Autosomal recessive osteopetrosis

Summary

Autosomal recessive osteopetrosis (MONDO:0019026) is a disease (an umbrella term covering 10 Mondo subtypes) caused by TCIRG1 (GenCC Definitive), with 4 cohort genes and 1 clinical trial.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe)
• Causal gene: TCIRG1 (GenCC Definitive)
• Umbrella term: 10 Mondo subtypes
• Cohort genes: 4
• ClinVar variants: 2
• Phenotypes (HPO): 43
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000		Europe	Not yet validated
Prevalence at birth	1-9 / 1 000 000	0.75	Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

43 HPO clinical features (Orphanet curated; top 43 by frequency):

HPO ID	Term	Frequency
HP:0000238	Hydrocephalus	Very frequent (80-99%)
HP:0000256	Macrocephaly	Very frequent (80-99%)
HP:0000365	Hearing impairment	Very frequent (80-99%)
HP:0000388	Otitis media	Very frequent (80-99%)
HP:0000505	Visual impairment	Very frequent (80-99%)
HP:0000639	Nystagmus	Very frequent (80-99%)
HP:0000649	Abnormality of visual evoked potentials	Very frequent (80-99%)
HP:0000684	Delayed eruption of teeth	Very frequent (80-99%)
HP:0000772	Abnormal rib morphology	Very frequent (80-99%)
HP:0000774	Narrow chest	Very frequent (80-99%)
HP:0000944	Abnormal metaphysis morphology	Very frequent (80-99%)
HP:0000980	Pallor	Very frequent (80-99%)
HP:0001337	Tremor	Very frequent (80-99%)
HP:0001363	Craniosynostosis	Very frequent (80-99%)
HP:0001510	Growth delay	Very frequent (80-99%)
HP:0001744	Splenomegaly	Very frequent (80-99%)
HP:0001903	Anemia	Very frequent (80-99%)
HP:0001939	Abnormality of metabolism/homeostasis	Very frequent (80-99%)
HP:0002205	Recurrent respiratory infections	Very frequent (80-99%)
HP:0002240	Hepatomegaly	Very frequent (80-99%)
HP:0002257	Chronic rhinitis	Very frequent (80-99%)
HP:0002653	Bone pain	Very frequent (80-99%)
HP:0002716	Lymphadenopathy	Very frequent (80-99%)
HP:0002757	Recurrent fractures	Very frequent (80-99%)
HP:0004349	Reduced bone mineral density	Very frequent (80-99%)
HP:0004370	Abnormality of temperature regulation	Very frequent (80-99%)
HP:0005930	Abnormality of epiphysis morphology	Very frequent (80-99%)
HP:0006323	Premature loss of primary teeth	Very frequent (80-99%)
HP:0006487	Bowing of the long bones	Very frequent (80-99%)
HP:0007807	Optic nerve compression	Very frequent (80-99%)
HP:0008066	Abnormal blistering of the skin	Very frequent (80-99%)
HP:0010543	Opsoclonus	Very frequent (80-99%)
HP:0010719	Abnormality of hair texture	Very frequent (80-99%)
HP:0011002	Osteopetrosis	Very frequent (80-99%)
HP:0100022	Abnormality of movement	Very frequent (80-99%)
HP:0000978	Bruising susceptibility	Occasional (5-29%)
HP:0001641	Abnormal pulmonary valve morphology	Occasional (5-29%)
HP:0002092	Pulmonary arterial hypertension	Occasional (5-29%)
HP:0002104	Apnea	Occasional (5-29%)
HP:0002148	Hypophosphatemia	Occasional (5-29%)
HP:0002901	Hypocalcemia	Occasional (5-29%)
HP:0004415	Pulmonary artery stenosis	Occasional (5-29%)
HP:0006824	Cranial nerve paralysis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive osteopetrosis
Mondo ID	MONDO:0019026
OMIM	259700
Orphanet	667
NCIT	C129733
SNOMED CT	367489004
UMLS	C4272578
MedGen	1385510
GARD	0015012
Is cancer (heuristic)	no

Also known as: autosomal recessive malignant osteopetrosis · autosomal recessive osteopetrosis · autosomal recessive osteopetrosis (disease) · infantile malignant osteopetrosis · OPTB · osteopetrosis (disease), autosomal recessive

Data availability: 2 ClinVar variants · 5 GenCC gene-disease records · 7 cell lines.

