Osteopetrosis

Summary

Osteopetrosis (MONDO:0017198) is a disease (an umbrella term covering 11 Mondo subtypes) caused by RASGRP2 (GenCC Strong), with 10 cohort genes and 18 clinical trials. Top therapeutic interventions include busulfan, interferon gamma-1b, and alemtuzumab.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: RASGRP2 (GenCC Strong)
• Umbrella term: 11 Mondo subtypes
• Cohort genes: 10
• ClinVar variants: 166
• Clinical trials: 18

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 100 000	1	Europe	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	osteopetrosis
Mondo ID	MONDO:0017198
MeSH	D010022
Orphanet	2781
DOID	DOID:13533
ICD-10-CM	Q78.2
ICD-11	1498426606
NCIT	C26840
SNOMED CT	1926006
UMLS	C0029454
MedGen	18223
GARD	0004155
MedDRA	10031280
NORD	1538
Is cancer (heuristic)	no

Also known as: Albers-Schoenberg disease · Albers-Schonberg disease · marble bone disease · marble bones · osteopetroses · osteopetrosis · osteopetrosis (disease) · osteosclerosis fragilis

Data availability: 166 ClinVar variants · 2 GenCC gene-disease records · 1 HPO phenotype.

Disease family

An umbrella term covering 11 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › skeletal dysplasia › osteopetrosis

Related subtypes (118): osteochondrodysplasia, diaphyseal medullary stenosis-bone malignancy syndrome, fibular aplasia-ectrodactyly syndrome, cerebrocostomandibular syndrome, cleidorhizomelic syndrome, dyschondrosteosis-nephritis syndrome, dysplasia epiphysealis hemimelica, carpotarsal osteochondromatosis, Camurati-Engelmann disease, genochondromatosis, autosomal dominant osteosclerosis, Worth type, coxopodopatellar syndrome, Lenz-Majewski hyperostotic dwarfism, delayed membranous cranial ossification, metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome, oculodentodigital dysplasia, Ollier disease, osteoglophonic dysplasia, parietal foramina with cleidocranial dysplasia, chondromalacia patellae, Currarino triad, Proteus syndrome, brachydactyly-elbow wrist dysplasia syndrome, tricho-dento-osseous syndrome, bird headed-dwarfism, Montreal type, Yunis-Varon syndrome, split hand-foot malformation 1 with sensorineural hearing loss, ghosal hematodiaphyseal dysplasia, hyperostosis corticalis generalisata, Larsen-like syndrome, B3GAT3 type, mesomelic dwarfism-cleft palate-camptodactyly syndrome, metaphyseal acroscyphodysplasia, metaphyseal dysostosis-intellectual disability-conductive deafness syndrome, familial osteodysplasia, Anderson type, pseudodiastrophic dysplasia, rhizomelic syndrome, Urbach type, Richieri Costa-Pereira syndrome, craniometadiaphyseal dysplasia, wormian bone type, Weaver syndrome, SHOX-related short stature, craniofrontonasal syndrome, Eiken syndrome, 2q37 microdeletion syndrome, skeletal dysplasia-epilepsy-short stature