Bone disorder
diseaseOn this page
Also known as bone element diseasebone element disease or disorderdisease of bone elementdisease or disorder of bone elementdisorder of bone element
Summary
Bone disorder (MONDO:0005381) is a disease (an umbrella term covering 27 Mondo subtypes) caused by NPR2 (GenCC Strong), with 8 cohort genes (105 GWAS associations across 46 studies) and 3 clinical trials.
At a glance
- Causal gene: NPR2 (GenCC Strong)
- Umbrella term: 27 Mondo subtypes
- Cohort genes: 8
- GWAS associations: 105
- ClinVar variants: 35
- Clinical trials: 3
Clinical features
No curated clinical features (Orphanet) for this disease.
Identifiers
Disease identifiers
| Field | Value |
|---|---|
| Canonical name | bone disorder |
| Mondo ID | MONDO:0005381 |
| EFO | EFO:0004260 |
| MeSH | D001847 |
| DOID | DOID:0080001 |
| ICD-10-CM | M80-M85 |
| SNOMED CT | 76069003 |
| UMLS | C0005940 |
| MedGen | 14182 |
| Anatomy (UBERON) | UBERON:0002481 |
| Is cancer (heuristic) | no |
Also known as: bone element disease · bone element disease or disorder · disease of bone element · disease or disorder of bone element · disorder of bone element
Data availability: 35 ClinVar variants · 105 GWAS associations (46 studies) · 1 GenCC gene-disease record.
Disease family
An umbrella term covering 27 Mondo subtypes.
Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › skeletal system disorder › bone disorder
Related subtypes (47): symphalangism, cartilage cancer, vertebral column disorder, patellar tendinitis, necrosis of ear ossicle, laryngeal cartilage cancer, ochronosis disorder, chondroma, periodontal disorder, posterior cranial fossa meningioma, anterior cranial fossa meningioma, middle cranial fossa meningioma, bone marrow disorder, cranial nodular fasciitis, flatfoot, skeletal tuberculosis, arthropathy, tooth disorder, primary basilar invagination, Brachymorphism-onychodysplasia-dysphalangism syndrome, cherubism, fibrodysplasia ossificans progressiva, Marfan syndrome, Buschke-Ollendorff syndrome, scalp defects-postaxial polydactyly syndrome, cartilage-hair hypoplasia, Teebi-Shaltout syndrome, short stature-auditory canal atresia-mandibular hypoplasia-skeletal anomalies syndrome, ossification of the posterior longitudinal ligament of the spine, temtamy preaxial brachydactyly syndrome, metaphyseal undermodeling, spondylar dysplasia, and overgrowth, Al-Gazali syndrome, brachydactyly-syndactyly syndrome, endocrine-cerebro-osteodysplasia syndrome, metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria, multiple congenital anomalies-hypotonia-seizures syndrome 3, Rienhoff syndrome, Coffin-Siris syndrome, microcephaly-brachydactyly-kyphoscoliosis syndrome, cartilage development disorder, syndactyly, polydactyly, brachydactyly, sternal neoplasm, short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis, skeletal ligament disorder, brachydactyly-syndactyly-oligodactyly syndrome
Subtypes (27): bone remodeling disease, disease of bone structure, mucopolysaccharidosis type 1, bone inflammation disease, Baastrup syndrome, periostitis, osteonecrosis, bone development disease, ainhum, cervical rib disease, coxoauricular syndrome, metachondromatosis, mucopolysaccharidosis type 9, Sagliker syndrome, mixed sclerosing bone dystrophy with extra-skeletal manifestations, GM1 gangliosidosis, skeletal dysplasia, autosomal dominant myopia-midfacial retrusion-sensorineural hearing loss-rhizomelic dysplasia syndrome, mucopolysaccharidosis type 3, bone neoplasm, skull disorder, Duane anomaly-myopathy-scoliosis syndrome, mueller-weiss syndrome, SLC10A7-congenital disorder of glycosylation, metabolic bone disorder, proteoglycan-related bone disorder, ACAN-related short stature spectrum