Disease family

An umbrella term covering 10 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal recessive disease › autosomal recessive osteopetrosis

Related subtypes (218): immunodeficiency-centromeric instability-facial anomalies syndrome, hypercalcemia, infantile, Ochoa syndrome, autosomal recessive Ehlers-Danlos syndrome, vascular type, hydrolethalus syndrome, 3-M syndrome, isolated hyperchlorhidrosis, dacryocystitis-osteopoikilosis syndrome, Hutchinson-Gilford progeria syndrome, achalasia microcephaly syndrome, acrorenal syndrome, autosomal recessive, beta-ketothiolase deficiency, autosomal recessive Alport syndrome, Alstrom syndrome, microphthalmia with limb anomalies, camptodactyly-arthropathy-coxa vara-pericarditis syndrome, Behr syndrome, bifid nose, autosomal recessive, Bloom syndrome, Bowen-Conradi syndrome, camptodactyly with fibrous tissue hyperplasia and skeletal dysplasia, heart defects-limb shortening syndrome, autosomal recessive palmoplantar keratoderma and congenital alopecia, COFS syndrome, craniometaphyseal dysplasia, autosomal recessive, Fraser syndrome, cystic fibrosis, polycystic lipomembranous osteodysplasia with sclerosing leukoencephaly, persistent hyperplastic primary vitreous, autosomal recessive, Donnai-Barrow syndrome, Schöpf-Schulz-Passarge syndrome, cleft lip/palate-ectodermal dysplasia syndrome, Ellis-van Creveld syndrome, Wolcott-Rallison syndrome, autosomal recessive faciodigitogenital syndrome, acromesomelic dysplasia 2B, brittle cornea syndrome, triple-A syndrome, autosomal recessive humeroradial synostosis, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, hydrocephalus, nonsyndromic, autosomal recessive 1, autosomal recessive hydrocephalus due to congenital stenosis of aqueduct of Sylvius, hypertelorism, microtia, facial clefting syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, Vici syndrome, Johanson-Blizzard syndrome, autosomal recessive Kenny-Caffey syndrome, Papillon-Lefevre disease, Haim-Munk syndrome, Laurence-Moon syndrome, Donohue syndrome, lipase deficiency, combined, autosomal recessive familial Mediterranean fever, thiamine-responsive megaloblastic anemia syndrome, cartilage-hair hypoplasia, Nijmegen breakage syndrome, pseudo-TORCH syndrome, Galloway-Mowat syndrome, mulibrey nanism, myotonia congenita, autosomal recessive, Schwartz-Jampel syndrome, proteosome-associated autoinflammatory syndrome, Netherton syndrome, Niemann-Pick disease type A, oculodentodigital dysplasia, autosomal recessive, odonto-onycho-dermal dysplasia, autosomal recessive omodysplasia, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, phenylketonuria, Bjornstad syndrome, Laron syndrome, autosomal recessive polycystic kidney disease, autosomal recessive inherited pseudoxanthoma elasticum, autosomal recessive multiple pterygium syndrome, rapadilino syndrome, short-rib thoracic dysplasia 9 with or without polydactyly, autosomal recessive Robinow syndrome, Sjogren-Larsson syndrome, scapuloperoneal spinal muscular atrophy, autosomal recessive, spondyloepiphyseal dysplasia tarda, autosomal recessive, inherited threoninemia, Pendred syndrome, autosomal recessive spondylocostal dysostosis, Werner syndrome, ABCD syndrome, Naxos disease, autosomal recessive amelia, human HOXA1 syndromes, sickle cell disease, autosomal recessive proximal renal tubular acidosis, hyper-IgM syndrome type 2, temtamy preaxial brachydactyly syndrome, TH-deficient dopa-responsive dystonia, craniosynostosis syndrome, autosomal recessive, Niemann-Pick disease type B, skin fragility-woolly hair-palmoplantar keratoderma syndrome, CoQ-responsive OXPHOS deficiency, familial adenomatous polyposis 2, Pierson syndrome, palmoplantar keratoderma-XX sex reversal-predisposition to squamous cell carcinoma syndrome, cardiomyopathy-hypotonia-lactic acidosis syndrome, PHARC syndrome, Kahrizi syndrome, cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies, congenital prothrombin deficiency, immunodeficiency 31B, dyskeratosis congenita, autosomal recessive 2, dyskeratosis congenita, autosomal recessive 3, Nestor-Guillermo progeria syndrome, leukoencephalopathy with calcifications and cysts, mitochondrial pyruvate carrier deficiency, branched-chain keto acid dehydrogenase kinase deficiency, dyskeratosis congenita, autosomal recessive 5, hypohidrosis-enamel hypoplasia-palmoplantar keratoderma-intellectual disability syndrome, alacrima, achalasia, and intellectual disability syndrome, hyperlipoproteinemia, type 1D, microcephaly and