syndrome, rhizomelic dysplasia, Patterson-Lowry type, pelvic dysplasia-arthrogryposis of lower limbs syndrome, Marshall-Smith syndrome, baby rattle pelvis dysplasia, metaphyseal dysplasia, Braun-Tinschert type, genitopatellar syndrome, osteofibrous dysplasia, Larsen-like osseous dysplasia-short stature syndrome, pancreatic insufficiency-anemia-hyperostosis syndrome, microcephalic primordial dwarfism due to ZNF335 deficiency, Hartsfield-Bixler-Demyer syndrome, colobomatous microphthalmia-rhizomelic dysplasia syndrome, Tatton-Brown-Rahman overgrowth syndrome, tall stature-scoliosis-macrodactyly of the great toes syndrome, Catel-Manzke syndrome, cognitive impairment - coarse facies - heart defects - obesity - pulmonary involvement - short stature - skeletal dysplasia syndrome, skeletal overgrowth-craniofacial dysmorphism-hyperelastic skin-white matter lesions syndrome, complex lethal osteochondrodysplasia, amniotic band syndrome, metaphyseal anadysplasia, syndromic craniosynostosis, thin ribs-tubular bones-dysmorphism syndrome, dysplasia of head of femur, Meyer type, epimetaphyseal skeletal dysplasia, melorheostosis with osteopoikilosis, Cole-Carpenter syndrome, spondylometaphyseal dysplasia, omodysplasia, Bruck syndrome, congenital absence of upper arm and forearm with hand present, congenital absence of thigh and lower leg with foot present, congenital absence of both forearm and hand, congenital absence of both lower leg and foot, acheiria, apodia, chondroectodermal dysplasia with night blindness, TRPV4-related bone disorder, adactyly of foot, short stature-advanced bone age-early-onset osteoarthritis syndrome, McCune-Albright syndrome, parietal foramina, Sotos syndrome, dysspondyloenchondromatosis, autosomal recessive cutis laxa type 2, FGFR3-related chondrodysplasia, filamin-related bone disorder, short rib dysplasia, spondylodysplastic dysplasia, acromelic dysplasia, bent bone dysplasia, chondrodysplasia punctata, primary osteolysis, non-syndromic limb reduction defect, Robinow syndrome, synpolydactyly, acrocoxomesomelic dysplasia, bone dysplasia Moore type, bone dysplasia corpus callosum agenesis, type 2 collagenopathy, LRP5-related primary osteoporosis, SLC26A2-related skeletal dysplasia, COMP-related skeletal dysplasia, primordial dwarfism and slender bone disorder, polydactyly-syndactyly-triphalangism, lysosomal storage disease with skeletal involvement, abnormal mineralization disorder, calvarial doughnut lesions with bone fragility and spondylometaphyseal dysplasia, de la Chapelle dysplasia, mesomelic dysplasia-digital anomalies-intellectual disability syndrome, proximal femoral focal deficiency, rhizomelic dysplasia, Ain-Naz type, craniotubular dysplasia, Ikegawa type, TRIP11-related skeletal dysplasia, FAM111A-related skeletal dysplasia

