OSTM1

Summary

OSTM1 (osteoclastogenesis associated transmembrane protein 1, HGNC:21652) is a protein-coding gene on chromosome 6q21, encoding Osteopetrosis-associated transmembrane protein 1 (Q86WC4). Required for osteoclast and melanocyte maturation and function.

This gene encodes a protein that may be involved in the degradation of G proteins via the ubiquitin-dependent proteasome pathway. The encoded protein binds to members of subfamily A of the regulator of the G-protein signaling (RGS) family through an N-terminal leucine-rich region. This protein also has a central RING finger-like domain and E3 ubiquitin ligase activity. This protein is highly conserved from flies to humans. Defects in this gene may cause the autosomal recessive, infantile malignant form of osteopetrosis.

Source: NCBI Gene 28962 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal recessive osteopetrosis 5 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 339 total — 21 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 68
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_014028

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:21652
Approved symbol	OSTM1
Name	osteoclastogenesis associated transmembrane protein 1
Location	6q21
Locus type	gene with protein product
Status	Approved
Aliases	HSPC019, GL
Ensembl gene	ENSG00000081087
Ensembl biotype	protein_coding
OMIM	607649
Entrez	28962

Gene structure

Transcript identifiers

Ensembl transcripts: 22 — 9 nonsense_mediated_decay, 6 protein_coding, 4 protein_coding_CDS_not_defined, 3 retained_intron

ENST00000193322, ENST00000440575, ENST00000467960, ENST00000477774, ENST00000492070, ENST00000492130, ENST00000699569, ENST00000699570, ENST00000699571, ENST00000699572, ENST00000699573, ENST00000699574, ENST00000699575, ENST00000699576, ENST00000699577, ENST00000699578, ENST00000699579, ENST00000699580, ENST00000699581, ENST00000699582, ENST00000699583, ENST00000699584

RefSeq mRNA: 1 — MANE Select: NM_014028 NM_014028

CCDS: CCDS5062

Canonical transcript exons

ENST00000193322 — 6 exons

Exon	Start	End
ENSE00001214019	108054490	108054587
ENSE00001214037	108051031	108051198
ENSE00001849310	108074250	108074741
ENSE00003524471	108049253	108049418
ENSE00003625927	108064185	108064299
ENSE00003976970	108041409	108044840

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 94.72.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 24.5000 / max 359.4613, expressed in 1800 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
74952	23.6515	1798
74951	0.7059	430
74950	0.1426	44

Top tissues by expression

292 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
choroid plexus epithelium	UBERON:0003911	94.72	gold quality
adrenal tissue	UBERON:0018303	94.53	gold quality
popliteal artery	UBERON:0002250	93.57	gold quality
tibial artery	UBERON:0007610	93.56	gold quality
stromal cell of endometrium	CL:0002255	93.35	gold quality
monocyte	CL:0000576	93.21	gold quality
leukocyte	CL:0000738	93.12	gold quality
mononuclear cell	CL:0000842	93.10	gold quality
aorta	UBERON:0000947	92.69	gold quality
left coronary artery	UBERON:0001626	92.18	gold quality
colonic epithelium	UBERON:0000397	92.02	gold quality
ascending aorta	UBERON:0001496	91.77	gold quality
thoracic aorta	UBERON:0001515	91.76	gold quality
islet of Langerhans	UBERON:0000006	91.63	gold quality
right coronary artery	UBERON:0001625	91.55	gold quality
decidua	UBERON:0002450	91.49	gold quality
buccal mucosa cell	CL:0002336	91.23	gold quality
pigmented layer of retina	UBERON:0001782	91.04	gold quality
retina	UBERON:0000966	91.01	gold quality
lower esophagus muscularis layer	UBERON:0035833	90.98	gold quality
left adrenal gland cortex	UBERON:0035825	90.95	gold quality
right lung	UBERON:0002167	90.94	gold quality
lower esophagus	UBERON:0013473	90.94	gold quality
left adrenal gland	UBERON:0001234	90.86	gold quality
coronary artery	UBERON:0001621	90.85	gold quality
descending thoracic aorta	UBERON:0002345	90.85	gold quality
right adrenal gland cortex	UBERON:0035827	90.84	gold quality
adrenal gland	UBERON:0002369	90.57	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	90.55	gold quality
calcaneal tendon	UBERON:0003701	90.51	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-MTAB-8142	yes	15.86
E-ANND-3	yes	5.95
E-GEOD-81383	no	1096.87