chorioretinopathy 2, congenital stationary night blindness 1G, combined oxidative phosphorylation deficiency 29, hypermanganesemia with dystonia 2, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, gnb5-related intellectual disability-cardiac arrhythmia syndrome, autosomal recessive spastic paraplegia type 78, autosomal recessive limb-girdle muscular dystrophy, Bardet-Biedl syndrome, autosomal recessive cerebellar ataxia, neuronopathy, distal hereditary motor, autosomal recessive, UV-sensitive syndrome, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Cockayne syndrome, hyperphenylalaninemia due to tetrahydrobiopterin deficiency, leukoencephalopathy-palmoplantar keratoderma syndrome, autosomal recessive hypohidrotic ectodermal dysplasia, Warburg micro syndrome, autosomal recessive primary microcephaly, autosomal recessive progressive external ophthalmoplegia, Meier-Gorlin syndrome, autosomal recessive sideroblastic anemia, autosomal recessive intermediate Charcot-Marie-Tooth disease, Perrault syndrome, autosomal recessive hypophosphatemic rickets, de Barsy syndrome, leukocyte adhesion deficiency, Senior-Loken syndrome, autosomal recessive spastic ataxia, childhood-onset autosomal recessive myopathy with external ophthalmoplegia, autosomal recessive cerebral atrophy, GM3 synthase deficiency, autosomal recessive distal renal tubular acidosis, pigmentation defects-palmoplantar keratoderma-skin carcinoma syndrome, autosomal recessive brachyolmia, Aicardi-Goutieres syndrome, homocystinuria without methylmalonic aciduria, Niemann-Pick disease type C, nephronophthisis, peroxisome biogenesis disorder, congenital non-bullous ichthyosiform erythroderma, Seckel syndrome, Usher syndrome, autosomal recessive cutis laxa type 1, autosomal recessive cutis laxa type 2, hearing loss, autosomal recessive, microcephaly, growth restriction, and increased sister chromatid exchange 2, encephalopathy, progressive, early-onset, with brain edema and/or leukoencephalopathy, 1, congenital vertebral-cardiac-renal anomalies syndrome, hair defect with photosensitivity and intellectual disability syndrome, autosomal recessive severe congenital neutropenia, severe combined immunodeficiency due to CARMIL2 deficiency, extraoral halitosis due to methanethiol oxidase deficiency, neurodevelopmental disorder with microcephaly, impaired language, epilepsy, and gait abnormalities, mitochondrial complex 2 deficiency, nuclear type 3, mitochondrial complex 2 deficiency, nuclear type 4, mismatch repair cancer syndrome, spondyloepimetaphyseal dysplasia with joint laxity, type 3, Kilquist syndrome, Duane anomaly-myopathy-scoliosis syndrome, autosomal recessive axonal charcot-marie-tooth disease due to copper metabolism defect, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, congenital myopathy with reduced type 2 muscle fibers, NAD(P)HX dehydratase deficiency, autosomal recessive ocular albinism, ichthyosis linearis circumflexa, eosinophil peroxidase deficiency, hyperphenylalaninemia due to DNAJC12 deficiency, autosomal recessive epidermolytic ichthyosis, Ehlers-Danlos syndrome, classic-like, 2, joint laxity, short stature, and myopia, HELIX syndrome, auditory neuropathy-optic atrophy syndrome, glycosylphosphatidylinositol biosynthesis defect 15, neurodegeneration, childhood-onset, stress-induced, with variable ataxia and seizures, SCN4A-related myopathy, autosomal recessive, Uner Tan Syndrome, nephropathic cystinosis, Imerslund-Grasbeck syndrome type 1, Imerslund-Grasbeck syndrome type 2, permanent neonatal diabetes mellitus 1, growth hormone insensitivity with immune dysregulation 1, autosomal recessive, Rajab interstitial lung disease with brain calcifications 1, Roberts-SC phocomelia syndrome, neurodevelopmental disorder with microcephaly, impaired language, and gait abnormalities, RPE65-related recessive retinopathy, GUCY2D-related recessive retinopathy, autosomal recessive titinopathy, intellectual disability, autosomal recessive, ALPL-related autosomal recessive hypophosphatasia, spastic paraplegia 18b, autosomal recessive, CEP164-related ciliopathy, RP1-related recessive retinopathy, pseudohypoaldosteronism, type IB2, autosomal recessive, pseudohypoaldosteronism, type IB3, autosomal recessive, spastic paraplegia 30B, autosomal recessive, cerebral arteriopathy, autosomal recessive, with subcortical infarcts and leukoencephalopathy 1, brain small vessel disease 2B, autosomal recessive, IMPG1-related recessive retinopathy, PROM1-related recessive retinopathy

