic, 19 pathogenic, 18 benign, 10 pathogenic/likely pathogenic, 10 benign/likely benign, 7 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1072834	NM_000782.5(CYP24A1):c.1396C>T (p.Arg466Ter)	CYP24A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1179111	GRCh37/hg19 20q13.2(chr20:52769985-52790525)	CYP24A1	Pathogenic	no assertion criteria provided
1455164	NM_000782.5(CYP24A1):c.1147G>C (p.Glu383Gln)	CYP24A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1460149	NM_000782.5(CYP24A1):c.999_1006del (p.Ser334fs)	CYP24A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1941936	NM_000782.5(CYP24A1):c.1384_1385del (p.Cys462fs)	CYP24A1	Pathogenic	criteria provided, multiple submitters, no conflicts
208571	NM_000782.5(CYP24A1):c.1039C>T (p.Gln347Ter)	CYP24A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2506936	NM_000782.5(CYP24A1):c.641-1G>A	CYP24A1	Pathogenic	criteria provided, single submitter
2506945	NM_000782.5(CYP24A1):c.364G>T (p.Glu122Ter)	CYP24A1	Pathogenic	criteria provided, multiple submitters, no conflicts
2869485	NM_000782.5(CYP24A1):c.678del (p.Leu227fs)	CYP24A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29675	NM_000782.5(CYP24A1):c.1426_1427del (p.Cys477fs)	CYP24A1	Pathogenic	no assertion criteria provided
29676	NM_000782.5(CYP24A1):c.476G>A (p.Arg159Gln)	CYP24A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29677	NM_000782.5(CYP24A1):c.425AAG[1] (p.Glu143del)	CYP24A1	Pathogenic	criteria provided, multiple submitters, no conflicts
29678	NM_000782.5(CYP24A1):c.451G>T (p.Glu151Ter)	CYP24A1	Pathogenic	no assertion criteria provided
29679	NM_000782.5(CYP24A1):c.1186C>T (p.Arg396Trp)	CYP24A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29680	NM_000782.5(CYP24A1):c.1226T>C (p.Leu409Ser)	CYP24A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29681	NM_000782.5(CYP24A1):c.964G>A (p.Glu322Lys)	CYP24A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3234027	NM_000782.5(CYP24A1):c.109C>T (p.Gln37Ter)	CYP24A1	Pathogenic	criteria provided, single submitter
3236073	NM_000782.5(CYP24A1):c.1320G>A (p.Trp440Ter)	CYP24A1	Pathogenic	criteria provided, single submitter
3236225	NM_000782.5(CYP24A1):c.670_673dup (p.Gly225fs)	CYP24A1	Pathogenic	criteria provided, single submitter
3587448	NM_000782.5(CYP24A1):c.845-2A>G	CYP24A1	Pathogenic	criteria provided, single submitter
3587450	NM_000782.5(CYP24A1):c.804G>A (p.Trp268Ter)	CYP24A1	Pathogenic	criteria provided, single submitter
3587457	NM_000782.5(CYP24A1):c.667A>T (p.Arg223Ter)	CYP24A1	Pathogenic	criteria provided, multiple submitters, no conflicts
4074266	NM_000782.5(CYP24A1):c.1339dup (p.Ile447fs)	CYP24A1	Pathogenic	criteria provided, single submitter
4294430	NM_000782.5(CYP24A1):c.1410dup (p.Gln471fs)	CYP24A1	Pathogenic	criteria provided, single submitter
631878	NM_000782.5(CYP24A1):c.443T>C (p.Leu148Pro)	CYP24A1	Pathogenic	criteria provided, multiple submitters, no conflicts
632376	NM_000782.5(CYP24A1):c.62del (p.Pro21fs)	CYP24A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
942179	NM_000782.5(CYP24A1):c.475C>T (p.Arg159Trp)	CYP24A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
953906	NM_000782.5(CYP24A1):c.1187G>A (p.Arg396Gln)	CYP24A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3779559	NM_001010851.3(ZNF766):c.274+2804_274+2806del	ZNF766	Pathogenic	criteria provided, single submitter
1324203	NM_000782.5(CYP24A1):c.685A>T (p.Lys229Ter)	CYP24A1	Likely 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
CYP24A1	Strong	Autosomal recessive	hypercalcemia, infantile, 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CYP24A1	Orphanet:300547	Autosomal recessive infantile hypercalcemia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CYP24A1	HGNC:2602	ENSG00000019186	Q07973	1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial	gencc,clinvar
ZNF766	HGNC:28063	ENSG00000196214	Q5HY98	Zinc finger protein 766	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CYP24A1	1,25-dihydroxyvitamin D(3) 24-hydroxylase, mitochondrial	A cytochrome P450 monooxygenase with a key role in vitamin D catabolism and calcium homeostasis.
ZNF766	Zinc finger protein 766	May be involved in transcriptional regulation.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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
Enzyme (other)	1	6.0×	0.228
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CYP24A1	Enzyme (other)	yes	1.14.14.24	Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_CS
ZNF766	Transcription factor	no		KRAB, Znf_C2H2_type, KRAB_dom_sf

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	2
olfactory segment of nasal mucosa	1
secondary oocyte	1
calcaneal tendon	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CYP24A1	163	broad	marker	olfactory segment of nasal mucosa, secondary oocyte, male germ line stem cell (sensu Vertebrata) in testis
ZNF766	251	ubiquitous	marker	sperm, calcaneal tendon, male germ line stem cell (sensu Vertebrata) in testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CYP24A1	2,143
ZNF766	530

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CYP24A1	Q07973	89.03
ZNF766	Q5HY98	66.08

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 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 CYP24A1 causes HCAI	1	11420.0×	3e-04	CYP24A1
Vitamins	1	1903.3×	8e-04	CYP24A1
Vitamin D (calciferol) metabolism	1	878.5×	0.001	CYP24A1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
vitamin D catabolic process	1	2106.5×	0.002	CYP24A1
vitamin metabolic process	1	1404.3×	0.002	CYP24A1
vitamin D receptor signaling pathway	1	1404.3×	0.002	CYP24A1
vitamin D metabolic process	1	766.0×	0.002	CYP24A1
response to vitamin D	1	401.2×	0.003	CYP24A1
osteoblast differentiation	1	60.6×	0.019	CYP24A1
regulation of transcription by RNA polymerase II	1	5.8×	0.164	ZNF766

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
CYP24A1	KETOCONAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CYP24A1	4	4
ZNF766	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
KETOCONAZOLE	4	CYP24A1
CALCITRIOL	4	CYP24A1
LUNACALCIPOL	2	CYP24A1
LIAROZOLE	2	CYP24A1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CYP24A1	35	Binding:28, ADMET:7

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CYP24A1	1.14.14.24, 1.14.15.16	vitamin D 25-hydroxylase, vitamin D3 24-hydroxylase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

4 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)
KETOCONAZOLE	4	CYP24A1
CALCITRIOL	4	CYP24A1
LUNACALCIPOL	2	CYP24A1
LIAROZOLE	2	CYP24A1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CYP24A1
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	ZNF766

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)
ZNF766	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.