Subtypes (11): melorheostosis, osteomesopyknosis, dysosteosclerosis, pycnodysostosis, anhidrotic ectodermal dysplasia-immunodeficiency-osteopetrosis-lymphedema syndrome, osteopathia striata with cranial sclerosis, infantile osteopetrosis with neuroaxonal dysplasia, osteosclerotic metaphyseal dysplasia, autosomal recessive osteopetrosis, autosomal dominant osteopetrosis, early-onset calcifying leukoencephalopathy-skeletal dysplasia

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

166 retrieved; paginated sample, class counts are floors:

56 uncertain significance, 49 conflicting classifications of pathogenicity, 33 benign, 7 pathogenic/likely pathogenic, 6 pathogenic, 5 benign/likely benign, 5 likely pathogenic, 5 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
288909	NM_000067.3(CA2):c.232+1G>A	CA2	Pathogenic	criteria provided, multiple submitters, no conflicts
1217234	NM_006019.4(TCIRG1):c.504-6C>A	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
189246	NM_006019.4(TCIRG1):c.1674-1G>A	TCIRG1	Pathogenic	criteria provided, multiple submitters, no conflicts
2579884	NM_006019.4(TCIRG1):c.2324C>G (p.Pro775Arg)	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3629877	NC_000011.9:g.(67812570_67814899)_(67815440_67816345)del	TCIRG1	Pathogenic	criteria provided, single submitter
5463	NM_006019.4(TCIRG1):c.1213G>A (p.Gly405Arg)	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
551284	NM_006019.4(TCIRG1):c.2008C>T (p.Arg670Ter)	TCIRG1	Pathogenic	criteria provided, multiple submitters, no conflicts
551450	NM_006019.4(TCIRG1):c.242del (p.Pro81fs)	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
552720	NM_006019.4(TCIRG1):c.1118del (p.Gly373fs)	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
555504	NM_006019.4(TCIRG1):c.1024G>T (p.Glu342Ter)	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
658416	NM_006019.4(TCIRG1):c.2066G>A (p.Trp689Ter)	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
830066	NM_006019.4(TCIRG1):c.1114C>T (p.Gln372Ter)	TCIRG1	Pathogenic	criteria provided, multiple submitters, no conflicts
852649	NM_006019.4(TCIRG1):c.1554+2T>A	TCIRG1	Pathogenic	criteria provided, multiple submitters, no conflicts
4526463	NM_005252.4(FOS):c.463C>T (p.Arg155Cys)	FOS	Likely pathogenic	criteria provided, single submitter
2501201	NM_014028.4(OSTM1):c.255_256delinsC (p.Glu86fs)	OSTM1	Likely pathogenic	criteria provided, single submitter
3384115	NM_013322.3(SNX10):c.112-1G>C	SNX10	Likely pathogenic	criteria provided, single submitter
3769171	NM_006019.4(TCIRG1):c.1228G>C (p.Gly410Arg)	TCIRG1	Likely pathogenic	criteria provided, single submitter
975009	NM_006019.4(TCIRG1):c.1549G>A (p.Asp517Asn)	TCIRG1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1013550	NM_001001548.3(CD36):c.1144C>T (p.Gln382Ter)	CD36	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
317938	NM_001287.6(CLCN7):c.*241G>A	CLCN7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
317942	NM_001287.6(CLCN7):c.2331+14G>A	CLCN7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
317943	NM_001287.6(CLCN7):c.2214C>T (p.Ser738=)	CLCN7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
317944	NM_001287.6(CLCN7):c.2154C>T (p.Phe718=)	CLCN7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
317948	NM_001287.6(CLCN7):c.1354-7C>T	CLCN7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
317949	NM_001287.6(CLCN7):c.1272G>A (p.Thr424=)	CLCN7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
317951	NM_001287.6(CLCN7):c.1098+15C>T	CLCN7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
317952	NM_001287.6(CLCN7):c.1098+11C>G	CLCN7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
317955	NM_001287.6(CLCN7):c.777C>T (p.Ala259=)	CLCN7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
317959	NM_001287.6(CLCN7):c.564C>T (p.Leu188=)	CLCN7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
317960	NM_001287.6(CLCN7):c.352-11G>A	CLCN7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 13 · 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
RASGRP2	Strong	Autosomal recessive	osteopetrosis	5
CCDC120	Limited	X-linked	osteopetrosis

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RASGRP2	Orphanet:420566	Bleeding disorder due to CalDAG-GEFI deficiency
TCIRG1	Orphanet:1782	Dysosteosclerosis
TCIRG1	Orphanet:210110	Intermediate osteopetrosis
TCIRG1	Orphanet:486	Autosomal dominant severe congenital neutropenia
TCIRG1	Orphanet:667	Autosomal recessive malignant osteopetrosis
CA2	Orphanet:2785	Osteopetrosis with renal tubular acidosis
SNX10	Orphanet:667	Autosomal recessive malignant osteopetrosis
NUP160	Orphanet:656	Hereditary steroid-resistant nephrotic syndrome
CLCN7	Orphanet:210110	Intermediate osteopetrosis
CLCN7	Orphanet:53	Albers-Schönberg osteopetrosis
CLCN7	Orphanet:667	Autosomal recessive malignant osteopetrosis
OSTM1	Orphanet:85179	Infantile osteopetrosis with neuroaxonal dysplasia
FOS	Orphanet:675396	Epithelioid hemangioma

Cohort genes → proteins

10 cohort genes, 10 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	10

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CCDC120	HGNC:28910	ENSG00000147144	Q96HB5	Coiled-coil domain-containing protein 120	gencc
RASGRP2	HGNC:9879	ENSG00000068831	Q7LDG7	RAS guanyl-releasing protein 2	gencc
TCIRG1	HGNC:11647	ENSG00000110719	Q13488	V-type proton ATPase 116 kDa subunit a 3	clinvar
CA2	HGNC:1373	ENSG00000104267	P00918	Carbonic anhydrase 2	clinvar
SNX10	HGNC:14974	ENSG00000086300	Q9Y5X0	Sorting nexin-10	clinvar
CD36	HGNC:1663	ENSG00000135218	P16671	Platelet glycoprotein 4	clinvar
NUP160	HGNC:18017	ENSG00000030066	Q12769	Nuclear pore complex protein Nup160	clinvar
CLCN7	HGNC:2025	ENSG00000103249	P51798	H(+)/Cl(-) exchange transporter 7	clinvar
OSTM1	HGNC:21652	ENSG00000081087	Q86WC4	Osteopetrosis-associated transmembrane protein 1	clinvar
FOS	HGNC:3796	ENSG00000170345	P01100	Protein c-Fos	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CCDC120	Coiled-coil domain-containing protein 120	Centriolar protein required for centriole subdistal appendage assembly and microtubule anchoring in interphase cells.
RASGRP2	RAS guanyl-releasing protein 2	Functions as a calcium- and DAG-regulated nucleotide exchange factor specifically activating Rap through the exchange of bound GDP for GTP.
TCIRG1	V-type proton ATPase 116 kDa subunit a 3	Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.
CA2	Carbonic anhydrase 2	Catalyzes the reversible hydration of carbon dioxide.
SNX10	Sorting nexin-10	Probable phosphoinositide-binding protein involved in protein sorting and membrane trafficking in endosomes.
CD36	Platelet glycoprotein 4	Multifunctional glycoprotein that acts as a receptor for a broad range of ligands.
NUP160	Nuclear pore complex protein Nup160	Functions as a component of the nuclear pore complex (NPC).
CLCN7	H(+)/Cl(-) exchange transporter 7	Slowly voltage-gated channel mediating the exchange of chloride ions against protons.
OSTM1	Osteopetrosis-associated transmembrane protein 1	Required for osteoclast and melanocyte maturation and function.
FOS	Protein c-Fos	Nuclear phosphoprotein which forms a tight but non-covalently linked complex with the JUN/AP-1 transcription factor.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 9 · Druggable fraction: 0.1

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	9	1.6×	0.052
Enzyme (other)	1	1.2×	0.581

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CCDC120	Other/Unknown	no		CUPID, CCDC120/INAVA
RASGRP2	Other/Unknown	no		Ras-like_Gua-exchang_fac_N, RASGEF_cat_dom, EF_hand_dom
TCIRG1	Other/Unknown	no		V-ATPase_116kDa_su, V-type_ATPase_116kDa_su_euka
CA2	Enzyme (other)	yes	4.2.1.1	CA_dom, Carbonic_anhydrase_a-class_CS, Carbonic_anhydrase_a-class
SNX10	Other/Unknown	no		PX_dom, PX_dom_sf, SNX10/11
CD36	Other/Unknown	no		CD36_fam, CD36/SCARB1/SNMP1
NUP160	Other/Unknown	no		Nucleoporin_Nup160, TPR_NUP160_M, TPR_NUP160_C
CLCN7	Other/Unknown	no		CBS_dom, ClC, CIC-7
OSTM1	Other/Unknown	no		Osteopetrosis-assoc_TM_1
FOS	Other/Unknown	no		AP-1, bZIP, bZIP_sf

Expression context

Cohort genes with no expression data: 0.

10 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)	10
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	2
monocyte	2
spleen	2
esophagus mucosa	1
lower esophagus mucosa	1
skin of leg	1
blood	1
colonic mucosa	1
mucosa of sigmoid colon	1
mucosa of transverse colon	1
lateral nuclear group of thalamus	1
substantia nigra pars compacta	1
substantia nigra pars reticulata	1
adipose tissue of abdominal region	1
omental fat pad	1
mucosa of paranasal sinus	1
oocyte	1
secondary oocyte	1
left adrenal gland cortex	1
metanephros cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CCDC120	162	ubiquitous	marker	lower esophagus mucosa, esophagus mucosa, skin of leg
RASGRP2	253	broad	marker	granulocyte, spleen, monocyte
TCIRG1	148	ubiquitous	marker	granulocyte, blood, spleen
CA2	275	ubiquitous	marker	colonic mucosa, mucosa of sigmoid colon, mucosa of transverse colon
SNX10	252	ubiquitous	marker	lateral nuclear group of thalamus, substantia nigra pars compacta, substantia nigra pars reticulata
CD36	252	broad	marker	adipose tissue of abdominal region, omental fat pad, monocyte
NUP160	278	ubiquitous	marker	oocyte, mucosa of paranasal sinus, secondary oocyte
CLCN7	296	ubiquitous	marker	metanephros cortex, right adrenal gland cortex, left adrenal gland cortex
OSTM1	287	ubiquitous	marker	choroid plexus epithelium, adrenal tissue, popliteal artery
FOS	294	ubiquitous	marker	mucosa of stomach, upper leg skin, gall bladder

