Infantile hypophosphatasia

Summary

Infantile hypophosphatasia (MONDO:1010169) is a disease with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 2
• ClinVar variants: 312
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	infantile hypophosphatasia
Mondo ID	MONDO:1010169
OMIM	241500
Orphanet	247651
DOID	DOID:0110914
ICD-11	1832803655
SNOMED CT	55236002
UMLS	C0268412
MedGen	75677
GARD	0028133
Is cancer (heuristic)	no

Also known as: infantile hypophosphatasia

Data availability: 312 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › metabolic disease › developmental anomaly of metabolic origin › hypophosphatasia › infantile hypophosphatasia

Related subtypes (7): odontohypophosphatasia, ALPL-related autosomal dominant hypophosphatasia, ALPL-related autosomal recessive hypophosphatasia, moderate hypophosphatasia, prenatal benign hypophosphatasia, adult hypophosphatasia, childhood hypophosphatasia

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

312 retrieved; paginated sample, class counts are floors:

93 pathogenic/likely pathogenic, 48 uncertain significance, 47 conflicting classifications of pathogenicity, 39 pathogenic, 38 likely pathogenic, 24 likely benign, 17 benign, 6 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1003680	NM_000478.6(ALPL):c.1022A>G (p.His341Arg)	ALPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1030812	NM_000478.6(ALPL):c.1328C>T (p.Ala443Val)	ALPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070177	NM_000478.6(ALPL):c.212G>A (p.Arg71His)	ALPL	Pathogenic	criteria provided, multiple submitters, no conflicts
1074126	NM_000478.6(ALPL):c.976G>C (p.Gly326Arg)	ALPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074643	NM_000478.6(ALPL):c.997G>T (p.Gly333Ter)	ALPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075198	NM_000478.6(ALPL):c.412del (p.Arg138fs)	ALPL	Pathogenic	criteria provided, multiple submitters, no conflicts
1076060	NM_000478.6(ALPL):c.203C>T (p.Thr68Met)	ALPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076087	NM_000478.6(ALPL):c.303C>A (p.Tyr101Ter)	ALPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076160	NM_000478.6(ALPL):c.532T>C (p.Tyr178His)	ALPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1076161	NM_000478.6(ALPL):c.659G>C (p.Gly220Ala)	ALPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1224381	NM_000478.6(ALPL):c.657G>T (p.Met219Ile)	ALPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1300140	NM_000478.6(ALPL):c.1427A>C (p.Glu476Ala)	ALPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323883	NM_000478.6(ALPL):c.874C>A (p.Pro292Thr)	ALPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339258	NM_000478.6(ALPL):c.247G>T (p.Glu83Ter)	ALPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13662	NM_000478.6(ALPL):c.535G>A (p.Ala179Thr)	ALPL	Pathogenic	criteria provided, multiple submitters, no conflicts
13663	NM_000478.6(ALPL):c.211C>T (p.Arg71Cys)	ALPL	Pathogenic	criteria provided, multiple submitters, no conflicts
13664	NM_000478.6(ALPL):c.881A>C (p.Asp294Ala)	ALPL	Pathogenic	criteria provided, multiple submitters, no conflicts
13665	NM_000478.6(ALPL):c.212G>C (p.Arg71Pro)	ALPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13666	NM_000478.6(ALPL):c.620A>C (p.Gln207Pro)	ALPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13667	NM_000478.6(ALPL):c.98C>T (p.Ala33Val)	ALPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13671	NM_000478.6(ALPL):c.1133A>T (p.Asp378Val)	ALPL	Pathogenic	criteria provided, multiple submitters, no conflicts
13672	NM_000478.6(ALPL):c.1001G>A (p.Gly334Asp)	ALPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13673	NM_000478.6(ALPL):c.979T>C (p.Phe327Leu)	ALPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13674	NM_000478.6(ALPL):c.1559del (p.Leu520fs)	ALPL	Pathogenic	criteria provided, multiple submitters, no conflicts
13675	NM_000478.6(ALPL):c.407G>A (p.Arg136His)	ALPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13676	NM_000478.6(ALPL):c.485G>T (p.Gly162Val)	ALPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13677	NM_000478.6(ALPL):c.346G>A (p.Ala116Thr)	ALPL	Pathogenic	criteria provided, multiple submitters, no conflicts
13678	NM_000478.6(ALPL):c.648+1G>A	ALPL	Pathogenic	criteria provided, multiple submitters, no conflicts
13679	NM_000478.6(ALPL):c.1250A>G (p.Asn417Ser)	ALPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13681	NM_000478.6(ALPL):c.1366G>A (p.Gly456Arg)	ALPL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COL11A2	Orphanet:1427	Autosomal recessive otospondylomegaepiphyseal dysplasia
COL11A2	Orphanet:166100	Autosomal dominant otospondylomegaepiphyseal dysplasia
COL11A2	Orphanet:2021	Fibrochondrogenesis
COL11A2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
COL11A2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
ALPL	Orphanet:247623	Perinatal lethal hypophosphatasia
ALPL	Orphanet:247638	Prenatal benign hypophosphatasia
ALPL	Orphanet:247651	Infantile hypophosphatasia
ALPL	Orphanet:247667	Childhood-onset hypophosphatasia
ALPL	Orphanet:247676	Adult hypophosphatasia
ALPL	Orphanet:247685	Odontohypophosphatasia

