Autosomal recessive osteopetrosis 1

Summary

Autosomal recessive osteopetrosis 1 (MONDO:0009815) is a disease caused by TCIRG1 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: TCIRG1 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 490

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive osteopetrosis 1
Mondo ID	MONDO:0009815
MeSH	C564915
OMIM	259700
DOID	DOID:0110942
NCIT	C167215
UMLS	C1850127
MedGen	376708
GARD	0002579
Is cancer (heuristic)	no

Also known as: autosomal recessive Albers-Schonberg disease · autosomal recessive malignant osteopetrosis caused by mutation in TCIRG1 · autosomal recessive osteopetrosis 1 · autosomal recessive osteopetrosis caused by mutation in TCIRG1 · autosomal recessive osteopetrosis type 1 · infantile malignant osteopetrosis 1 · marble bones autosomal recessive · OPTB1 · osteopetrosis autosomal recessive 1 · osteopetrosis infantile malignant 1 · osteopetrosis, autosomal recessive 1 · osteopetrosis, autosomal recessive type 1 · TCIRG1 autosomal recessive malignant osteopetrosis · TCIRG1 autosomal recessive osteopetrosis

Data availability: 490 ClinVar variants · 4 GenCC gene-disease records · 4 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 1

Related subtypes (9): 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

490 retrieved; paginated sample, class counts are floors:

161 uncertain significance, 99 likely pathogenic, 63 pathogenic/likely pathogenic, 58 conflicting classifications of pathogenicity, 52 likely benign, 37 pathogenic, 11 benign/likely benign, 9 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068056	NM_006019.4(TCIRG1):c.196+1G>T	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068057	NM_006019.4(TCIRG1):c.631-2A>C	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068788	NM_006019.4(TCIRG1):c.797del (p.Glu266fs)	TCIRG1	Pathogenic	criteria provided, multiple submitters, no conflicts
1069252	NM_006019.4(TCIRG1):c.824_825del (p.Glu275fs)	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070231	NM_006019.4(TCIRG1):c.449_452del (p.Glu150fs)	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070809	NM_006019.4(TCIRG1):c.376C>T (p.Gln126Ter)	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1073552	NM_006019.4(TCIRG1):c.1371del (p.Gly458fs)	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1075994	NM_006019.4(TCIRG1):c.2218_2219del (p.Leu740fs)	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1217234	NM_006019.4(TCIRG1):c.504-6C>A	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1400096	NM_006019.4(TCIRG1):c.787C>T (p.Gln263Ter)	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1406783	NM_006019.4(TCIRG1):c.530_537del (p.His177fs)	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1447238	NM_006019.4(TCIRG1):c.2383_2384del (p.Ala796fs)	TCIRG1	Pathogenic	criteria provided, multiple submitters, no conflicts
1451764	NM_006019.4(TCIRG1):c.1978del (p.Arg660fs)	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452934	NM_006019.4(TCIRG1):c.971dup (p.Cys324fs)	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452936	NM_006019.4(TCIRG1):c.1230del (p.Leu411fs)	TCIRG1	Pathogenic	criteria provided, multiple submitters, no conflicts
1454531	NM_006019.4(TCIRG1):c.523G>T (p.Glu175Ter)	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454681	NM_006019.4(TCIRG1):c.1320_1321del (p.Phe441fs)	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456297	NM_006019.4(TCIRG1):c.1648_1651dup (p.Val551fs)	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456669	NM_006019.4(TCIRG1):c.1312C>T (p.Gln438Ter)	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456773	NM_006019.4(TCIRG1):c.1459del (p.Trp487fs)	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458586	NM_006019.4(TCIRG1):c.630G>A (p.Thr210=)	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458624	NM_006019.4(TCIRG1):c.1348_1376dup (p.Phe459fs)	TCIRG1	Pathogenic	criteria provided, multiple submitters, no conflicts
1460225	NM_006019.4(TCIRG1):c.688C>T (p.Gln230Ter)	TCIRG1	Pathogenic	criteria provided, multiple submitters, no conflicts
1507699	NM_006019.4(TCIRG1):c.2161_2163del (p.Ile721del)	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1684665	NM_006019.4(TCIRG1):c.807+2T>G	TCIRG1	Pathogenic	criteria provided, single submitter
1684666	NM_006019.4(TCIRG1):c.2014-1G>A	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1684667	NM_006019.4(TCIRG1):c.1165+1G>C	TCIRG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1684673	NM_006019.4(TCIRG1):c.969G>A (p.Trp323Ter)	TCIRG1	Pathogenic	criteria provided, single submitter
1684679	NM_006019.4(TCIRG1):c.2236+1G>C	TCIRG1	Pathogenic	criteria provided, single submitter
1684680	NM_006019.4(TCIRG1):c.1885C>T (p.Gln629Ter)	TCIRG1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 5 · 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
TCIRG1	Definitive	Autosomal recessive	autosomal recessive osteopetrosis 1	9

