Autosomal dominant osteopetrosis 2

Summary

Autosomal dominant osteopetrosis 2 (MONDO:0008156) is a disease caused by CLCN7 (GenCC Definitive), with 1 cohort gene and 1 clinical trial. Top therapeutic interventions include interferon gamma-1b.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Causal gene: CLCN7 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 41
• Phenotypes (HPO): 36
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	5	Europe	Validated
Point prevalence	1-9 / 100 000	5.5	Denmark	Validated
Point prevalence	1-9 / 1 000 000	0.2	Brazil	Validated
Point prevalence	1-9 / 100 000	1	Worldwide	Not yet validated

Signs & symptoms

Clinical features (HPO)

36 HPO clinical features (Orphanet curated; top 36 by frequency):

HPO ID	Term	Frequency
HP:0000256	Macrocephaly	Very frequent (80-99%)
HP:0000944	Abnormal metaphysis morphology	Very frequent (80-99%)
HP:0001369	Arthritis	Very frequent (80-99%)
HP:0001373	Joint dislocation	Very frequent (80-99%)
HP:0002007	Frontal bossing	Very frequent (80-99%)
HP:0002653	Bone pain	Very frequent (80-99%)
HP:0002754	Osteomyelitis	Very frequent (80-99%)
HP:0002757	Recurrent fractures	Very frequent (80-99%)
HP:0002758	Osteoarthritis	Very frequent (80-99%)
HP:0005789	Generalized osteosclerosis	Very frequent (80-99%)
HP:0005916	Abnormal metacarpal morphology	Very frequent (80-99%)
HP:0005930	Abnormality of epiphysis morphology	Very frequent (80-99%)
HP:0006824	Cranial nerve paralysis	Very frequent (80-99%)
HP:0007626	Mandibular osteomyelitis	Very frequent (80-99%)
HP:0009882	Short distal phalanx of finger	Very frequent (80-99%)
HP:0010628	Facial palsy	Very frequent (80-99%)
HP:0010885	Avascular necrosis	Very frequent (80-99%)
HP:0000164	Abnormality of the dentition	Frequent (30-79%)
HP:0000648	Optic atrophy	Frequent (30-79%)
HP:0001903	Anemia	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0002857	Genu valgum	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0000238	Hydrocephalus	Occasional (5-29%)
HP:0000365	Hearing impairment	Occasional (5-29%)
HP:0000618	Blindness	Occasional (5-29%)
HP:0000670	Carious teeth	Occasional (5-29%)
HP:0001873	Thrombocytopenia	Occasional (5-29%)
HP:0001881	Abnormal leukocyte morphology	Occasional (5-29%)
HP:0002901	Hypocalcemia	Occasional (5-29%)
HP:0005746	Osteosclerosis of the base of the skull	Occasional (5-29%)
HP:0012145	Abnormality of multiple cell lineages in the bone marrow	Occasional (5-29%)
HP:0030757	Tooth abscess	Occasional (5-29%)
HP:0000505	Visual impairment	Very rare (<1-4%)
HP:0001293	Cranial nerve compression	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant osteopetrosis 2
Mondo ID	MONDO:0008156
OMIM	166600
Orphanet	53
DOID	DOID:0110938
SNOMED CT	725050005
UMLS	C3179239
MedGen	465707
GARD	0000383
Is cancer (heuristic)	no

Also known as: Albers-Schönberg osteopetrosis · autosomal dominant osteopetrosis type 2 · OPTA2 · osteopetrosis autosomal dominant type 2 · osteopetrosis, autosomal dominant 2 · osteopetrosis, autosomal dominant type 2

Data availability: 41 ClinVar variants · 6 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 dominant disease › autosomal dominant osteopetrosis › autosomal dominant osteopetrosis 2

Related subtypes (3): autosomal dominant osteopetrosis 1, osteopetrosis, autosomal dominant 3, osteopetrosis, autosomal dominant 4

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

41 retrieved; paginated sample, class counts are floors:

