Autosomal recessive osteopetrosis 2

Summary

Autosomal recessive osteopetrosis 2 (MONDO:0009816) is a disease caused by TNFSF11 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: TNFSF11 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 68

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive osteopetrosis 2
Mondo ID	MONDO:0009816
MeSH	C536059
OMIM	259710
DOID	DOID:0110943
UMLS	C1850126
MedGen	342420
GARD	0004157
Is cancer (heuristic)	no

Also known as: autosomal recessive malignant osteopetrosis caused by mutation in TNFSF11 · autosomal recessive osteopetrosis caused by mutation in TNFSF11 · autosomal recessive osteopetrosis type 2 · OPTB2 · osteopetrosis autosomal recessive 2 · osteopetrosis osteoclast-poor · osteopetrosis, autosomal recessive 2 · osteopetrosis, autosomal recessive type 2 · TNFSF11 autosomal recessive malignant osteopetrosis · TNFSF11 autosomal recessive osteopetrosis · TNFSF11-related osteopetrosis

Data availability: 68 ClinVar variants · 4 GenCC gene-disease records.

Disease family

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 › autosomal recessive osteopetrosis 2

Related subtypes (9): autosomal recessive osteopetrosis 1, 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

68 retrieved; paginated sample, class counts are floors:

37 uncertain significance, 13 benign, 8 conflicting classifications of pathogenicity, 4 pathogenic, 3 likely benign, 2 benign/likely benign, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1684676	NM_003701.4(TNFSF11):c.929del (p.Ala310fs)	TNFSF11	Pathogenic	criteria provided, single submitter
6973	NM_003701.4(TNFSF11):c.532+4_532+8del	TNFSF11	Pathogenic	no assertion criteria provided
6974	NM_003701.4(TNFSF11):c.596T>A (p.Met199Lys)	TNFSF11	Pathogenic	no assertion criteria provided
6975	NM_003701.4(TNFSF11):c.828_829del (p.Val277fs)	TNFSF11	Pathogenic	no assertion criteria provided
1526053	NM_003701.4(TNFSF11):c.667C>T (p.Arg223Ter)	TNFSF11	Likely pathogenic	criteria provided, single submitter
882482	NM_003701.4(TNFSF11):c.420C>G (p.Ile140Met)	LOC126861753	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
884197	NM_003701.4(TNFSF11):c.435G>A (p.Ala145=)	LOC126861753	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
884198	NM_003701.4(TNFSF11):c.520G>A (p.Asp174Asn)	LOC126861753	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193255	NM_003701.4(TNFSF11):c.214G>A (p.Ala72Thr)	TNFSF11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
312228	NM_003701.4(TNFSF11):c.98C>A (p.Pro33Gln)	TNFSF11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
312235	NM_003701.4(TNFSF11):c.534T>C (p.Gly178=)	TNFSF11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
884199	NM_003701.4(TNFSF11):c.533-8C>T	TNFSF11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
884200	NM_003701.4(TNFSF11):c.618A>G (p.Leu206=)	TNFSF11	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
312232	NM_003701.4(TNFSF11):c.254A>T (p.His85Leu)	LOC126861752	Uncertain significance	criteria provided, single submitter
312233	NM_003701.4(TNFSF11):c.403G>A (p.Val135Ile)	LOC126861753	Uncertain significance	criteria provided, multiple submitters, no conflicts
884196	NM_003701.4(TNFSF11):c.433+13C>G	LOC126861753	Uncertain significance	criteria provided, single submitter
1474050	NM_003701.4(TNFSF11):c.92A>T (p.His31Leu)	LOC130009662	Uncertain significance	criteria provided, single submitter
312226	NM_003701.4(TNFSF11):c.-4C>T	LOC130009662	Uncertain significance	criteria provided, single submitter
501658	NM_003701.4(TNFSF11):c.83G>A (p.Gly28Asp)	LOC130009662	Uncertain significance	criteria provided, multiple submitters, no conflicts
880856	NM_003701.4(TNFSF11):c.-94C>T	LOC130009662	Uncertain significance	criteria provided, single submitter
880857	NM_003701.4(TNFSF11):c.-7G>C	LOC130009662	Uncertain significance	criteria provided, single submitter
1177514	NM_003701.4(TNFSF11):c.2T>G (p.Met1Arg)	TNFSF11	Uncertain significance	criteria provided, multiple submitters, no conflicts
2437134	NM_003701.4(TNFSF11):c.2T>C (p.Met1Thr)	TNFSF11	Uncertain significance	criteria provided, single submitter
312220	NM_003701.4(TNFSF11):c.-144G>C	TNFSF11	Uncertain significance	criteria provided, single submitter
312223	NM_003701.4(TNFSF11):c.-81C>A	TNFSF11	Uncertain significance	criteria provided, single submitter
312224	NM_003701.4(TNFSF11):c.-74C>T	TNFSF11	Uncertain significance	criteria provided, single submitter
312225	NM_003701.4(TNFSF11):c.-64C>G	TNFSF11	Uncertain significance	criteria provided, single submitter
312230	NM_003701.4(TNFSF11):c.148G>A (p.Val50Met)	TNFSF11	Uncertain significance	criteria provided, multiple submitters, no conflicts
312234	NM_003701.4(TNFSF11):c.424G>A (p.Ala142Thr)	TNFSF11	Uncertain significance	criteria provided, multiple submitters, no conflicts
312236	NM_003701.4(TNFSF11):c.911A>G (p.Asp304Gly)	TNFSF11	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
TNFSF11	Strong	Autosomal recessive	autosomal recessive osteopetrosis 2	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TNFSF11	Orphanet:667	Autosomal recessive malignant osteopetrosis

