Autosomal recessive osteopetrosis 3

Summary

Autosomal recessive osteopetrosis 3 (MONDO:0009818) is a disease caused by CA2 (GenCC Definitive), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: CA2 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 90
• Phenotypes (HPO): 60

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		100	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

60 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0001947	Renal tubular acidosis	Very frequent (80-99%)
HP:0011002	Osteopetrosis	Very frequent (80-99%)
HP:0012379	Abnormal enzyme/coenzyme activity	Very frequent (80-99%)
HP:0000164	Abnormality of the dentition	Frequent (30-79%)
HP:0001263	Global developmental delay	Frequent (30-79%)
HP:0001293	Cranial nerve compression	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0002049	Proximal renal tubular acidosis	Frequent (30-79%)
HP:0002135	Basal ganglia calcification	Frequent (30-79%)
HP:0002514	Cerebral calcification	Frequent (30-79%)
HP:0002757	Recurrent fractures	Frequent (30-79%)
HP:0002901	Hypocalcemia	Frequent (30-79%)
HP:0003148	Elevated serum acid phosphatase	Frequent (30-79%)
HP:0003236	Elevated circulating creatine kinase concentration	Frequent (30-79%)
HP:0004322	Short stature	Frequent (30-79%)
HP:0008341	Distal renal tubular acidosis	Frequent (30-79%)
HP:0000126	Hydronephrosis	Occasional (5-29%)
HP:0000160	Narrow mouth	Occasional (5-29%)
HP:0000179	Thick lower lip vermilion	Occasional (5-29%)
HP:0000218	High palate	Occasional (5-29%)
HP:0000248	Brachycephaly	Occasional (5-29%)
HP:0000278	Retrognathia	Occasional (5-29%)
HP:0000347	Micrognathia	Occasional (5-29%)
HP:0000400	Macrotia	Occasional (5-29%)
HP:0000479	Abnormal retinal morphology	Occasional (5-29%)
HP:0000592	Blue sclerae	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0000692	Tooth malposition	Occasional (5-29%)
HP:0000767	Pectus excavatum	Occasional (5-29%)
HP:0000787	Nephrolithiasis	Occasional (5-29%)
HP:0000867	Secondary hyperparathyroidism	Occasional (5-29%)
HP:0001105	Retinal atrophy	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001328	Specific learning disability	Occasional (5-29%)
HP:0001357	Plagiocephaly	Occasional (5-29%)
HP:0001508	Failure to thrive	Occasional (5-29%)
HP:0001562	Oligohydramnios	Occasional (5-29%)
HP:0001873	Thrombocytopenia	Occasional (5-29%)
HP:0001876	Pancytopenia	Occasional (5-29%)
HP:0001882	Leukopenia	Occasional (5-29%)
HP:0001903	Anemia	Occasional (5-29%)
HP:0002240	Hepatomegaly	Occasional (5-29%)
HP:0002518	Abnormal periventricular white matter morphology	Occasional (5-29%)
HP:0002684	Thickened calvaria	Occasional (5-29%)
HP:0004445	Elliptocytosis	Occasional (5-29%)
HP:0005461	Craniofacial disproportion	Occasional (5-29%)
HP:0005528	Bone marrow hypocellularity	Occasional (5-29%)
HP:0006335	Persistence of primary teeth	Occasional (5-29%)
HP:0006641	Prominent floating ribs	Occasional (5-29%)
HP:0006824	Cranial nerve paralysis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive osteopetrosis 3
Mondo ID	MONDO:0009818
MeSH	C536058
OMIM	259730
Orphanet	2785
DOID	DOID:0110941
NCIT	C118438
SNOMED CT	254122007
UMLS	C0345407
MedGen	91042
GARD	0004154
Is cancer (heuristic)	no

Also known as: autosomal recessive osteopetrosis type 3 · Autosomal Recessive osteopetrosis, type 3 · CA2 osteopetrosis (disease) · carbonic anhydrase 2 deficiency · carbonic anhydrase II deficiency · Guibaud Vainsel syndrome · Guibaud-Vainsel syndrome · marble brain disease · mixed renal tubular acidosis · mixed RTA · OPTB3 · osteopetrosis (disease) caused by mutation in CA2 · osteopetrosis autosomal recessive 3 · osteopetrosis with renal tubular acidosis · osteopetrosis, autosomal recessive 3 · osteopetrosis, autosomal recessive 3, with renal tubular acidosis · osteopetrosis, autosomal recessive type 3 · renal tubular acidosis type 3

Data availability: 90 ClinVar variants · 4 GenCC gene-disease records · 5 cell lines.

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 3

Related subtypes (9): autosomal recessive osteopetrosis 1, autosomal recessive osteopetrosis 2, autosomal recessive osteopetrosis 5, 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

90 retrieved; paginated sample, class counts are floors:

54 uncertain significance, 7 pathogenic, 7 likely pathogenic, 6 conflicting classifications of pathogenicity, 6 likely benign, 4 benign, 3 pathogenic/likely pathogenic, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1810040	NM_000067.3(CA2):c.630_641delinsCACA (p.Leu211fs)	CA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2691368	NM_000067.3(CA2):c.610G>T (p.Glu204Ter)	CA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
288909	NM_000067.3(CA2):c.232+1G>A	CA2	Pathogenic	criteria provided, multiple submitters, no conflicts
4292335	NM_000067.3(CA2):c.381T>G (p.Tyr127Ter)	CA2	Pathogenic	criteria provided, single submitter
632527	NM_000067.3(CA2):c.681del (p.Lys227fs)	CA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
916	NM_000067.3(CA2):c.319C>T (p.His107Tyr)	CA2	Pathogenic	no assertion criteria provided
917	NM_000067.3(CA2):c.508-1G>C	CA2	Pathogenic	no assertion criteria provided
919	NM_000067.3(CA2):c.120T>G (p.Tyr40Ter)	CA2	Pathogenic	no assertion criteria provided
920	NM_000067.3(CA2):c.621del (p.Trp208fs)	CA2	Pathogenic	no assertion criteria provided
522744	NM_000067.3(CA2):c.21C>A (p.Tyr7Ter)	CA3-AS1	Pathogenic	criteria provided, single submitter
3595893	NM_000067.3(CA2):c.165_166insGAGGA (p.Ser56fs)	CA2	Likely pathogenic	criteria provided, single submitter
3595900	NM_000067.3(CA2):c.233-1G>A	CA2	Likely pathogenic	criteria provided, single submitter
3595901	NM_000067.3(CA2):c.314C>G (p.Ser105Ter)	CA2	Likely pathogenic	criteria provided, single submitter
3595904	NM_000067.3(CA2):c.445-2_445-1delinsTC	CA2	Likely pathogenic	criteria provided, single submitter
3595915	NM_000067.3(CA2):c.672del (p.Lys224fs)	CA2	Likely pathogenic	criteria provided, single submitter
804410	NM_000067.3(CA2):c.579C>G (p.Tyr193Ter)	CA2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
973759	NM_000067.3(CA2):c.275A>C (p.Gln92Pro)	CA2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1482044	NM_000067.3(CA2):c.339A>G (p.Lys113=)	CA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1495624	NM_000067.3(CA2):c.657C>T (p.Ser219=)	CA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
195010	NM_000067.3(CA2):c.35-7C>A	CA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2900404	NM_000067.3(CA2):c.651C>G (p.Val217=)	CA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
363834	NM_000067.3(CA2):c.508-7G>A	CA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
911481	NM_000067.3(CA2):c.462G>A (p.Pro154=)	CA2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1030577	NM_000067.3(CA2):c.311G>T (p.Gly104Val)	CA2	Uncertain significance	criteria provided, single submitter
1393124	NM_000067.3(CA2):c.541C>T (p.Arg181Cys)	CA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1476471	NM_000067.3(CA2):c.281A>G (p.His94Arg)	CA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1515382	NM_000067.3(CA2):c.445G>A (p.Val149Ile)	CA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1517076	NM_000067.3(CA2):c.709G>A (p.Glu237Lys)	CA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
198387	NM_000067.3(CA2):c.677G>A (p.Arg226His)	CA2	Uncertain significance	criteria provided, multiple submitters, no conflicts
1985815	NM_000067.3(CA2):c.434T>C (p.Ile145Thr)	CA2	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · 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
CA2	Definitive	Autosomal recessive	autosomal recessive osteopetrosis 3	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CA2	Orphanet:2785	Osteopetrosis with renal tubular acidosis

Cohort genes → proteins

2 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CA2	HGNC:1373	ENSG00000104267	P00918	Carbonic anhydrase 2	gencc,clinvar
CA3-AS1	HGNC:51657	ENSG00000253549		CA3 antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CA2	Carbonic anhydrase 2	Catalyzes the reversible hydration of carbon dioxide.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CA2	Enzyme (other)	yes	4.2.1.1	CA_dom, Carbonic_anhydrase_a-class_CS, Carbonic_anhydrase_a-class
CA3-AS1	Other/Unknown	no

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
mucosa of transverse colon	2
colonic mucosa	1
mucosa of sigmoid colon	1
male germ line stem cell (sensu Vertebrata) in testis	1
putamen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CA2	275	ubiquitous	marker	colonic mucosa, mucosa of sigmoid colon, mucosa of transverse colon
CA3-AS1	131	tissue_specific	yes	male germ line stem cell (sensu Vertebrata) in testis, mucosa of transverse colon, putamen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CA2	2,454
CA3-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CA2	P00918	1,241

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 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
Erythrocytes take up oxygen and release carbon dioxide	1	1268.9×	0.002	CA2
O2/CO2 exchange in erythrocytes	1	1268.9×	0.002	CA2
Reversible hydration of carbon dioxide	1	951.7×	0.002	CA2
Erythrocytes take up carbon dioxide and release oxygen	1	878.5×	0.002	CA2
Developmental Lineage of Pancreatic Ductal Cells	1	228.4×	0.006	CA2
Transport of small molecules	1	25.1×	0.046	CA2
Metabolism	1	11.6×	0.086	CA2

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 dipeptide transmembrane transport	1	8426.0×	8e-04	CA2
obsolete positive regulation of cellular pH reduction	1	4213.0×	8e-04	CA2
regulation of chloride transport	1	4213.0×	8e-04	CA2
regulation of monoatomic anion transport	1	3370.4×	8e-04	CA2
secretion	1	2106.5×	0.001	CA2
angiotensin-activated signaling pathway	1	1532.0×	0.001	CA2
carbon dioxide transport	1	1296.3×	0.001	CA2
positive regulation of synaptic transmission, GABAergic	1	991.3×	0.001	CA2
regulation of intracellular pH	1	601.9×	0.002	CA2
neuron cellular homeostasis	1	455.5×	0.002	CA2
morphogenesis of an epithelium	1	343.9×	0.003	CA2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) 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
CA3-AS1	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

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: 1; 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	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	CA3-AS1

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)
CA3-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.