Genetics & variants
GWAS landscape
105 GWAS associations across 46 studies. Top hits map to 14 distinct genes (as reported by GWAS).
Top associations by p-value
| rsID | p-value | Gene | Risk allele | Odds ratio |
|---|---|---|---|---|
| chr7:121326736 | 1e-37 | G | 0.11 | |
| chr11:68450822 | 4e-26 | T | 0.09 | |
| chr17:43749471 | 3e-25 | C | 0.15 | |
| chr7:38101778 | 4e-25 | A | 0.08 | |
| rs9533090 | 3e-23 | LINC02341 | C | 0.08 |
| chr6:151687789 | 2e-21 | T | 0.07 | |
| chr1:22365822 | 2e-21 | C | 0.1 | |
| chr13:42378009 | 2e-21 | T | 0.07 | |
| chr1:22692078 | 4e-20 | A | 0.1 | |
| rs34568051 | 2e-19 | PPIAP34 - ZBTB40 | C | 0.09 |
| chr6:127147129 | 3e-19 | C | 0.07 | |
| rs114335056 | 2e-18 | HLA-DRB1 - HLA-DQA1 | A | 0.14 |
| rs4869743 | 2e-18 | CCDC170 | T | 0.07 |
| rs17817497 | 3e-18 | FTO | T | 0.12 |
| chr6:152010534 | 1e-17 | T | 0.07 | |
| chr3:41082244 | 1e-17 | T | 0.07 | |
| rs7188250 | 2e-17 | FTO | T | 0.12 |
| chr2:118752917 | 2e-17 | GC | 0.37 | |
| chr21:38969070 | 7e-17 | ACAGCCACC | 0.07 | |
| rs2836800 | 1e-16 | LINC01700 | C | 0.07 |
| chr7:96588353 | 1e-16 | A | 0.06 | |
| rs10875906 | 5e-15 | WNT1 - DDN | C | 0.07 |
| rs9921222 | 6e-15 | AXIN1 | C | 0.06 |
| rs4437116 | 6e-15 | RPS27P4 - MRPS31P1 | C | 0.06 |
| rs1524058 | 7e-15 | SFRP4 - STARD3NL | T | 0.06 |
| chr4:87910097 | 8e-15 | A | 0.06 | |
| rs2414098 | 9e-15 | CYP19A1, MIR4713HG | T | 0.06 |
| chr2:119507607 | 4e-14 | C | 0.36 | |
| chr7:96133319 | 6e-14 | A | 0.06 | |
| rs7903146 | 1e-13 | TCF7L2 | C | 0.1 |
Top studies (by case count)
| Study | Lead author | Year | Cases | Controls | Title |
|---|---|---|---|---|---|
| GCST90474131 | UK Biobank Whole-Genome Sequencing Consortium | 2025 | 39,493 | 418,947 | Whole-genome sequencing of 490,640 UK Biobank participants. |
| GCST90667834 | UK Biobank Whole-Genome Sequencing Consortium | 2025 | 39,493 | 418,947 | Whole-genome sequencing of 490,640 UK Biobank participants. |
| GCST90476258 | Verma A | 2024 | 37,640 | 391,860 | Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program. |
| GCST90474138 | UK Biobank Whole-Genome Sequencing Consortium | 2025 | 15,459 | 442,981 | Whole-genome sequencing of 490,640 UK Biobank participants. |
| GCST90667936 | UK Biobank Whole-Genome Sequencing Consortium | 2025 | 15,459 | 442,981 | Whole-genome sequencing of 490,640 UK Biobank participants. |
| GCST90038652 | Donertas HM | 2021 | 10,730 | 473,868 | Common genetic associations between age-related diseases. |
| GCST90474141 | UK Biobank Whole-Genome Sequencing Consortium | 2025 | 10,604 | 447,836 | Whole-genome sequencing of 490,640 UK Biobank participants. |
| GCST90667922 | UK Biobank Whole-Genome Sequencing Consortium | 2025 | 10,604 | 447,836 | Whole-genome sequencing of 490,640 UK Biobank participants. |
| GCST90476220 | Verma A | 2024 | 10,361 | 436,629 | Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program. |
| GCST90436737 | Zhou W | 2018 | 7,682 | 401,279 | Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies. |
Variant details and genetic-evidence tiers
Tier distribution (top 50 variants)
| Tier | Variants |
|---|---|
| Tier 1: coding | 0 |
| Tier 2: splice/UTR | 0 |
| Tier 3: regulatory | 1 |
| Tier 4: intronic/intergenic | 49 |
MAF distribution
| Bucket | Variants |
|---|---|
| common (>=0.05) | 27 |
| low_freq (0.01-0.05) | 0 |
| rare (<0.01) | 1 |
| unknown | 22 |
Functional consequences
| Consequence | Count |
|---|---|
| unknown | 30 |
| intron_variant | 11 |
| intergenic_variant | 7 |
| non_coding_transcript_exon_variant | 1 |
| regulatory_region_variant | 1 |
Top variants
| rsID | Chr | Pos | Alleles | MAF | Consequence | Gene | p-value | Tier |
|---|---|---|---|---|---|---|---|---|
| chr7:121326736 | 1e-37 | Tier 4: intronic/intergenic | ||||||
| chr11:68450822 | 4e-26 | Tier 4: intronic/intergenic | ||||||
| chr17:43749471 | 3e-25 | Tier 4: intronic/intergenic | ||||||
| chr7:38101778 | 4e-25 | Tier 4: intronic/intergenic | ||||||