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
COL11A2	HGNC:2187	ENSG00000204248	P13942	Collagen alpha-2(XI) chain	clinvar
ALPL	HGNC:438	ENSG00000162551	P05186	Alkaline phosphatase, tissue-nonspecific isozyme	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COL11A2	Collagen alpha-2(XI) chain	May play an important role in fibrillogenesis by controlling lateral growth of collagen II fibrils.
ALPL	Alkaline phosphatase, tissue-nonspecific isozyme	Alkaline phosphatase that metabolizes various phosphate compounds and plays a key role in skeletal mineralization and adaptive thermogenesis.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · 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
Phosphatase	1	42.0×	0.047
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COL11A2	Other/Unknown	no		Fib_collagen_C, Laminin_G, Collagen
ALPL	Phosphatase	yes	3.1.3.1	Alkaline_phosphatase, Alkaline_phosphatase_core_sf, Alkaline_phosphatase_AS

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adenohypophysis	1
male germ line stem cell (sensu Vertebrata) in testis	1
pituitary gland	1
left adrenal gland cortex	1
right adrenal gland	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COL11A2	134	broad	yes	pituitary gland, male germ line stem cell (sensu Vertebrata) in testis, adenohypophysis
ALPL	200	broad	marker	right adrenal gland, right adrenal gland cortex, left adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ALPL	2,146
COL11A2	1,583

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ALPL	P05186	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
COL11A2	P13942	50.18

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
MET activates PTK2 signaling	1	190.3×	0.013	COL11A2
Collagen chain trimerization	1	129.8×	0.013	COL11A2
Developmental Lineage of Pancreatic Ductal Cells	1	114.2×	0.013	COL11A2
Assembly of collagen fibrils and other multimeric structures	1	100.2×	0.013	COL11A2
Collagen degradation	1	87.8×	0.013	COL11A2
Collagen biosynthesis and modifying enzymes	1	85.2×	0.013	COL11A2
Post-translational modification: synthesis of GPI-anchored proteins	1	84.0×	0.013	ALPL
Non-integrin membrane-ECM interactions	1	77.2×	0.013	COL11A2

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
pyridoxal 5’-phosphate metabolic process	1	8426.0×	0.002	ALPL
response to vitamin B6	1	4213.0×	0.002	ALPL
futile creatine cycle	1	4213.0×	0.002	ALPL
skeletal system development	2	125.8×	0.002	COL11A2, ALPL
response to macrophage colony-stimulating factor	1	2106.5×	0.002	ALPL
inhibition of non-skeletal tissue mineralization	1	2106.5×	0.002	ALPL
developmental process involved in reproduction	1	1685.2×	0.002	ALPL
soft palate development	1	1685.2×	0.002	COL11A2
cementum mineralization	1	1203.7×	0.002	ALPL
response to sodium phosphate	1	842.6×	0.003	ALPL
phosphate ion homeostasis	1	526.6×	0.004	ALPL
cellular homeostasis	1	401.2×	0.005	ALPL
response to vitamin D	1	401.2×	0.005	ALPL
response to antibiotic	1	351.1×	0.005	ALPL
endochondral ossification	1	271.8×	0.006	ALPL
calcium ion homeostasis	1	221.7×	0.007	ALPL
response to glucocorticoid	1	162.0×	0.009	ALPL
bone mineralization	1	135.9×	0.010	ALPL
cartilage development	1	125.8×	0.010	COL11A2
roof of mouth development	1	123.9×	0.010	COL11A2
response to insulin	1	115.4×	0.010	ALPL
collagen fibril organization	1	112.3×	0.010	COL11A2
positive regulation of cold-induced thermogenesis	1	81.8×	0.014	ALPL
response to lipopolysaccharide	1	62.4×	0.017	ALPL
osteoblast differentiation	1	60.6×	0.017	ALPL
sensory perception of sound	1	50.5×	0.020	COL11A2

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
ALPL	SULCONAZOLE NITRATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ALPL	7	4
COL11A2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SULCONAZOLE NITRATE	4	ALPL
THEOPHYLLINE	4	ALPL
LEVAMISOLE	4	ALPL
MICONAZOLE NITRATE	4	ALPL
LEVAMISOLE HYDROCHLORIDE	4	ALPL
ISOQUERCETIN	2	ALPL
(-)-EPICATECHIN	2	ALPL

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ALPL	58	Binding:50, Functional:4, ADMET:3, Toxicity:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ALPL	3.1.3.1	alkaline phosphatase

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

7 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)
SULCONAZOLE NITRATE	4	ALPL
THEOPHYLLINE	4	ALPL
LEVAMISOLE	4	ALPL
MICONAZOLE NITRATE	4	ALPL
LEVAMISOLE HYDROCHLORIDE	4	ALPL
ISOQUERCETIN	2	ALPL
(-)-EPICATECHIN	2	ALPL

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ALPL
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	COL11A2

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)
COL11A2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford