Arterial calcification, generalized, of infancy, 1

Summary

Arterial calcification, generalized, of infancy, 1 (MONDO:0008817) is a disease caused by ENPP1 (GenCC Definitive), with 3 cohort genes and 2 clinical trials. Top therapeutic interventions include inz-701.

At a glance

• Causal gene: ENPP1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 339
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	arterial calcification, generalized, of infancy, 1
Mondo ID	MONDO:0008817
OMIM	208000
NCIT	C128805
UMLS	C4551985
MedGen	1631685
GARD	0024642
Is cancer (heuristic)	no

Also known as: arterial calcification of infancy caused by mutation in ENPP1 · arterial calcification, generalized, of infancy, 1 · arterial calcification, generalized, of infancy, type 1 · ENPP1 arterial calcification of infancy · GACI1 · generalised arterial calcification of infancy 1 · generalized arterial calcification of infancy 1

Data availability: 339 ClinVar variants · 3 GenCC gene-disease records · 3 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › arterial calcification of infancy › arterial calcification, generalized, of infancy, 1

Related subtypes (1): arterial calcification, generalized, of infancy, 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

339 retrieved; paginated sample, class counts are floors:

163 uncertain significance, 56 benign, 42 conflicting classifications of pathogenicity, 30 pathogenic, 20 likely pathogenic, 17 likely benign, 6 pathogenic/likely pathogenic, 5 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1179191	NM_006208.3(ENPP1):c.2344C>T (p.Arg782Ter)	ENPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
13585	NM_006208.3(ENPP1):c.2677G>T (p.Glu893Ter)	ENPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
13587	NM_006208.3(ENPP1):c.1072_1082del (p.Gln358fs)	ENPP1	Pathogenic	no assertion criteria provided
13591	NM_006208.3(ENPP1):c.1025G>T (p.Gly342Val)	ENPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13592	NM_006208.3(ENPP1):c.1112A>T (p.Tyr371Phe)	ENPP1	Pathogenic	no assertion criteria provided
13594	NM_006208.3(ENPP1):c.797G>T (p.Gly266Val)	ENPP1	Pathogenic	criteria provided, single submitter
13597	NM_006208.3(ENPP1):c.783C>G (p.Tyr261Ter)	ENPP1	Pathogenic	criteria provided, single submitter
13598	NM_006208.3(ENPP1):c.878_879del (p.Lys293fs)	ENPP1	Pathogenic	no assertion criteria provided
1685769	NM_006208.3(ENPP1):c.1366C>T (p.Arg456Ter)	ENPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1699955	NM_006208.3(ENPP1):c.915+1G>A	ENPP1	Pathogenic	criteria provided, single submitter
1699956	NM_006208.3(ENPP1):c.2741T>A (p.Leu914Ter)	ENPP1	Pathogenic	criteria provided, single submitter
1699957	NM_006208.3(ENPP1):c.511A>T (p.Lys171Ter)	ENPP1	Pathogenic	criteria provided, single submitter
1699959	NM_006208.3(ENPP1):c.574del (p.Glu192fs)	ENPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1699961	NM_006208.3:c.(1091+1_1092-1)_(1164+1_1165-1)del	ENPP1	Pathogenic	criteria provided, single submitter
1699962	NM_006208.3(ENPP1):c.1094del (p.Pro365fs)	ENPP1	Pathogenic	criteria provided, single submitter
1699964	NM_006208.3(ENPP1):c.196_197del (p.Ala66fs)	ENPP1	Pathogenic	criteria provided, single submitter
1699966	NM_006208.3(ENPP1):c.2230C>T (p.Gln744Ter)	ENPP1	Pathogenic	criteria provided, single submitter
1699967	NM_006208.3(ENPP1):c.26dup (p.Gly10fs)	ENPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1699971	NM_006208.3(ENPP1):c.1273+2T>C	ENPP1	Pathogenic	criteria provided, single submitter
1699972	NM_006208.3(ENPP1):c.208A>T (p.Lys70Ter)	ENPP1	Pathogenic	criteria provided, single submitter
1699973	NM_006208.3(ENPP1):c.2192del (p.Asn731fs)	ENPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
1699974	NM_006208.3(ENPP1):c.2300del (p.Gln767fs)	ENPP1	Pathogenic	criteria provided, single submitter
1699975	NM_006208.3(ENPP1):c.2664del (p.Ile889fs)	ENPP1	Pathogenic	criteria provided, single submitter
2584779	NM_006208.3(ENPP1):c.2230+5G>A	ENPP1	Pathogenic	no assertion criteria provided
282087	NM_006208.3(ENPP1):c.1756G>A (p.Gly586Arg)	ENPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29842	NM_006208.3(ENPP1):c.913C>A (p.Pro305Thr)	ENPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
29843	NM_006208.3(ENPP1):c.1612G>C (p.Asp538His)	ENPP1	Pathogenic	no assertion criteria provided
2991390	NM_006208.3(ENPP1):c.2631G>A (p.Trp877Ter)	ENPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3064553	NM_006208.3(ENPP1):c.2230+1G>A	ENPP1	Pathogenic	criteria provided, single submitter
3593055	NM_006208.3(ENPP1):c.313+1G>A	ENPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 5 · 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
ENPP1	Definitive	Autosomal recessive	arterial calcification, generalized, of infancy, 1	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ENPP1	Orphanet:289176	Autosomal recessive hypophosphatemic rickets
ENPP1	Orphanet:324561	Hypopigmentation-punctate palmoplantar keratoderma syndrome
ENPP1	Orphanet:51608	Generalized arterial calcification of infancy
ENPP1	Orphanet:758	Pseudoxanthoma elasticum
ZNF292	Orphanet:528084	Non-specific syndromic intellectual disability