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ELF1, MITF, NFKB, NR4A1, REL, SPI1, STAT6

miRNA regulators (miRDB)

181 targeting OSTM1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-200B-3P	100.00	73.31	2693
HSA-MIR-200C-3P	100.00	73.35	2685
HSA-MIR-429	100.00	73.44	2698
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-302E	99.96	70.74	2669
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 16)

• mutation in the human GL gene leads to severe recessive osteopetrosis (PMID:12627228)
• The human GIPN gene has 6 exons and 5 introns, and encodes a 334-aa protein. (PMID:12826607)
• A novel mutation affecting the OSTM1 locus responsible for ARO. In addition to common clinical features of osteopetrosis, the patient developed a unique neuronal pathology that provided evidence for the role of OSTM1 in normal neuronal cell development. (PMID:17922613)
• This study reports on a 12-month-old female with recessive OSMT1 mutations and neuroimaging findings suggesting a malignant infantile osteopetrosis. (PMID:17985267)
• mutations in OSTM1 such as the C-terminal deletion mutant studied herein provoke dysregulation of the canonical Wnt/beta-catenin signaling pathway, providing a molecular basis for severe autosomal recessive osteopetrosis (PMID:18296023)
• Mutations in TCIRG1, OSTM1, ClCN7, and TNFRSF11A genes were detected in nine, three, one, and one patientswith infantile malignant osteopetrosis, respectively. (PMID:19507210)
• The authors show that both the aminoterminus and transmembrane span of the Ostm1 beta-subunit are required for ClC-7 Cl(-)/H(+)-exchange, whereas the Ostm1 transmembrane domain suffices for its ClC-7-dependent trafficking to lysosomes. (PMID:21527911)
• we describe for the first time homozygous microdeletions of different sizes affecting the OSTM1 gene in two unrelated consanguineous families with children suffering from neuronopathic infantile malignant osteopetrosi (PMID:23685543)
• Common gating underlies the slow voltage activation of ClC-7. (PMID:23983121)
• Ostm1 has a primary and autonomous role in neuronal homeostasis (PMID:24719316)
• KIF5B is essential for Ostm1 intracellular dispersion. (PMID:26598607)
• Homozygous splice defect in OSTM1, coexisting with MANEAL mutation was identified in a patient with neurological disorder with brain iron accumulation. (PMID:28612835)
• These studies defined bifunctional roles for Ostm1 as a major regulator of preosteoclast cytoskeletal rearrangements toward cell multinucleation and of mature osteoclast intracellular lysosomal trafficking and exocytosis mechanism, both of which are essential for bone resorption. (PMID:29297601)
• Osteopetrosis-Associated Transmembrane Protein 1 Recruits RNA Exosome To Restrict Hepatitis B Virus Replication. (PMID:32188736)
• Cryo-EM structure of the lysosomal chloride-proton exchanger CLC-7 in complex with OSTM1. (PMID:32749217)
• OSTM1 pleiotropic roles from osteopetrosis to neurodegeneration. (PMID:35902071)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ostm1	ENSDARG00000069808
mus_musculus	Ostm1	ENSMUSG00000038280
rattus_norvegicus	Ostm1	ENSRNOG00000037647
drosophila_melanogaster	CG14969	FBGN0035440
caenorhabditis_elegans		WBGENE00009627

Protein

Protein identifiers

Osteopetrosis-associated transmembrane protein 1 — Q86WC4 (reviewed: Q86WC4)

Alternative names: Chloride channel 7 beta subunit

All UniProt accessions (11): Q86WC4, A0A0A0MSP4, A0A8V8TNF1, A0A8V8TNF7, A0A8V8TNK5, A0A8V8TNX2, A0A8V8TNX7, A0A8V8TPT2, A0A8V8TPT7, A0A8V8TQ75, A0A8V8TQ80

UniProt curated annotations — full annotation on UniProt →

Function. Required for osteoclast and melanocyte maturation and function.