| rs9533090 | 13 | 42377313 | C>G,T | 0.471 | intron_variant | LINC02341 | 3e-23 | Tier 4: intronic/intergenic |
| chr6:151687789 | 2e-21 | Tier 4: intronic/intergenic | ||||||
| chr1:22365822 | 2e-21 | Tier 4: intronic/intergenic | ||||||
| chr13:42378009 | 2e-21 | Tier 4: intronic/intergenic | ||||||
| chr1:22692078 | 0.18 | 4e-20 | Tier 4: intronic/intergenic | |||||
| rs34568051 | 1 | 22375232 | C>T | 0.198 | intergenic_variant | PPIAP34 - ZBTB40 | 2e-19 | Tier 4: intronic/intergenic |
| chr6:127147129 | 3e-19 | Tier 4: intronic/intergenic | ||||||
| rs114335056 | 6 | 32591414 | A>G | 0.111 | intergenic_variant | HLA-DRB1 - HLA-DQA1 | 2e-18 | Tier 4: intronic/intergenic |
| rs4869743 | 6 | 151586823 | T>A,C | 0.387 | intron_variant | CCDC170 | 2e-18 | Tier 4: intronic/intergenic |
| rs17817497 | 16 | 53781523 | T>C | 0.322 | intron_variant | FTO | 3e-18 | Tier 4: intronic/intergenic |
| chr6:152010534 | 0.415 | 1e-17 | Tier 4: intronic/intergenic | |||||
| chr3:41082244 | 1e-17 | Tier 4: intronic/intergenic | ||||||
| rs7188250 | 16 | 53800695 | T>C | 0.411 | intron_variant | FTO | 2e-17 | Tier 4: intronic/intergenic |
| chr2:118752917 | 2e-17 | Tier 4: intronic/intergenic | ||||||
| chr21:38969070 | 7e-17 | Tier 4: intronic/intergenic | ||||||
| rs2836800 | 21 | 38975759 | C>T | 0.303 | non_coding_transcript_exon_variant | LINC01700 | 1e-16 | Tier 4: intronic/intergenic |
| chr7:96588353 | 1e-16 | Tier 4: intronic/intergenic | ||||||
| rs10875906 | 12 | 48991896 | C>A,G,T | 0.279 | intergenic_variant | WNT1 - DDN | 5e-15 | Tier 4: intronic/intergenic |
| rs9921222 | 16 | 325782 | C>T | 0.459 | intron_variant | AXIN1 | 6e-15 | Tier 4: intronic/intergenic |
| rs4437116 | 3 | 41119852 | C>T | 0.459 | intergenic_variant | RPS27P4 - MRPS31P1 | 6e-15 | Tier 4: intronic/intergenic |
| rs1524058 | 7 | 38096675 | T>A,C | 0.422 | intergenic_variant | SFRP4 - STARD3NL | 7e-15 | Tier 4: intronic/intergenic |
| chr4:87910097 | 8e-15 | Tier 4: intronic/intergenic | ||||||
| rs2414098 | 15 | 51245609 | T>A,C,G | 0.394 | intron_variant | CYP19A1, MIR4713HG | 9e-15 | Tier 4: intronic/intergenic |
| chr2:119507607 | 0.01 | 4e-14 | Tier 4: intronic/intergenic | |||||
| chr7:96133319 | 0.329 | 6e-14 | Tier 4: intronic/intergenic | |||||
| rs7903146 | 10 | 112998590 | C>G,T | 0.292 | intron_variant | TCF7L2 | 1e-13 | Tier 4: intronic/intergenic |
ClinVar germline variants
35 retrieved; paginated sample, class counts are floors:
12 benign, 12 benign/likely benign, 5 conflicting classifications of pathogenicity, 3 uncertain significance, 2 pathogenic/likely pathogenic, 1 pathogenic
| ClinVar | Variant (HGVS) | Gene | Classification | Review |
|---|---|---|---|---|
| 1068483 | NM_001287.6(CLCN7):c.856C>T (p.Arg286Trp) | CLCN7 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 438670 | NM_001287.6(CLCN7):c.857G>A (p.Arg286Gln) | CLCN7 | Pathogenic/Likely pathogenic | criteria provided, multiple submitters, no conflicts |
| 6280 | NM_002335.4(LRP5):c.512G>T (p.Gly171Val) | LRP5 | Pathogenic | criteria provided, multiple submitters, no conflicts |
| 1478516 | NM_001287.6(CLCN7):c.689A>G (p.Lys230Arg) | CLCN7 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1482073 | NM_001287.6(CLCN7):c.2030G>T (p.Gly677Val) | 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 |
| 6276 | NM_002335.4(LRP5):c.1999G>A (p.Val667Met) | LRP5 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 235702 | NM_006019.4(TCIRG1):c.1249G>A (p.Ala417Thr) | TCIRG1 | Conflicting classifications of pathogenicity | criteria provided, conflicting classifications |
| 1701975 | NM_001287.6(CLCN7):c.698_712dup (p.Ser237_Val238insGlyValIleLeuSer) | CLCN7 | Uncertain significance | criteria provided, single submitter |
| 327738 | NM_003839.4(TNFRSF11A):c.1618A>G (p.Met540Val) | TNFRSF11A | Uncertain significance | criteria provided, multiple submitters, no conflicts |
| 1701974 | NM_003701.4(TNFSF11):c.704A>G (p.Tyr235Cys) | TNFSF11 | Uncertain significance | criteria provided, single submitter |