11 benign, 7 uncertain significance, 6 pathogenic, 6 pathogenic/likely pathogenic, 5 conflicting classifications of pathogenicity, 5 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1012215	NM_001287.6(CLCN7):c.952T>C (p.Phe318Leu)	CLCN7	Pathogenic	criteria provided, single submitter
1029299	NM_001287.6(CLCN7):c.739-18G>A	CLCN7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068483	NM_001287.6(CLCN7):c.856C>T (p.Arg286Trp)	CLCN7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453929	NM_001287.6(CLCN7):c.1576C>T (p.Arg526Trp)	CLCN7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1685637	NM_001287.6(CLCN7):c.2066del (p.Lys689fs)	CLCN7	Pathogenic	criteria provided, single submitter
1685638	NM_001287.6(CLCN7):c.1562G>C (p.Gly521Ala)	CLCN7	Pathogenic	criteria provided, single submitter
1932544	NM_001287.6(CLCN7):c.1194G>A (p.Trp398Ter)	CLCN7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372326	NM_001287.6(CLCN7):c.2144A>G (p.Tyr715Cys)	CLCN7	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
56890	NM_001287.6(CLCN7):c.296A>G (p.Tyr99Cys)	CLCN7	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
65635	NM_001287.6(CLCN7):c.643G>A (p.Gly215Arg)	CLCN7	Pathogenic	criteria provided, multiple submitters, no conflicts
6863	NM_001287.6(CLCN7):c.2299C>T (p.Arg767Trp)	CLCN7	Pathogenic	criteria provided, multiple submitters, no conflicts
1334479	NM_001287.6(CLCN7):c.1077C>A (p.Asn359Lys)	CLCN7	Likely pathogenic	criteria provided, single submitter
1526273	NM_001287.6(CLCN7):c.994A>G (p.Met332Val)	CLCN7	Likely pathogenic	criteria provided, single submitter
1802224	NM_001287.6(CLCN7):c.1448-2A>G	CLCN7	Likely pathogenic	criteria provided, single submitter
3578465	NM_001287.6(CLCN7):c.1883+1G>A	CLCN7	Likely pathogenic	criteria provided, single submitter
867226	NM_001287.6(CLCN7):c.1841T>G (p.Leu614Arg)	CLCN7	Likely pathogenic	criteria provided, single submitter
1017574	NM_001287.6(CLCN7):c.2240C>T (p.Thr747Met)	CLCN7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1371048	NM_001287.6(CLCN7):c.2385_2386del (p.Gly796fs)	CLCN7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1400616	NM_001287.6(CLCN7):c.812G>A (p.Arg271Gln)	CLCN7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1684675	NM_001287.6(CLCN7):c.2274C>G (p.Phe758Leu)	CLCN7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2098880	NM_001287.6(CLCN7):c.1750A>G (p.Met584Val)	CLCN7	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1220179	NM_001287.6(CLCN7):c.1531G>C (p.Ala511Pro)	CLCN7	Uncertain significance	criteria provided, multiple submitters, no conflicts
1465926	NM_001287.6(CLCN7):c.1797+4C>T	CLCN7	Uncertain significance	criteria provided, multiple submitters, no conflicts
1475213	NM_001287.6(CLCN7):c.871G>A (p.Ala291Thr)	CLCN7	Uncertain significance	criteria provided, multiple submitters, no conflicts
1516248	NM_001287.6(CLCN7):c.712G>A (p.Val238Met)	CLCN7	Uncertain significance	criteria provided, single submitter
2627406	NM_001287.6(CLCN7):c.1751T>C (p.Met584Thr)	CLCN7	Uncertain significance	criteria provided, single submitter
3894560	NM_001287.6(CLCN7):c.2283C>G (p.Phe761Leu)	CLCN7	Uncertain significance	criteria provided, single submitter
626086	NM_001287.6(CLCN7):c.2073+4C>T	CLCN7	Uncertain significance	criteria provided, multiple submitters, no conflicts
1164119	NM_001287.6(CLCN7):c.141+19C>G	CLCN7	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 16 · Orphanet: 3 · 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

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CLCN7	Orphanet:210110	Intermediate osteopetrosis
CLCN7	Orphanet:53	Albers-Schönberg osteopetrosis
CLCN7	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
CLCN7	HGNC:2025	ENSG00000103249	P51798	H(+)/Cl(-) exchange transporter 7	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CLCN7	H(+)/Cl(-) exchange transporter 7	Slowly voltage-gated channel mediating the exchange of chloride ions against protons.

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)
CLCN7	Other/Unknown	no		CBS_dom, ClC, CIC-7

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
left adrenal gland cortex	1
metanephros cortex	1
right adrenal gland cortex	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CLCN7	296	ubiquitous	marker	metanephros cortex, right adrenal gland cortex, left adrenal gland cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CLCN7	1,991

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CLCN7	P51798	9

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. 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
Stimuli-sensing channels	1	135.9×	0.007	CLCN7

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
response to pH	1	2808.7×	8e-04	CLCN7
transepithelial chloride transport	1	1872.4×	8e-04	CLCN7
chloride transmembrane transport	1	237.3×	0.004	CLCN7

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CLCN7	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	CLCN7

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)
CLCN7	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02584608	PHASE2	COMPLETED	Use of ACTIMMUNE in Patients With ADO2

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
INTERFERON GAMMA-1B	4	1