Subtypes (10): autosomal recessive osteopetrosis 1, autosomal recessive osteopetrosis 2, autosomal recessive osteopetrosis 5, autosomal recessive osteopetrosis 3, autosomal recessive osteopetrosis 4, autosomal recessive osteopetrosis 6, autosomal recessive osteopetrosis 7, leukocyte adhesion deficiency 3, autosomal recessive osteopetrosis 8, osteopetrosis, autosomal recessive 9

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

2 retrieved; paginated sample, class counts are floors:

1 uncertain significance, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
5462	NM_006019.4(TCIRG1):c.117+4A>T	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1516248	NM_001287.6(CLCN7):c.712G>A (p.Val238Met)	CLCN7	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 34 · Orphanet: 9 · 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
CLCN7	Definitive	Autosomal recessive	autosomal recessive osteopetrosis 4	16
TCIRG1	Definitive	Autosomal recessive	autosomal recessive osteopetrosis 1	9
SNX10	Strong	Autosomal recessive	autosomal recessive osteopetrosis 8	4
TNFSF11	Strong	Autosomal recessive	autosomal recessive osteopetrosis 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TCIRG1	Orphanet:1782	Dysosteosclerosis
TCIRG1	Orphanet:210110	Intermediate osteopetrosis
TCIRG1	Orphanet:486	Autosomal dominant severe congenital neutropenia
TCIRG1	Orphanet:667	Autosomal recessive malignant osteopetrosis
CLCN7	Orphanet:210110	Intermediate osteopetrosis
CLCN7	Orphanet:53	Albers-Schönberg osteopetrosis
CLCN7	Orphanet:667	Autosomal recessive malignant osteopetrosis
TNFSF11	Orphanet:667	Autosomal recessive malignant osteopetrosis
SNX10	Orphanet:667	Autosomal recessive malignant osteopetrosis

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TCIRG1	HGNC:11647	ENSG00000110719	Q13488	V-type proton ATPase 116 kDa subunit a 3	gencc,clinvar
CLCN7	HGNC:2025	ENSG00000103249	P51798	H(+)/Cl(-) exchange transporter 7	gencc,clinvar
TNFSF11	HGNC:11926	ENSG00000120659	O14788	Tumor necrosis factor ligand superfamily member 11	gencc
SNX10	HGNC:14974	ENSG00000086300	Q9Y5X0	Sorting nexin-10	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
CLCN7	H(+)/Cl(-) exchange transporter 7	Slowly voltage-gated channel mediating the exchange of chloride ions against protons.
TNFSF11	Tumor necrosis factor ligand superfamily member 11	Cytokine that binds to TNFRSF11B/OPG and to TNFRSF11A/RANK.
SNX10	Sorting nexin-10	Probable phosphoinositide-binding protein involved in protein sorting and membrane trafficking in endosomes.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.0

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
Other/Unknown	4	1.8×	0.097

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TCIRG1	Other/Unknown	no		V-ATPase_116kDa_su, V-type_ATPase_116kDa_su_euka
CLCN7	Other/Unknown	no		CBS_dom, ClC, CIC-7
TNFSF11	Other/Unknown	no		TNF_dom, Tumour_necrosis_fac-like_dom, TNF_ligand_10/11
SNX10	Other/Unknown	no		PX_dom, PX_dom_sf, SNX10/11

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	1
granulocyte	1
spleen	1
left adrenal gland cortex	1
metanephros cortex	1
right adrenal gland cortex	1
lymph node	1
primordial germ cell in gonad	1
tibia	1
lateral nuclear group of thalamus	1
substantia nigra pars compacta	1
substantia nigra pars reticulata	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TCIRG1	148	ubiquitous	marker	granulocyte, blood, spleen
CLCN7	296	ubiquitous	marker	metanephros cortex, right adrenal gland cortex, left adrenal gland cortex
TNFSF11	98	tissue_specific	marker	primordial germ cell in gonad, tibia, lymph node
SNX10	252	ubiquitous	marker	lateral nuclear group of thalamus, substantia nigra pars compacta, substantia nigra pars reticulata