| 193627 | NM_001287.6(CLCN7):c.900G>A (p.Ala300=) | CLCN7 | Benign | criteria provided, multiple submitters, no conflicts |
| 257953 | NM_001287.6(CLCN7):c.1798-10C>T | CLCN7 | Benign | criteria provided, multiple submitters, no conflicts |
| 317954 | NM_001287.6(CLCN7):c.801G>A (p.Thr267=) | CLCN7 | Benign/Likely benign | criteria provided, multiple submitters, no conflicts |
| 317957 | NM_001287.6(CLCN7):c.696C>T (p.Ser232=) | CLCN7 | Benign | criteria provided, multiple submitters, no conflicts |
| 317963 | NM_001287.6(CLCN7):c.350C>T (p.Thr117Met) | CLCN7 | Benign/Likely benign | criteria provided, multiple submitters, no conflicts |
| 65634 | NM_001287.6(CLCN7):c.1252G>A (p.Val418Met) | CLCN7 | Benign/Likely benign | criteria provided, multiple submitters, no conflicts |
| 716176 | NM_003701.4(TNFSF11):c.396A>G (p.Gln132=) | LOC126861753 | Benign | criteria provided, multiple submitters, no conflicts |
| 193256 | NM_003701.4(TNFSF11):c.80A>G (p.Glu27Gly) | LOC130009662 | Benign | criteria provided, multiple submitters, no conflicts |
| 312229 | NM_003701.4(TNFSF11):c.107C>G (p.Pro36Arg) | LOC130009662 | Benign/Likely benign | criteria provided, multiple submitters, no conflicts |
| 193639 | NM_002335.4(LRP5):c.2220C>T (p.Asn740=) | LRP5 | Benign | criteria provided, multiple submitters, no conflicts |
| 194836 | NM_002335.4(LRP5):c.4000+10T>A | LRP5 | Benign | criteria provided, multiple submitters, no conflicts |
| 194943 | NM_002335.4(LRP5):c.4089C>T (p.Asp1363=) | LRP5 | Benign/Likely benign | criteria provided, multiple submitters, no conflicts |
| 197206 | NM_002335.4(LRP5):c.687-8G>A | LRP5 | Benign | criteria provided, multiple submitters, no conflicts |
| 204504 | NM_002335.4(LRP5):c.34CTG[6] (p.Leu18_Leu20del) | LRP5 | Benign/Likely benign | criteria provided, multiple submitters, no conflicts |
| 258640 | NM_002335.4(LRP5):c.3989C>T (p.Ala1330Val) | LRP5 | Benign | criteria provided, multiple submitters, no conflicts |
| 36481 | NM_002335.4(LRP5):c.4000+9C>T | LRP5 | Benign/Likely benign | criteria provided, multiple submitters, no conflicts |
| 36482 | NM_002335.4(LRP5):c.4635C>T (p.Thr1545=) | LRP5 | Benign/Likely benign | criteria provided, multiple submitters, no conflicts |
| 1291719 | NM_014798.3(PLEKHM1):c.2913G>A (p.Gly971=) | PLEKHM1 | Benign | criteria provided, multiple submitters, no conflicts |
| 194393 | NM_006019.4(TCIRG1):c.1672G>C (p.Val558Leu) | TCIRG1 | Benign | criteria provided, multiple submitters, no conflicts |
Genes & proteins
Mendelian disease overlap and somatic drivers
GenCC: 29 · Orphanet: 26 · 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 |
|---|---|---|---|---|
| NPR2 | Strong | Autosomal dominant | bone disorder | 12 |
| NPRL2 | Strong | Autosomal dominant | bone disorder | 17 |
Orphanet rare-disease linkage (cohort genes)
| Gene | Orphanet ID | Rare disease |
|---|---|---|
| NPRL2 | Orphanet:98820 | Familial focal epilepsy with variable foci |
| NPR2 | Orphanet:329191 | Tall stature-long halluces-multiple extra-epiphyses syndrome |
| NPR2 | Orphanet:40 | Acromesomelic dysplasia, Maroteaux type |
| TCIRG1 | Orphanet:1782 | Dysosteosclerosis |
| TCIRG1 | Orphanet:210110 | Intermediate osteopetrosis |
| TCIRG1 | Orphanet:486 | Autosomal dominant severe congenital neutropenia |
| TCIRG1 | Orphanet:667 | Autosomal recessive malignant osteopetrosis |
| TNFRSF11A | Orphanet:1782 | Dysosteosclerosis |
| TNFRSF11A | Orphanet:178389 | Osteopetrosis-hypogammaglobulinemia syndrome |
| TNFRSF11A | Orphanet:2801 | Juvenile Paget disease |
| TNFRSF11A | Orphanet:391490 | Adult-onset myasthenia gravis |
| TNFRSF11A | Orphanet:85195 | Familial expansile osteolysis |
| TNFSF11 | Orphanet:667 | Autosomal recessive malignant osteopetrosis |
| CLCN7 | Orphanet:210110 | Intermediate osteopetrosis |
| CLCN7 | Orphanet:53 | Albers-Schönberg osteopetrosis |
| CLCN7 | Orphanet:667 | Autosomal recessive malignant osteopetrosis |
| PLEKHM1 | Orphanet:210110 | Intermediate osteopetrosis |
| LRP5 | Orphanet:178377 | Osteosclerosis-developmental delay-craniosynostosis syndrome |