Subunit / interactions. Chloride channel 7 are heteromers of alpha (CLCN7) and beta (OSTM1) subunits.

Subcellular location. Lysosome membrane.

Post-translational modifications. Undergoes proteolytic cleavage in the luminal domain, the cleaved fragments might be linked by disulfide bonds with the remnant of the protein. Highly N-glycosylated.

Disease relevance. Osteopetrosis, autosomal recessive 5 (OPTB5) [MIM:259720] A rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. Osteopetrosis occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Recessive osteopetrosis commonly manifests in early infancy with macrocephaly, feeding difficulties, evolving blindness and deafness, bone marrow failure, severe anemia, and hepatosplenomegaly. Deafness and blindness are generally thought to represent effects of pressure on nerves. OPTB5 patients manifest primary central nervous system involvement in addition to the classical stigmata of severe bone sclerosis, growth failure, anemia, thrombocytopenia and visual impairment with optic atrophy. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the OSTM1 family.

RefSeq proteins (1): NP_054747* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR019172	Osteopetrosis-assoc_TM_1	Family

Pfam: PF09777

UniProt features (38 total): helix 11, glycosylation site 10, strand 5, modified residue 3, topological domain 2, turn 2, signal peptide 1, chain 1, sequence variant 1, sequence conflict 1, transmembrane region 1

Structure

Experimental structures (PDB)

9 structures.

PDB	Method	Resolution (Å)
9G6C	ELECTRON MICROSCOPY	1.8
7CQ5	ELECTRON MICROSCOPY	2.6
9G6E	ELECTRON MICROSCOPY	2.6
9G6D	ELECTRON MICROSCOPY	2.7
7JM7	ELECTRON MICROSCOPY	2.82
7CQ6	ELECTRON MICROSCOPY	3
7CQ7	ELECTRON MICROSCOPY	3.55
8HVT	ELECTRON MICROSCOPY	3.6
7BXU	ELECTRON MICROSCOPY	3.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86WC4-F1	74.62	0.44

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (3): 322, 325, 333

Glycosylation sites (10): 135, 163, 177, 184, 194, 216, 263, 274, 93, 128

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-2672351	Stimuli-sensing channels

MSigDB gene sets: 336 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, WAMUNYOKOLI_OVARIAN_CANCER_LMP_DN, ELVIDGE_HYPOXIA_DN, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOCC_VACUOLAR_MEMBRANE, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_INORGANIC_ANION_TRANSPORT, GOBP_MYELOID_LEUKOCYTE_DIFFERENTIATION, PATIL_LIVER_CANCER, WEI_MYCN_TARGETS_WITH_E_BOX, RICKMAN_TUMOR_DIFFERENTIATED_WELL_VS_POORLY_DN, AAACCAC_MIR140, GOBP_CHLORIDE_TRANSPORT, WANG_LMO4_TARGETS_DN, GOBP_TRANSEPITHELIAL_TRANSPORT

GO Biological Process (2): osteoclast differentiation (GO:0030316), transepithelial chloride transport (GO:0030321)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (5): lysosomal membrane (GO:0005765), cytosol (GO:0005829), chloride channel complex (GO:0034707), lysosome (GO:0005764), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Ion channel transport	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
myeloid leukocyte differentiation	1
chloride transport	1
transepithelial transport	1
binding	1
lysosome	1
lytic vacuole membrane	1
cytoplasm	1
monoatomic ion channel complex	1
lytic vacuole	1

Protein interactions and networks

STRING

976 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
OSTM1	CLCN7	P51798	999
OSTM1	TCIRG1	Q13488	964
OSTM1	PLEKHM1	Q9Y4G2	919
OSTM1	CLCN6	P51797	810
OSTM1	CA2	P00918	795
OSTM1	TNFRSF11A	Q9Y6Q6	779
OSTM1	SNX10	Q9Y5X0	772
OSTM1	TNFSF11	O14788	751
OSTM1	CLCN3	P51790	738
OSTM1	ATP4A	P20648	694
OSTM1	ATP12A	P54707	692
OSTM1	BSND	Q8WZ55	670
OSTM1	CLCN5	P51795	621
OSTM1	CLCN4	P51793	577
OSTM1	MSANTD1	Q6ZTZ1	569

