Hypophosphatemic rickets, autosomal recessive, 2

Summary

Hypophosphatemic rickets, autosomal recessive, 2 (MONDO:0013219) is a disease caused by ENPP1 (GenCC Strong), with 1 cohort gene and 2 clinical trials. Top therapeutic interventions include inz-701.

At a glance

• Causal gene: ENPP1 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 310
• Clinical trials: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hypophosphatemic rickets, autosomal recessive, 2
Mondo ID	MONDO:0013219
MeSH	C567647
OMIM	613312
UMLS	C2750078
MedGen	442380
GARD	0018417
NORD	2000
Is cancer (heuristic)	no

Also known as: ARHR2 · autosomal recessive hypophosphatemic rickets caused by mutation in ENPP1 · Autosomal Recessive Hypophosphatemic Rickets Type 2 · ENPP1 autosomal recessive hypophosphatemic rickets · hypophosphatemic rickets, autosomal recessive, 2 · hypophosphatemic rickets, autosomal recessive, type 2

Data availability: 310 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary hypophosphatemic rickets › autosomal recessive hypophosphatemic rickets › hypophosphatemic rickets, autosomal recessive, 2

Related subtypes (1): hypophosphatemic rickets, autosomal recessive, 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

310 retrieved; paginated sample, class counts are floors:

157 uncertain significance, 56 benign, 38 conflicting classifications of pathogenicity, 18 pathogenic, 17 likely benign, 14 likely pathogenic, 5 benign/likely benign, 5 pathogenic/likely pathogenic

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
13593	NM_006208.3(ENPP1):c.2444+702_*868del	ENPP1	Pathogenic	criteria provided, single submitter
13594	NM_006208.3(ENPP1):c.797G>T (p.Gly266Val)	ENPP1	Pathogenic	criteria provided, single submitter
13595	NM_006208.3(ENPP1):c.2248dup (p.Ser750fs)	ENPP1	Pathogenic	criteria provided, single submitter
13596	NM_006208.3(ENPP1):c.2702A>C (p.Tyr901Ser)	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
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
1699963	NM_006208.3(ENPP1):c.1273+1G>A	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
1699973	NM_006208.3(ENPP1):c.2192del (p.Asn731fs)	ENPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
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
2991390	NM_006208.3(ENPP1):c.2631G>A (p.Trp877Ter)	ENPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3593055	NM_006208.3(ENPP1):c.313+1G>A	ENPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3593077	NM_006208.3(ENPP1):c.1426C>T (p.Arg476Ter)	ENPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
3593097	NM_006208.3(ENPP1):c.2375A>G (p.Asn792Ser)	ENPP1	Pathogenic	criteria provided, multiple submitters, no conflicts
444060	NM_006208.3(ENPP1):c.430+1del	ENPP1	Pathogenic	criteria provided, single submitter
547983	NM_006208.3(ENPP1):c.1441C>T (p.Arg481Trp)	ENPP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2686042	NM_006208.3(ENPP1):c.195_197delinsAA (p.Ala66fs)	ENPP1	Likely pathogenic	criteria provided, single submitter
2686043	NM_006208.3(ENPP1):c.1724-1G>T	ENPP1	Likely pathogenic	criteria provided, single submitter
3593042	NM_006208.3(ENPP1):c.2T>G (p.Met1Arg)	ENPP1	Likely pathogenic	criteria provided, single submitter
3593043	NM_006208.3(ENPP1):c.6del (p.Glu2fs)	ENPP1	Likely pathogenic	criteria provided, single submitter
3593047	NM_006208.3(ENPP1):c.124del (p.Asp42fs)	ENPP1	Likely pathogenic	criteria provided, single submitter
3593067	NM_006208.3(ENPP1):c.769_770del (p.Phe257fs)	ENPP1	Likely pathogenic	criteria provided, single submitter
3593080	NM_006208.3(ENPP1):c.1709A>G (p.Tyr570Cys)	ENPP1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · 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
ENPP1	Strong	Autosomal recessive	hypophosphatemic rickets, autosomal recessive, 2	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

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
ENPP1	HGNC:3356	ENSG00000197594	P22413	Ectonucleotide pyrophosphatase/phosphodiesterase family member 1	gencc,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.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Phosphatase	1	83.9×	0.012

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

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
cartilage tissue	1
decidua	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ENPP1	227	ubiquitous	marker	tibia, decidua, cartilage tissue

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ENPP1	1,911

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ENPP1	P22413	7

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
Vitamin B2 (riboflavin) metabolism	1	1631.4×	0.001	ENPP1
Vitamin B5 (pantothenate) metabolism	1	761.3×	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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
obsolete negative regulation of hh target transcription factor activity	1	16852.0×	0.001	ENPP1
inorganic diphosphate transport	1	8426.0×	0.001	ENPP1
nucleoside triphosphate catabolic process	1	3370.4×	0.002	ENPP1
nucleic acid metabolic process	1	2808.7×	0.002	ENPP1
negative regulation of glycogen biosynthetic process	1	2106.5×	0.002	ENPP1
intracellular phosphate ion homeostasis	1	1532.0×	0.002	ENPP1
negative regulation of D-glucose import across plasma membrane	1	1203.7×	0.002	ENPP1
3’-phosphoadenosine 5’-phosphosulfate metabolic process	1	1123.5×	0.002	ENPP1
phosphate ion homeostasis	1	1053.2×	0.002	ENPP1
phosphate-containing compound metabolic process	1	991.3×	0.002	ENPP1
response to ATP	1	991.3×	0.002	ENPP1
negative regulation of bone mineralization	1	936.2×	0.002	ENPP1
melanocyte differentiation	1	802.5×	0.002	ENPP1
regulation of bone mineralization	1	732.7×	0.002	ENPP1
ATP metabolic process	1	468.1×	0.003	ENPP1
negative regulation of insulin receptor signaling pathway	1	374.5×	0.004	ENPP1
generation of precursor metabolites and energy	1	343.9×	0.004	ENPP1
negative regulation of fat cell differentiation	1	312.1×	0.004	ENPP1
bone mineralization	1	271.8×	0.004	ENPP1
cellular response to insulin stimulus	1	170.2×	0.007	ENPP1
negative regulation of cell growth	1	144.0×	0.008	ENPP1
gene expression	1	79.9×	0.013	ENPP1
immune response	1	47.1×	0.021	ENPP1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · 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).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ENPP1	1	3

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SURAMIN	3	ENPP1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ENPP1	167	Binding:154, ADMET:13

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ENPP1	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: 1; 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

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	1	ENPP1
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: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06462547	PHASE2	RECRUITING	ADAPT Study: Long-term Safety Study of INZ-701 in Patients With ENPP1 Deficiency and ABCC6 Deficiency
NCT04372446	Not specified	COMPLETED	Understanding the Spectrum of ENPP1 Deficiency and Acute ABCC6 Deficiency

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
INZ-701	3	1