| LRP5 | Orphanet:2783 | Autosomal dominant osteopetrosis type 1 |
| LRP5 | Orphanet:2788 | Osteoporosis-pseudoglioma syndrome |
| LRP5 | Orphanet:2790 | Endosteal hyperostosis, Worth type |
| LRP5 | Orphanet:2924 | Isolated polycystic liver disease |
| LRP5 | Orphanet:3416 | Hyperostosis corticalis generalisata |
| LRP5 | Orphanet:498481 | LRP5-related primary osteoporosis |
| LRP5 | Orphanet:891 | Familial exudative vitreoretinopathy |
| LRP5 | Orphanet:90050 | Retinopathy of prematurity |
Cohort genes → proteins
8 cohort genes, 8 distinct canonical proteins.
Evidence partition
| Subset | Genes |
|---|---|
| multi_evidence | 8 |
Cohort genes (full)
| Symbol | HGNC | Ensembl | UniProt | Name | Evidence |
|---|---|---|---|---|---|
| NPRL2 | HGNC:24969 | ENSG00000114388 | Q8WTW4 | GATOR1 complex protein NPRL2 | gencc |
| NPR2 | HGNC:7944 | ENSG00000159899 | P20594 | Atrial natriuretic peptide receptor 2 | gencc |
| TCIRG1 | HGNC:11647 | ENSG00000110719 | Q13488 | V-type proton ATPase 116 kDa subunit a 3 | clinvar |
| TNFRSF11A | HGNC:11908 | ENSG00000141655 | Q9Y6Q6 | Tumor necrosis factor receptor superfamily member 11A | clinvar |
| TNFSF11 | HGNC:11926 | ENSG00000120659 | O14788 | Tumor necrosis factor ligand superfamily member 11 | clinvar |
| CLCN7 | HGNC:2025 | ENSG00000103249 | P51798 | H(+)/Cl(-) exchange transporter 7 | clinvar |
| PLEKHM1 | HGNC:29017 | ENSG00000225190 | Q9Y4G2 | Pleckstrin homology domain-containing family M member 1 | clinvar |
| LRP5 | HGNC:6697 | ENSG00000162337 | O75197 | Low-density lipoprotein receptor-related protein 5 | clinvar |
Cohort function summary
Lead sentence per gene, UniProt-curated.
| Symbol | Protein name | Function (lead sentence) |
|---|---|---|
| NPRL2 | GATOR1 complex protein NPRL2 | Catalytic component of the GATOR1 complex, a multiprotein complex that functions as an inhibitor of the amino acid-sensing branch of the mTORC1 pathway. |
| NPR2 | Atrial natriuretic peptide receptor 2 | Receptor for the C-type natriuretic peptide NPPC/CNP hormone. |
| 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. |
| TNFRSF11A | Tumor necrosis factor receptor superfamily member 11A | Receptor for TNFSF11/RANKL/TRANCE/OPGL; essential for RANKL-mediated osteoclastogenesis. |
| TNFSF11 | Tumor necrosis factor ligand superfamily member 11 | Cytokine that binds to TNFRSF11B/OPG and to TNFRSF11A/RANK. |
| CLCN7 | H(+)/Cl(-) exchange transporter 7 | Slowly voltage-gated channel mediating the exchange of chloride ions against protons. |
| PLEKHM1 | Pleckstrin homology domain-containing family M member 1 | Acts as a multivalent adapter protein that regulates Rab7-dependent and HOPS complex-dependent fusion events in the endolysosomal system and couples autophagic and the endocytic trafficking pathways. |
| LRP5 | Low-density lipoprotein receptor-related protein 5 | Acts as a coreceptor with members of the frizzled family of seven-transmembrane spanning receptors to transduce signal by Wnt proteins. |
Protein-family classification
Druggable: 1 · Difficult: 1 · Unknown: 6 · Druggable fraction: 0.12
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 |
|---|---|---|---|
| Kinase | 1 | 3.5× | 0.379 |
| Scaffold/PPI | 1 | 2.2× | 0.379 |
| Other/Unknown | 6 | 1.3× | 0.379 |
Per-gene assignment
| Symbol | Family | Druggable? | EC | InterPro (top 3) |
|---|---|---|---|---|
| NPRL2 | Other/Unknown | no | NPR2-like | |
| NPR2 | Kinase | yes | 4.6.1.2 | Prot_kinase_dom, A/G_cyclase, ANPR/GUC |
| TCIRG1 | Other/Unknown | no | V-ATPase_116kDa_su, V-type_ATPase_116kDa_su_euka | |
| TNFRSF11A | Other/Unknown | no | TNFR/NGFR_Cys_rich_reg, TNFR_11, TNFR_11A | |
| TNFSF11 | Other/Unknown | no | TNF_dom, Tumour_necrosis_fac-like_dom, TNF_ligand_10/11 | |
| CLCN7 | Other/Unknown | no | CBS_dom, ClC, CIC-7 | |
| PLEKHM1 | Scaffold/PPI | no | PH_domain, PKC_DAG/PE, Run_dom | |
| LRP5 | Other/Unknown | no | LDLR_classB_rpt, EGF, LDrepeatLR_classA_rpt |
Expression context
Cohort genes with no expression data: 0.