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
TNFSF11	HGNC:11926	ENSG00000120659	O14788	Tumor necrosis factor ligand superfamily member 11	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TNFSF11	Tumor necrosis factor ligand superfamily member 11	Cytokine that binds to TNFRSF11B/OPG and to TNFRSF11A/RANK.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TNFSF11	Other/Unknown	no		TNF_dom, Tumour_necrosis_fac-like_dom, TNF_ligand_10/11

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
lymph node	1
primordial germ cell in gonad	1
tibia	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TNFSF11	98	tissue_specific	marker	primordial germ cell in gonad, tibia, lymph node

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TNFSF11	3,410

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TNFSF11	O14788	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. 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
TNF receptor superfamily (TNFSF) members mediating non-canonical NF-kB pathway	1	671.8×	0.005	TNFSF11
TNFs bind their physiological receptors	1	393.8×	0.005	TNFSF11
TNFR2 non-canonical NF-kB pathway	1	181.3×	0.006	TNFSF11
Transcriptional and post-translational regulation of MITF-M expression and activity	1	178.4×	0.006	TNFSF11

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
positive regulation of corticotropin-releasing hormone secretion	1	8426.0×	0.002	TNFSF11
positive regulation of fever generation by positive regulation of prostaglandin secretion	1	8426.0×	0.002	TNFSF11
positive regulation of osteoclast development	1	4213.0×	0.002	TNFSF11
osteoclast proliferation	1	3370.4×	0.002	TNFSF11
tooth eruption	1	3370.4×	0.002	TNFSF11
paracrine signaling	1	2808.7×	0.002	TNFSF11
positive regulation of homotypic cell-cell adhesion	1	2407.4×	0.002	TNFSF11
osteoclast development	1	2106.5×	0.002	TNFSF11
mammary gland epithelial cell proliferation	1	1532.0×	0.003	TNFSF11
positive regulation of bone resorption	1	991.3×	0.003	TNFSF11
mammary gland alveolus development	1	991.3×	0.003	TNFSF11
positive regulation of intracellular signal transduction	1	648.1×	0.004	TNFSF11
monocyte chemotaxis	1	581.1×	0.004	TNFSF11
bone resorption	1	581.1×	0.004	TNFSF11
positive regulation of osteoclast differentiation	1	581.1×	0.004	TNFSF11
positive regulation of extrinsic apoptotic signaling pathway	1	455.5×	0.005	TNFSF11
positive regulation of T cell activation	1	443.5×	0.005	TNFSF11
calcium ion homeostasis	1	443.5×	0.005	TNFSF11
osteoclast differentiation	1	343.9×	0.006	TNFSF11
tumor necrosis factor-mediated signaling pathway	1	330.4×	0.006	TNFSF11
JNK cascade	1	271.8×	0.006	TNFSF11
positive regulation of non-canonical NF-kappaB signal transduction	1	255.3×	0.007	TNFSF11
ossification	1	227.7×	0.007	TNFSF11
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1	210.7×	0.007	TNFSF11
calcium-mediated signaling	1	183.2×	0.008	TNFSF11
positive regulation of JNK cascade	1	163.6×	0.009	TNFSF11
cellular response to leukemia inhibitory factor	1	159.0×	0.009	TNFSF11
cytokine-mediated signaling pathway	1	130.6×	0.010	TNFSF11
positive regulation of ERK1 and ERK2 cascade	1	85.1×	0.015	TNFSF11
positive regulation of MAPK cascade	1	80.6×	0.015	TNFSF11

Therapeutics

Drug target analysis

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

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
TNFSF11	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: 1; 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	1	TNFSF11

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TNFSF11	30	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.