Protein interactions among cohort

Intra-cohort edges: 9.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FOS	8,853
CD36	5,268
CA2	2,454
NUP160	2,086
CLCN7	1,991
TCIRG1	1,931
RASGRP2	1,688
CCDC120	1,218
OSTM1	1,108
SNX10	820

Intra-cohort edges

A	B	Sources
CA2	CLCN7	string_interaction
CA2	OSTM1	string_interaction
CA2	TCIRG1	string_interaction
CLCN7	OSTM1	biogrid_interaction, intact, string_interaction
CLCN7	SNX10	string_interaction
CLCN7	TCIRG1	string_interaction
OSTM1	SNX10	string_interaction
OSTM1	TCIRG1	string_interaction
SNX10	TCIRG1	string_interaction

Structural data

PDB: 8 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CA2	P00918	1,241
CLCN7	P51798	9
OSTM1	Q86WC4	9
NUP160	Q12769	4
SNX10	Q9Y5X0	3
FOS	P01100	3
RASGRP2	Q7LDG7	2
CD36	P16671	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TCIRG1	Q13488	83.52
CCDC120	Q96HB5	56.34

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 111. Enrichment computed across 10 evidence-associated genes (8 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 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Free fatty acids regulate insulin secretion	1	475.8×	0.068	CD36
Intracellular metabolism of fatty acids regulates insulin secretion	1	475.8×	0.068	CD36
Cross-presentation of particulate exogenous antigens (phagosomes)	1	178.4×	0.068	CD36
Erythrocytes take up oxygen and release carbon dioxide	1	158.6×	0.068	CA2
O2/CO2 exchange in erythrocytes	1	158.6×	0.068	CA2
Activation of the AP-1 family of transcription factors	1	142.8×	0.068	FOS
Scavenging by Class B Receptors	1	129.8×	0.068	CD36
Reversible hydration of carbon dioxide	1	119.0×	0.068	CA2
Erythrocytes take up carbon dioxide and release oxygen	1	109.8×	0.068	CA2
Diseases of Immune System	1	109.8×	0.068	CD36
Diseases associated with the TLR signaling cascade	1	109.8×	0.068	CD36
Rap1 signalling	1	89.2×	0.068	RASGRP2
MyD88 deficiency (TLR2/4)	1	75.1×	0.068	CD36
IRAK4 deficiency (TLR2/4)	1	71.4×	0.068	CD36
Binding and Uptake of Ligands by Scavenger Receptors	1	68.0×	0.068	CD36
Regulation of TLR by endogenous ligand	1	62.1×	0.068	CD36
NPAS4 regulates expression of target genes	1	62.1×	0.068	FOS
Effects of PIP2 hydrolysis	1	57.1×	0.068	RASGRP2
Estrogen-dependent nuclear events downstream of ESR-membrane signaling	1	54.9×	0.068	FOS
Integrin signaling	1	52.9×	0.068	RASGRP2
Postmitotic nuclear pore complex (NPC) reformation	1	51.0×	0.068	NUP160
IPs transport between nucleus and cytosol	1	47.6×	0.068	NUP160
IP3 and IP4 transport between cytosol and nucleus	1	47.6×	0.068	NUP160
IP6 and IP7 transport between cytosol and nucleus	1	47.6×	0.068	NUP160
Insulin receptor recycling	1	47.6×	0.068	TCIRG1
Transferrin endocytosis and recycling	1	46.0×	0.068	TCIRG1
Transport of Ribonucleoproteins into the Host Nucleus	1	44.6×	0.068	NUP160
Regulation of Glucokinase by Glucokinase Regulatory Protein	1	44.6×	0.068	NUP160
Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)	1	44.6×	0.068	NUP160
NEP/NS2 Interacts with the Cellular Export Machinery	1	43.3×	0.068	NUP160