7 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) | 8 |
| unknown | 0 |
Top tissues across cohort
| Tissue | Cohort genes |
|---|---|
| cerebellar hemisphere | 2 |
| granulocyte | 2 |
| right hemisphere of cerebellum | 2 |
| blood | 2 |
| right uterine tube | 1 |
| spleen | 1 |
| jejunal mucosa | 1 |
| mucosa of sigmoid colon | 1 |
| parotid gland | 1 |
| lymph node | 1 |
| primordial germ cell in gonad | 1 |
| tibia | 1 |
| left adrenal gland cortex | 1 |
| metanephros cortex | 1 |
| right adrenal gland cortex | 1 |
| esophagus mucosa | 1 |
| lower esophagus mucosa | 1 |
| ascending aorta | 1 |
| mucosa of transverse colon | 1 |
| right lobe of liver | 1 |
Per-gene tissue summary (top 30)
| Symbol | Bgee breadth | FANTOM5 breadth | SCXA | Top tissues |
|---|---|---|---|---|
| NPRL2 | 285 | ubiquitous | marker | granulocyte, right hemisphere of cerebellum, cerebellar hemisphere |
| NPR2 | 267 | ubiquitous | marker | right uterine tube, right hemisphere of cerebellum, cerebellar hemisphere |
| TCIRG1 | 148 | ubiquitous | marker | granulocyte, blood, spleen |
| TNFRSF11A | 221 | broad | marker | parotid gland, mucosa of sigmoid colon, jejunal mucosa |
| TNFSF11 | 98 | tissue_specific | marker | primordial germ cell in gonad, tibia, lymph node |
| CLCN7 | 296 | ubiquitous | marker | metanephros cortex, right adrenal gland cortex, left adrenal gland cortex |
| PLEKHM1 | 134 | broad | yes | lower esophagus mucosa, esophagus mucosa, blood |
| LRP5 | 224 | ubiquitous | marker | right lobe of liver, mucosa of transverse colon, ascending aorta |
Protein interactions among cohort
Intra-cohort edges: 9.
Hub genes (top 10 by interactor count)
| Symbol | Interactor count |
|---|---|
| TNFSF11 | 3,410 |
| LRP5 | 2,619 |
| CLCN7 | 1,991 |
| TCIRG1 | 1,931 |
| NPRL2 | 1,222 |
| TNFRSF11A | 1,186 |
| PLEKHM1 | 1,038 |
| NPR2 | 885 |
Intra-cohort edges
| A | B | Sources |
|---|---|---|
| CLCN7 | LRP5 | string_interaction |
| CLCN7 | PLEKHM1 | string_interaction |
| CLCN7 | TCIRG1 | string_interaction |
| CLCN7 | TNFRSF11A | string_interaction |
| CLCN7 | TNFSF11 | string_interaction |
| PLEKHM1 | TCIRG1 | string_interaction |
| PLEKHM1 | TNFRSF11A | string_interaction |
| TCIRG1 | TNFRSF11A | string_interaction |
| TNFRSF11A | TNFSF11 | intact, string_interaction |
Structural data
PDB: 5 · AlphaFold-only: 3 · No structure: 0
Cohort genes with PDB structures (top 30)
| Symbol | UniProt | PDB entries |
|---|---|---|
| NPRL2 | Q8WTW4 | 10 |
| CLCN7 | P51798 | 9 |
| PLEKHM1 | Q9Y4G2 | 5 |
| TNFSF11 | O14788 | 2 |
| TNFRSF11A | Q9Y6Q6 | 1 |
AlphaFold-only cohort genes (top 30 by pLDDT)
| Symbol | UniProt | pLDDT |
|---|---|---|
| NPR2 | P20594 | 84.00 |
| TCIRG1 | Q13488 | 83.52 |
| LRP5 | O75197 | 78.65 |
Function
Pathway analysis
Distinct Reactome pathways touched by cohort: 25. Enrichment computed across 8 evidence-associated genes (7 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 7 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 | 2 | 191.9× | 0.001 | TNFRSF11A, TNFSF11 |
| Amino acids regulate mTORC1 | 2 | 57.2× | 0.005 | TCIRG1, NPRL2 |
| TNFR2 non-canonical NF-kB pathway | 2 | 51.8× | 0.005 | TNFRSF11A, TNFSF11 |
| Signaling by LRP5 mutants | 1 | 233.1× | 0.027 | LRP5 |
| Signaling by RNF43 mutants | 1 | 181.3× | 0.028 | LRP5 |
| Negative regulation of TCF-dependent signaling by WNT ligand antagonists | 1 | 102.0× | 0.036 | LRP5 |
| Physiological factors | 1 | 96.0× | 0.036 | NPR2 |
| Signaling by WNT in cancer | 1 | 85.9× | 0.036 | LRP5 |
| Regulation of FZD by ubiquitination | 1 | 74.2× | 0.037 | LRP5 |