IntAct

22 interactions, top by confidence:

A	B	Type	Score
OSTM1	CLCN7	psi-mi:“MI:0407”(direct interaction)	0.790
OSTM1	CLCN7	psi-mi:“MI:0915”(physical association)	0.790
CLCN7	OSTM1	psi-mi:“MI:0915”(physical association)	0.790
BIRC7	HTRA2	psi-mi:“MI:0914”(association)	0.640
SCGB1D1	FAM234B	psi-mi:“MI:0914”(association)	0.530
FAM177A1	SLC27A2	psi-mi:“MI:0914”(association)	0.530
FBXO2	TMEM131L	psi-mi:“MI:0914”(association)	0.530
LGALS3	PODXL	psi-mi:“MI:0914”(association)	0.530
CFTR	OSTM1	psi-mi:“MI:0915”(physical association)	0.370
ATP6AP2	TMUB1	psi-mi:“MI:0914”(association)	0.350
	SNAP23	psi-mi:“MI:0914”(association)	0.350
LGALS8	SLC22A23	psi-mi:“MI:0914”(association)	0.350
LGALS9	PODXL	psi-mi:“MI:0914”(association)	0.350
LGALS3	PODXL	psi-mi:“MI:0914”(association)	0.350
BIRC7	HTRA2	psi-mi:“MI:0914”(association)	0.350
P		psi-mi:“MI:0914”(association)	0.350
OSTM1	ILVBL	psi-mi:“MI:0914”(association)	0.350
OSTM1	ASMTL	psi-mi:“MI:0914”(association)	0.350

BioGRID (110): OSTM1 (Affinity Capture-MS), OSTM1 (Affinity Capture-MS), OSTM1 (Affinity Capture-MS), OSTM1 (Affinity Capture-MS), OSTM1 (Affinity Capture-MS), OSTM1 (Affinity Capture-MS), OSTM1 (Affinity Capture-MS), OSTM1 (Affinity Capture-MS), OSTM1 (Affinity Capture-MS), OSTM1 (Affinity Capture-MS), OSTM1 (Affinity Capture-MS), OSTM1 (Affinity Capture-MS), RGS19 (Reconstituted Complex), GPSM1 (Reconstituted Complex), RGS19 (Two-hybrid)

ESM2 similar proteins: A7MBM2, E9PY61, O00391, O08542, O60894, O60895, O76095, O77049, O88824, P52798, Q15904, Q16586, Q5Q0T9, Q5RJL6, Q641Q3, Q6IUU3, Q6P5F7, Q6PRD1, Q6UWJ8, Q6ZVN8, Q6ZVW7, Q7TQ32, Q80YF6, Q864V4, Q867C0, Q86WC4, Q8BGT0, Q8BH06, Q8BND5, Q8C1Q4, Q8K4C2, Q8N271, Q8N7M5, Q8NAC3, Q8R4C4, Q8R4C5, Q8R4C6, Q8VE43, Q91ZV8, Q96F46

Diamond homologs: Q86WC4, Q8BGT0

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

339 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	21
Likely pathogenic	5
Uncertain significance	123
Likely benign	131
Benign	38

Top pathogenic / likely-pathogenic (26)