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
osteoclast differentiation	4	137.6×	3e-06	TCIRG1, SNX10, OSTM1, FOS
tooth eruption	2	674.1×	3e-04	TCIRG1, SNX10
transepithelial chloride transport	2	374.5×	7e-04	CLCN7, OSTM1
bone resorption	2	116.2×	0.006	TCIRG1, SNX10
response to silver ion	1	1685.2×	0.010	TCIRG1
short-chain fatty acid transport	1	1685.2×	0.010	CD36
medium-term memory	1	1685.2×	0.010	FOS
dentin mineralization	1	1685.2×	0.010	TCIRG1
oxidised low-density lipoprotein particle clearance	1	1685.2×	0.010	CD36
mononuclear cell differentiation	1	1685.2×	0.010	FOS
cellular response to prolactin	1	1685.2×	0.010	FOS
protein catabolic process in the vacuole	1	842.6×	0.014	TCIRG1
memory T cell activation	1	842.6×	0.014	TCIRG1
response to forskolin	1	842.6×	0.014	FOS
positive regulation of blood microparticle formation	1	842.6×	0.014	CD36
positive regulation of dipeptide transmembrane transport	1	842.6×	0.014	CA2
cellular response to calcium ion	2	40.1×	0.014	FOS, RASGRP2
conditioned taste aversion	1	561.7×	0.015	FOS
regulation of proton transport	1	561.7×	0.015	TCIRG1
T-helper 1 cell activation	1	561.7×	0.015	TCIRG1
low-density lipoprotein particle mediated signaling	1	561.7×	0.015	CD36
response to linoleic acid	1	561.7×	0.015	CD36
regulation of action potential	1	561.7×	0.015	CD36
long-chain fatty acid import across plasma membrane	1	421.3×	0.015	CD36
regulation of lipopolysaccharide-mediated signaling pathway	1	421.3×	0.015	CD36
obsolete positive regulation of cellular pH reduction	1	421.3×	0.015	CA2
triglyceride transport	1	421.3×	0.015	CD36
plasma lipoprotein particle clearance	1	421.3×	0.015	CD36
cellular response to diacyl bacterial lipopeptide	1	421.3×	0.015	CD36
regulation of chloride transport	1	421.3×	0.015	CA2

Therapeutics

Drugs indicated for this disease

1 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
INTERFERON GAMMA-1B	Approved (phase 4)
Calcitriol	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Alemtuzumab, Busulfan, Clofarabine, Fludarabine Phosphate, Methotrexate.

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 8

Druggability breadth: 4 of 10 evidence-associated genes (40%) 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
CA2	CLOTRIMAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CA2	89	4
FOS	1	3
CCDC120	0	0
RASGRP2	0	0
TCIRG1	0	0
SNX10	0	0
CD36	0	0
NUP160	0	0
CLCN7	0	0
OSTM1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CLOTRIMAZOLE	4	CA2
TRICHLORMETHIAZIDE	4	CA2
CHLORTHALIDONE	4	CA2
BUMETANIDE	4	CA2
ACETAMINOPHEN	4	CA2
NITROUS ACID	4	CA2
CELECOXIB	4	CA2
ZINC CHLORIDE	4	CA2
ROSIGLITAZONE	4	CA2
SULFUR	4	CA2
LEVETIRACETAM	4	CA2
SODIUM BENZOATE	4	CA2
PHENOL	4	CA2
BENDROFLUMETHIAZIDE	4	CA2
DICHLORPHENAMIDE	4	CA2
ETHOXZOLAMIDE	4	CA2
METHAZOLAMIDE	4	CA2
ACETAZOLAMIDE	4	CA2
SULFANILAMIDE	4	CA2
VERALIPRIDE	4	CA2
DORZOLAMIDE	4	CA2
BRINZOLAMIDE	4	CA2
TOPIRAMATE	4	CA2
NILOTINIB	4	CA2
SULPIRIDE	4	CA2
BORTEZOMIB	4	CA2
SULTHIAME	4	CA2
FUROSEMIDE	4	CA2
INDAPAMIDE	4	CA2
TROGLITAZONE	4	CA2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CA2	1,226	Binding:1183, ADMET:35, Functional:8
FOS	11	Binding:10, Functional:1
CD36	6	Binding:5, Functional:1
NUP160	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CA2	4.2.1.1	carbonic anhydrase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CA2	1,226

Pharmacogenomics

Cohort genes with a PharmGKB record: 10; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