| TNFs bind their physiological receptors | 1 | 56.3× | 0.037 | TNFSF11 |
| Insulin receptor recycling | 1 | 54.4× | 0.037 | TCIRG1 |
| Transferrin endocytosis and recycling | 1 | 52.6× | 0.037 | TCIRG1 |
| Disassembly of the destruction complex and recruitment of AXIN to the membrane | 1 | 51.0× | 0.037 | LRP5 |
| ROS and RNS production in phagocytes | 1 | 48.0× | 0.037 | TCIRG1 |
| Transcriptional and post-translational regulation of MITF-M expression and activity | 1 | 25.5× | 0.064 | TNFSF11 |
| Stimuli-sensing channels | 1 | 19.4× | 0.079 | CLCN7 |
| TCF dependent signaling in response to WNT | 1 | 16.8× | 0.082 | LRP5 |
| Signaling by WNT | 1 | 16.0× | 0.082 | LRP5 |
| Cardiac conduction | 1 | 15.5× | 0.082 | NPR2 |
| Ion channel transport | 1 | 13.7× | 0.088 | TCIRG1 |
| Muscle contraction | 1 | 11.0× | 0.104 | NPR2 |
| Diseases of signal transduction by growth factor receptors and second messengers | 1 | 8.1× | 0.133 | LRP5 |
| Neutrophil degranulation | 1 | 3.3× | 0.290 | TCIRG1 |
| Disease | 1 | 1.9× | 0.445 | LRP5 |
| Signal Transduction | 1 | 1.4× | 0.516 | LRP5 |
GO biological processes 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.
| GO term | Cohort genes | Fold | FDR | Sample cohort genes |
|---|---|---|---|---|
| positive regulation of bone resorption | 3 | 371.7× | 9e-06 | TNFRSF11A, TNFSF11, PLEKHM1 |
| positive regulation of fever generation by positive regulation of prostaglandin secretion | 2 | 2106.5× | 2e-05 | TNFRSF11A, TNFSF11 |
| osteoclast proliferation | 2 | 842.6× | 7e-05 | TCIRG1, TNFSF11 |
| tooth eruption | 2 | 842.6× | 7e-05 | TCIRG1, TNFSF11 |
| osteoclast differentiation | 3 | 129.0× | 7e-05 | TCIRG1, TNFRSF11A, TNFSF11 |
| ossification | 3 | 85.4× | 1e-04 | TCIRG1, TNFRSF11A, TNFSF11 |
| mammary gland alveolus development | 2 | 247.8× | 7e-04 | TNFRSF11A, TNFSF11 |
| monocyte chemotaxis | 2 | 145.3× | 0.001 | TNFRSF11A, TNFSF11 |
| bone resorption | 2 | 145.3× | 0.001 | TCIRG1, TNFSF11 |
| positive regulation of osteoclast differentiation | 2 | 145.3× | 0.001 | TNFRSF11A, TNFSF11 |
| tumor necrosis factor-mediated signaling pathway | 2 | 82.6× | 0.004 | TNFRSF11A, TNFSF11 |
| response to silver ion | 1 | 2106.5× | 0.006 | TCIRG1 |
| vestibulocochlear nerve maturation | 1 | 2106.5× | 0.006 | NPR2 |
| dentin mineralization | 1 | 2106.5× | 0.006 | TCIRG1 |
| positive regulation of non-canonical NF-kappaB signal transduction | 2 | 63.8× | 0.006 | TNFRSF11A, TNFSF11 |
| regulation of blood pressure | 2 | 55.4× | 0.006 | LRP5, NPR2 |
| protein catabolic process in the vacuole | 1 | 1053.2× | 0.008 | TCIRG1 |
| response to luteinizing hormone | 1 | 1053.2× | 0.008 | NPR2 |
| memory T cell activation | 1 | 1053.2× | 0.008 | TCIRG1 |
| positive regulation of corticotropin-releasing hormone secretion | 1 | 1053.2× | 0.008 | TNFSF11 |
| activation of meiosis involved in egg activation | 1 | 1053.2× | 0.008 | NPR2 |
| cumulus cell differentiation | 1 | 702.2× | 0.008 | NPR2 |
| regulation of proton transport | 1 | 702.2× | 0.008 | TCIRG1 |
| gastric emptying | 1 | 702.2× | 0.008 | NPR2 |
| T-helper 1 cell activation | 1 | 702.2× | 0.008 | TCIRG1 |
| circadian temperature homeostasis | 1 | 702.2× | 0.008 | TNFRSF11A |
| cell-cell signaling involved in mammary gland development | 1 | 702.2× | 0.008 | LRP5 |
| c-di-GMP signaling | 1 | 702.2× | 0.008 | NPR2 |
| multinuclear osteoclast differentiation | 1 | 702.2× | 0.008 | TNFRSF11A |
| positive regulation of JNK cascade | 2 | 40.9× | 0.008 | TNFRSF11A, TNFSF11 |
Therapeutics
Drugs indicated for this disease
11 approved, 7 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.