Variant ID	HGVS	Classification
1072381	NM_014028.4(OSTM1):c.442del (p.Met148fs)	Pathogenic
1382109	NM_014028.4(OSTM1):c.410C>G (p.Ser137Ter)	Pathogenic
1453192	NM_014028.4(OSTM1):c.692dup (p.Ser232fs)	Pathogenic
195291	NM_014028.4(OSTM1):c.415_416del (p.Gln140fs)	Pathogenic
2032896	NM_014028.4(OSTM1):c.564T>G (p.Tyr188Ter)	Pathogenic
2089700	NM_014028.4(OSTM1):c.352del (p.Leu118fs)	Pathogenic
2692631	NM_014028.4(OSTM1):c.421_422del (p.Ser141fs)	Pathogenic
2703439	NM_014028.4(OSTM1):c.358C>T (p.Gln120Ter)	Pathogenic
2746162	NM_014028.4(OSTM1):c.560del (p.Val187fs)	Pathogenic
2767207	NM_014028.4(OSTM1):c.402_402+1dup	Pathogenic
2869196	NM_014028.4(OSTM1):c.498G>A (p.Trp166Ter)	Pathogenic
2888219	NM_014028.4(OSTM1):c.551del (p.Asn184fs)	Pathogenic
2915422	NM_014028.4(OSTM1):c.256G>T (p.Glu86Ter)	Pathogenic
2942	NM_014028.4(OSTM1):c.949+5G>A	Pathogenic
3246215	NC_000006.11:g.(?108395434)(108395855_?)del	Pathogenic
3246216	NC_000006.11:g.(?108385369)(108385523_?)del	Pathogenic
3255027	NM_014028.4(OSTM1):c.811C>T (p.Arg271Ter)	Pathogenic
3639746	NM_014028.4(OSTM1):c.548C>G (p.Ser183Ter)	Pathogenic
488566	NM_014028.4(OSTM1):c.783+5G>T	Pathogenic
632470	NM_014028.4(OSTM1):c.796C>T (p.Arg266Ter)	Pathogenic
802255	NM_014028.4(OSTM1):c.486del (p.Phe162fs)	Pathogenic
2501201	NM_014028.4(OSTM1):c.255_256delinsC (p.Glu86fs)	Likely pathogenic
2825542	NM_014028.4(OSTM1):c.402+1G>A	Likely pathogenic
3246217	NC_000006.11:g.(?108385369)(108385523_?)dup	Likely pathogenic
3246218	NC_000006.11:g.(?108375674)(108375811_?)dup	Likely pathogenic
3605425	NM_014028.4(OSTM1):c.517+1G>T	Likely pathogenic

SpliceAI

1791 predictions. Top by Δscore:

Variant	Effect	Δscore
6:108044649:A:AC	donor_gain	1.0000
6:108044666:AAGT:A	donor_gain	1.0000
6:108044667:AGT:A	donor_gain	1.0000
6:108044669:T:TA	donor_gain	1.0000
6:108048376:AGAAG:A	donor_gain	1.0000
6:108049252:CG:C	donor_gain	1.0000
6:108051025:A:AC	donor_gain	1.0000
6:108051025:ACTT:A	donor_loss	1.0000
6:108051026:C:CC	donor_gain	1.0000
6:108051026:CT:C	donor_loss	1.0000
6:108051026:CTTA:C	donor_gain	1.0000
6:108051027:TTACT:T	donor_loss	1.0000
6:108051028:TA:T	donor_loss	1.0000
6:108051029:A:AC	donor_gain	1.0000
6:108051029:ACTG:A	donor_gain	1.0000
6:108051029:ACTGC:A	donor_loss	1.0000
6:108051030:C:CC	donor_gain	1.0000
6:108051030:CT:C	donor_gain	1.0000
6:108051030:CTG:C	donor_gain	1.0000
6:108051030:CTGC:C	donor_gain	1.0000
6:108051030:CTGCA:C	donor_gain	1.0000
6:108051194:TTCCC:T	acceptor_gain	1.0000
6:108051196:CCC:C	acceptor_gain	1.0000
6:108051197:CCC:C	acceptor_gain	1.0000
6:108051199:C:CC	acceptor_gain	1.0000
6:108051199:CT:C	acceptor_loss	1.0000
6:108054584:CAAT:C	acceptor_gain	1.0000
6:108064179:ACTT:A	donor_loss	1.0000
6:108064180:CTT:C	donor_loss	1.0000
6:108064181:TTA:T	donor_loss	1.0000