Protein interactions among cohort

Intra-cohort edges: 4.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TNFSF11	3,410
CLCN7	1,991
TCIRG1	1,931
SNX10	820

Intra-cohort edges

A	B	Sources
CLCN7	SNX10	string_interaction
CLCN7	TCIRG1	string_interaction
CLCN7	TNFSF11	string_interaction
SNX10	TCIRG1	string_interaction

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CLCN7	P51798	9
SNX10	Q9Y5X0	3
TNFSF11	O14788	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TCIRG1	Q13488	83.52

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway	1	223.9×	0.020	TNFSF11
TNFs bind their physiological receptors	1	131.3×	0.020	TNFSF11
Insulin receptor recycling	1	126.9×	0.020	TCIRG1
Transferrin endocytosis and recycling	1	122.8×	0.020	TCIRG1
ROS and RNS production in phagocytes	1	112.0×	0.020	TCIRG1
Amino acids regulate mTORC1	1	66.8×	0.023	TCIRG1
TNFR2 non-canonical NF-kB pathway	1	60.4×	0.023	TNFSF11
Transcriptional and post-translational regulation of MITF-M expression and activity	1	59.5×	0.023	TNFSF11
Stimuli-sensing channels	1	45.3×	0.027	CLCN7
Ion channel transport	1	32.0×	0.034	TCIRG1
Neutrophil degranulation	1	7.7×	0.124	TCIRG1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
tooth eruption	3	2527.8×	4e-09	TCIRG1, TNFSF11, SNX10
bone resorption	3	435.8×	8e-07	TCIRG1, TNFSF11, SNX10
osteoclast differentiation	3	257.9×	3e-06	TCIRG1, TNFSF11, SNX10
osteoclast proliferation	2	1685.2×	9e-06	TCIRG1, TNFSF11
calcium ion homeostasis	2	221.7×	5e-04	TNFSF11, SNX10
ossification	2	113.9×	0.002	TCIRG1, TNFSF11
response to silver ion	1	4213.0×	0.002	TCIRG1
dentin mineralization	1	4213.0×	0.002	TCIRG1
cellular response to leukemia inhibitory factor	2	79.5×	0.002	TNFSF11, SNX10
protein catabolic process in the vacuole	1	2106.5×	0.003	TCIRG1
memory T cell activation	1	2106.5×	0.003	TCIRG1
positive regulation of corticotropin-releasing hormone secretion	1	2106.5×	0.003	TNFSF11
positive regulation of fever generation by positive regulation of prostaglandin secretion	1	2106.5×	0.003	TNFSF11
regulation of proton transport	1	1404.3×	0.004	TCIRG1
T-helper 1 cell activation	1	1404.3×	0.004	TCIRG1
positive regulation of osteoclast development	1	1053.2×	0.005	TNFSF11
response to pH	1	702.2×	0.006	CLCN7
bone mineralization involved in bone maturation	1	702.2×	0.006	SNX10
paracrine signaling	1	702.2×	0.006	TNFSF11
positive regulation of homotypic cell-cell adhesion	1	601.9×	0.006	TNFSF11
pH reduction	1	601.9×	0.006	TCIRG1
establishment of vesicle localization	1	601.9×	0.006	TCIRG1
phagosome acidification	1	601.9×	0.006	TCIRG1
gastric acid secretion	1	526.6×	0.006	SNX10
osteoclast development	1	526.6×	0.006	TNFSF11
transepithelial chloride transport	1	468.1×	0.007	CLCN7
mammary gland epithelial cell proliferation	1	383.0×	0.008	TNFSF11
ruffle organization	1	324.1×	0.009	TCIRG1
regulation of osteoblast differentiation	1	324.1×	0.009	TCIRG1
ruffle assembly	1	324.1×	0.009	SNX10

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TCIRG1	0	0
CLCN7	0	0
TNFSF11	0	0
SNX10	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TNFSF11	30	Binding:30

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	TCIRG1, CLCN7, TNFSF11, SNX10

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TCIRG1	0	—
CLCN7	0	—
TNFSF11	30	—
SNX10	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04525352	PHASE1	TERMINATED	A Trial to Evaluate Safety and Efficacy of RP-L401-0120 in Subjects With Infantile Malignant Osteopetrosis