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
ENPP1	HGNC:3356	ENSG00000197594	P22413	Ectonucleotide pyrophosphatase/phosphodiesterase family member 1	gencc,clinvar
ZNF292	HGNC:18410	ENSG00000188994	O60281	Zinc finger protein 292	clinvar
ENPP3	HGNC:3358	ENSG00000154269	O14638	Ectonucleotide pyrophosphatase/phosphodiesterase family member 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ENPP1	Ectonucleotide pyrophosphatase/phosphodiesterase family member 1	Nucleotide pyrophosphatase that generates diphosphate (PPi) and functions in bone mineralization and soft tissue calcification by regulating pyrophosphate levels.
ZNF292	Zinc finger protein 292	May be involved in transcriptional regulation.
ENPP3	Ectonucleotide pyrophosphatase/phosphodiesterase family member 3	Hydrolase that metabolizes extracellular nucleotides, including ATP, GTP, UTP and CTP.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 0 · Druggable fraction: 0.67

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	2	55.9×	8e-04
Transcription factor	1	2.8×	0.321

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ENPP1	Phosphatase	yes	3.6.1.9	Somatomedin_B_dom, Endo_G_ENPP1-like_dom, Phosphodiest/P_Trfase
ZNF292	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GH-ZnFinger_Regulators
ENPP3	Phosphatase	yes	3.6.1.9	Somatomedin_B_dom, Endo_G_ENPP1-like_dom, Phosphodiest/P_Trfase

Expression context

Cohort genes with no expression data: 0.

3 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
cartilage tissue	1
decidua	1
tibia	1
calcaneal tendon	1
caput epididymis	1
cauda epididymis	1
ileal mucosa	1
jejunal mucosa	1
seminal vesicle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ENPP1	227	ubiquitous	marker	tibia, decidua, cartilage tissue
ZNF292	293	ubiquitous	marker	caput epididymis, calcaneal tendon, cauda epididymis
ENPP3	181	tissue_specific	marker	jejunal mucosa, ileal mucosa, seminal vesicle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ENPP1	1,911
ZNF292	1,657
ENPP3	1,152

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ENPP1	P22413	7
ENPP3	O14638	3
ZNF292	O60281	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 3 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
Vitamin B5 (pantothenate) metabolism	2	761.3×	3e-06	ENPP1, ENPP3
Vitamin B2 (riboflavin) metabolism	1	815.7×	0.001	ENPP1

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
nucleoside triphosphate catabolic process	2	2246.9×	6e-06	ENPP1, ENPP3
phosphate ion homeostasis	2	702.2×	3e-05	ENPP1, ENPP3
phosphate-containing compound metabolic process	2	660.9×	3e-05	ENPP1, ENPP3
ATP metabolic process	2	312.1×	1e-04	ENPP1, ENPP3
obsolete negative regulation of hh target transcription factor activity	1	5617.3×	0.001	ENPP1
basophil activation involved in immune response	1	2808.7×	0.002	ENPP3
inorganic diphosphate transport	1	2808.7×	0.002	ENPP1
negative regulation of mast cell proliferation	1	1872.4×	0.002	ENPP3
pyrimidine nucleotide metabolic process	1	1404.3×	0.002	ENPP3
negative regulation of mast cell activation involved in immune response	1	1404.3×	0.002	ENPP3
nucleic acid metabolic process	1	936.2×	0.003	ENPP1
negative regulation of glycogen biosynthetic process	1	702.2×	0.004	ENPP1
intracellular phosphate ion homeostasis	1	510.7×	0.005	ENPP1
negative regulation of D-glucose import across plasma membrane	1	401.2×	0.005	ENPP1
3’-phosphoadenosine 5’-phosphosulfate metabolic process	1	374.5×	0.005	ENPP1
negative regulation of cGAS/STING signaling pathway	1	351.1×	0.005	ENPP3
response to ATP	1	330.4×	0.005	ENPP1
negative regulation of bone mineralization	1	312.1×	0.005	ENPP1
melanocyte differentiation	1	267.5×	0.006	ENPP1
regulation of bone mineralization	1	244.2×	0.006	ENPP1
negative regulation of insulin receptor signaling pathway	1	124.8×	0.011	ENPP1
generation of precursor metabolites and energy	1	114.6×	0.012	ENPP1
negative regulation of fat cell differentiation	1	104.0×	0.012	ENPP1
bone mineralization	1	90.6×	0.014	ENPP1
cellular response to insulin stimulus	1	56.7×	0.021	ENPP1
negative regulation of cell growth	1	48.0×	0.024	ENPP1
negative regulation of inflammatory response	1	45.7×	0.024	ENPP3
gene expression	1	26.6×	0.040	ENPP1
immune response	1	15.7×	0.065	ENPP1
regulation of transcription by RNA polymerase II	1	3.9×	0.236	ZNF292

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 1

Druggability breadth: 2 of 3 evidence-associated genes (67%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ENPP1	1	3
ENPP3	1	3
ZNF292	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SURAMIN	3	ENPP1, ENPP3

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
ENPP1	167	Binding:154, ADMET:13
ENPP3	58	Binding:51, ADMET:7

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ENPP1	3.6.1.9	nucleotide diphosphatase
ENPP3	3.6.1.9	nucleotide diphosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
ENPP1	167

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

1 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)
SURAMIN	3	ENPP1, ENPP3

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	2	ENPP1, ENPP3
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	ZNF292

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)
ZNF292	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	1
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07473973	PHASE3	RECRUITING	ENERGY 2: Evaluation of the Efficacy and Safety of INZ-701 in Infants With ENPP1 Deficiency
NCT06739980	PHASE2	WITHDRAWN	The ENABLE Study: Safety and Efficacy Study of INZ-701 in Patients With ENPP1 Deficiency

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
INZ-701	3	2