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
PLEKHM1	Orphanet:210110	Intermediate osteopetrosis

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

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
PLEKHM1	HGNC:29017	ENSG00000225190	Q9Y4G2	Pleckstrin homology domain-containing family M member 1	clinvar
MIR6753	HGNC:50255	ENSG00000275022		microRNA 6753	clinvar

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.
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.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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
Scaffold/PPI	1	5.8×	0.327
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TCIRG1	Other/Unknown	no		V-ATPase_116kDa_su, V-type_ATPase_116kDa_su_euka
PLEKHM1	Scaffold/PPI	no		PH_domain, PKC_DAG/PE, Run_dom
MIR6753	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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
blood	3
granulocyte	2
spleen	1
esophagus mucosa	1
lower esophagus mucosa	1
body of pancreas	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TCIRG1	148	ubiquitous	marker	granulocyte, blood, spleen
PLEKHM1	134	broad	yes	lower esophagus mucosa, esophagus mucosa, blood
MIR6753	115		yes	blood, granulocyte, body of pancreas

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TCIRG1	1,931
PLEKHM1	1,038
MIR6753	0

Intra-cohort edges

A	B	Sources
PLEKHM1	TCIRG1	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PLEKHM1	Q9Y4G2	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TCIRG1	Q13488	83.52

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 3 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
Insulin receptor recycling	1	380.7×	0.006	TCIRG1
Transferrin endocytosis and recycling	1	368.4×	0.006	TCIRG1
ROS and RNS production in phagocytes	1	335.9×	0.006	TCIRG1
Amino acids regulate mTORC1	1	200.3×	0.007	TCIRG1
Ion channel transport	1	96.0×	0.013	TCIRG1
Neutrophil degranulation	1	23.1×	0.043	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 2 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 silver ion	1	8426.0×	0.003	TCIRG1
dentin mineralization	1	8426.0×	0.003	TCIRG1
protein catabolic process in the vacuole	1	4213.0×	0.003	TCIRG1
memory T cell activation	1	4213.0×	0.003	TCIRG1
regulation of proton transport	1	2808.7×	0.003	TCIRG1
T-helper 1 cell activation	1	2808.7×	0.003	TCIRG1
osteoclast proliferation	1	1685.2×	0.003	TCIRG1
tooth eruption	1	1685.2×	0.003	TCIRG1
pH reduction	1	1203.7×	0.003	TCIRG1
establishment of vesicle localization	1	1203.7×	0.003	TCIRG1
phagosome acidification	1	1203.7×	0.003	TCIRG1
ruffle organization	1	648.1×	0.005	TCIRG1
regulation of osteoblast differentiation	1	648.1×	0.005	TCIRG1
optic nerve development	1	601.9×	0.005	TCIRG1
autophagosome-lysosome fusion	1	601.9×	0.005	PLEKHM1
enamel mineralization	1	601.9×	0.005	TCIRG1
positive regulation of bone resorption	1	495.6×	0.005	PLEKHM1
positive regulation of ruffle assembly	1	495.6×	0.005	PLEKHM1
late endosome to lysosome transport	1	495.6×	0.005	PLEKHM1
vacuolar acidification	1	366.4×	0.006	TCIRG1
immunoglobulin mediated immune response	1	351.1×	0.006	TCIRG1
lysosomal lumen acidification	1	337.0×	0.006	TCIRG1
bone resorption	1	290.6×	0.007	TCIRG1
hematopoietic stem cell homeostasis	1	280.9×	0.007	TCIRG1
cellular response to cytokine stimulus	1	271.8×	0.007	TCIRG1
lysosome localization	1	263.3×	0.007	PLEKHM1
T cell homeostasis	1	227.7×	0.007	TCIRG1
regulation of insulin secretion	1	195.9×	0.008	TCIRG1
establishment of cell polarity	1	191.5×	0.008	TCIRG1
T cell differentiation	1	191.5×	0.008	TCIRG1

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
TCIRG1	0	0
PLEKHM1	0	0
MIR6753	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	3	TCIRG1, PLEKHM1, MIR6753

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TCIRG1	0	—
PLEKHM1	0	—
MIR6753	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.