30 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)
CLOTRIMAZOLE	4	CA2
TRICHLORMETHIAZIDE	4	CA2
CHLORTHALIDONE	4	CA2
BUMETANIDE	4	CA2
ACETAMINOPHEN	4	CA2
NITROUS ACID	4	CA2
CELECOXIB	4	CA2
ZINC CHLORIDE	4	CA2
ROSIGLITAZONE	4	CA2
SULFUR	4	CA2
LEVETIRACETAM	4	CA2
SODIUM BENZOATE	4	CA2
PHENOL	4	CA2
BENDROFLUMETHIAZIDE	4	CA2
DICHLORPHENAMIDE	4	CA2
ETHOXZOLAMIDE	4	CA2
METHAZOLAMIDE	4	CA2
ACETAZOLAMIDE	4	CA2
SULFANILAMIDE	4	CA2
VERALIPRIDE	4	CA2
DORZOLAMIDE	4	CA2
BRINZOLAMIDE	4	CA2
TOPIRAMATE	4	CA2
NILOTINIB	4	CA2
SULPIRIDE	4	CA2
BORTEZOMIB	4	CA2
SULTHIAME	4	CA2
FUROSEMIDE	4	CA2
INDAPAMIDE	4	CA2
TROGLITAZONE	4	CA2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CA2
B	Phased (≥1) drug, not yet approved	1	FOS
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	8	CCDC120, RASGRP2, TCIRG1, SNX10, CD36, NUP160, CLCN7, OSTM1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
OSTM1	0	CA2
CCDC120	0	—
RASGRP2	0	—
TCIRG1	0	—
SNX10	0	—
CD36	6	—
NUP160	1	—
CLCN7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 18.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	6
PHASE2	4
PHASE2/PHASE3	3
PHASE1/PHASE2	3
PHASE3	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00004402	PHASE3	COMPLETED	Phase III Randomized Study of Interferon Gamma in Children With Severe, Congenital Osteopetrosis
NCT00775931	PHASE2/PHASE3	COMPLETED	Allogeneic Transplantation For Severe Osteopetrosis
NCT01019876	PHASE2/PHASE3	COMPLETED	Risk-Adapted Allogeneic Stem Cell Transplantation For Mixed Donor Chimerism In Patients With Non-Malignant Diseases
NCT01087398	PHASE2/PHASE3	UNKNOWN	Hematopoietic Stem Cell Transplantation for Malignant Infantile Osteopetrosis
NCT02171104	PHASE2	ACTIVE_NOT_RECRUITING	MT2013-31: Allo HCT for Metabolic Disorders and Severe Osteopetrosis
NCT03301168	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Study of Gene Modified Donor T-cells Following TCR Alpha Beta Positive Depleted Stem Cell Transplant
NCT00638820	PHASE2	TERMINATED	Reduced Intensity AlloTransplant For Osteopetrosis
NCT00730314	PHASE1/PHASE2	COMPLETED	Unrelated Hematopoietic Stem Cell Transplantation(HSCT) for Genetic Diseases of Blood Cells
NCT00968864	PHASE2	TERMINATED	T-cell Depleted Alternative Donor Transplantation
NCT02065869	PHASE1/PHASE2	TERMINATED	Safety Study of Gene Modified Donor T-cells Following TCRαβ+ Depleted Stem Cell Transplant
NCT02666768	PHASE2	COMPLETED	ACTIMMUNE in Intermediate Osteopetrosis
NCT00145886	PHASE1	TERMINATED	rhPTH Therapy for Low Turnover Bone Fragility
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT00043329	Not specified	COMPLETED	Post Marketing Surveillance Study of Actimmune in Patients With Severe, Malignant Osteopetrosis
NCT00145587	Not specified	TERMINATED	Stem Cell Transplantation for Children Affected With Osteopetrosis
NCT01199094	Not specified	COMPLETED	Clinical Assessment of Patients With High Bone Mass Due to Mutation in Lrp5
NCT01200017	Not specified	NO_LONGER_AVAILABLE	Expanded Access Protocol (EAP) Using the CliniMACS® Device for Pediatric Haplocompatible Donor Stem Cell Transplant
NCT06521580	Not specified	COMPLETED	Outcomes of Patients With Osteopetrosis Weight-bearing Bone Fractures

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
BUSULFAN	4	3
INTERFERON GAMMA-1B	4	3
ALEMTUZUMAB	4	2
FLUDARABINE PHOSPHATE	4	2
CALCITRIOL	4	1
CLOFARABINE	4	1
FLUDARABINE	3	1
RIMIDUCID	2	2
ANTILYMPHOCYTE IMMUNOGLOBULIN (HORSE)	2	1
CHEMBL290077	0	1