| Drug | Development status |
|---|---|
| Alendronic Acid | Approved (phase 4) |
| Burosumab | Approved (phase 4) |
| Denosumab | Approved (phase 4) |
| Dibotermin Alfa | Approved (phase 4) |
| Eptotermin Alfa | Approved (phase 4) |
| Etidronic Acid | Approved (phase 4) |
| Pamidronic Acid | Approved (phase 4) |
| Risedronic Acid | Approved (phase 4) |
| Romosozumab | Approved (phase 4) |
| Tiludronic Acid | Approved (phase 4) |
| Vosoritide | Approved (phase 4) |
| Clodronic Acid | Phase 3 (in late-stage trials) |
| Estrogens, Conjugated | Phase 3 (in late-stage trials) |
| Ibandronic Acid | Phase 3 (in late-stage trials) |
| Medroxyprogesterone Acetate | Phase 3 (in late-stage trials) |
| Menatetrenone | Phase 3 (in late-stage trials) |
| Progesterone | Phase 3 (in late-stage trials) |
| Zoledronic Acid Anhydrous | Phase 3 (in late-stage trials) |
Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Mecasermin.
Drug target analysis
Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 8
Druggability breadth: 3 of 8 evidence-associated genes (38%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).
Top cohort targets by molecule count
| Symbol | Molecules | Max phase |
|---|---|---|
| NPRL2 | 0 | 0 |
| NPR2 | 0 | 0 |
| TCIRG1 | 0 | 0 |
| TNFRSF11A | 0 | 0 |
| TNFSF11 | 0 | 0 |
| CLCN7 | 0 | 0 |
| PLEKHM1 | 0 | 0 |
| LRP5 | 0 | 0 |
Bioactivity and enzyme data
Enzyme cohort genes (≥1 EC): 1.
Cohort genes with ChEMBL bioactivity (full, sorted by assay count)
| Symbol | Assays | Type breakdown |
|---|---|---|
| TNFSF11 | 30 | Binding:30 |
| NPR2 | 11 | Binding:11 |
| LRP5 | 1 | Binding:1 |
Cohort enzymes (BRENDA EC)
| Symbol | EC numbers | Names |
|---|---|---|
| NPR2 | 4.6.1.2 | guanylate cyclase |
Pharmacogenomics
Cohort genes with a PharmGKB record: 8; 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 | 1 | NPR2 |
| E | Difficult family or no structure, no drug | 7 | NPRL2, TCIRG1, TNFRSF11A, TNFSF11, CLCN7, PLEKHM1, LRP5 |
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) |
|---|---|---|
| NPRL2 | 0 | — |
| NPR2 | 11 | — |
| TCIRG1 | 0 | — |
| TNFRSF11A | 0 | — |
| TNFSF11 | 30 | — |
| CLCN7 | 0 | — |
| PLEKHM1 | 0 | — |
| LRP5 | 1 | — |
Clinical trials & evidence
Clinical trials
Clinical trials: 3.
Phase distribution (across all retrieved trials)
| Phase | Trials |
|---|---|
| Not specified | 3 |
Top trials by phase / activity
| NCT | Phase | Status | Title |
|---|---|---|---|
| NCT01166854 | Not specified | RECRUITING | Characterization of Familial Myopathy and Paget Disease of Bone |
| NCT06444503 | Not specified | RECRUITING | Clinico-biological Collection of Bone, Calcium and Growth Plate Pathologies |
| NCT03527511 | Not specified | COMPLETED | Effect of Active Vitamin D and Etelcalcetide on Human Osteoclasts in Patients With Chronic Kidney Disease |