AlphaMissense

2187 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:108049395:C:A	W269C	1.000
6:108049395:C:G	W269C	1.000
6:108049296:A:C	S302R	0.999
6:108049296:A:T	S302R	0.999
6:108049298:T:G	S302R	0.999
6:108049397:A:G	W269R	0.999
6:108049397:A:T	W269R	0.999
6:108049315:G:C	P296R	0.998
6:108049342:G:T	A287D	0.998
6:108049377:A:C	C275W	0.998
6:108049413:G:C	N263K	0.998
6:108049413:G:T	N263K	0.998
6:108051033:C:G	A261P	0.998
6:108051050:C:G	C255S	0.998
6:108051051:A:G	C255R	0.998
6:108051051:A:T	C255S	0.998
6:108064204:C:A	W166C	0.998
6:108064204:C:G	W166C	0.998
6:108049300:A:G	L301P	0.997
6:108049378:C:G	C275S	0.997
6:108049378:C:T	C275Y	0.997
6:108049379:A:G	C275R	0.997
6:108049379:A:T	C275S	0.997
6:108049405:C:G	R266P	0.997
6:108051036:C:G	D260H	0.997
6:108051049:G:C	C255W	0.997
6:108051050:C:T	C255Y	0.997
6:108051142:G:C	C224W	0.997
6:108051152:C:G	C221S	0.997
6:108051153:A:T	C221S	0.997

dbSNP variants (sampled 300 via entrez): RS1000013029 (6:108048177 A>C), RS1000043411 (6:108076218 C>T), RS1000044779 (6:108050651 G>A,C), RS1000165955 (6:108064268 C>T), RS1000224707 (6:108057628 A>C), RS1000261834 (6:108075949 A>C), RS1000368497 (6:108070392 T>C), RS1000450712 (6:108063921 A>G), RS1000469624 (6:108052432 C>A), RS1000606063 (6:108074781 C>T), RS1000785037 (6:108043627 A>T), RS1000852681 (6:108045386 C>G), RS1000954680 (6:108076672 G>A), RS1001028607 (6:108057780 G>A,C), RS1001071739 (6:108043885 C>T)

Disease associations

OMIM: gene MIM:607649 | disease phenotypes: MIM:259720

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal recessive osteopetrosis 5	Definitive	Autosomal recessive
infantile osteopetrosis with neuroaxonal dysplasia	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
autosomal recessive osteopetrosis 5	Definitive	AR

Mondo (3): autosomal recessive osteopetrosis 5 (MONDO:0009817), osteopetrosis (MONDO:0017198), infantile osteopetrosis with neuroaxonal dysplasia (MONDO:0010866)

Orphanet (2): Infantile osteopetrosis with neuroaxonal dysplasia (Orphanet:85179), Osteopetrosis and related disorders (Orphanet:2781)

HPO phenotypes

68 total (30 of 68 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000212	Gingival overgrowth
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000321	Square face
HP:0000343	Long philtrum
HP:0000347	Micrognathia
HP:0000405	Conductive hearing impairment
HP:0000505	Visual impairment
HP:0000520	Proptosis
HP:0000543	Optic disc pallor
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000737	Irritability
HP:0001141	Severely reduced visual acuity
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001274	Agenesis of corpus callosum
HP:0001276	Hypertonia
HP:0001290	Generalized hypotonia
HP:0001338	Partial agenesis of the corpus callosum
HP:0001347	Hyperreflexia
HP:0001399	Hepatic failure
HP:0001433	Hepatosplenomegaly
HP:0001510	Growth delay
HP:0001541	Ascites
HP:0001744	Splenomegaly
HP:0001873	Thrombocytopenia
HP:0001876	Pancytopenia
HP:0001903	Anemia

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST005108_1	Major depressive disorder	3.000000e-07
GCST011109_3	Psoriasis	1.000000e-08

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D010022	Osteopetrosis	C05.116.099.708.702.678
C536055	Osteopetrosis and infantile neuroaxonal dystrophy (supp.)
C566883	Osteopetrosis, Autosomal Recessive 5 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

58 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression	4
bisphenol A	increases abundance, affects cotreatment, increases methylation, decreases methylation, increases expression (+1 more)	2
sodium arsenite	increases expression, decreases expression, increases abundance	2
apilimod	affects response to substance	2
Air Pollutants	increases expression, decreases expression, increases abundance	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
Tretinoin	increases expression	2
Cyclosporine	increases expression	2
Aflatoxin B1	affects expression, increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
bisphenol F	increases expression	1
ginger extract	decreases reaction, increases abundance, increases expression	1
methylmercuric chloride	decreases expression	1
kojic acid	decreases expression	1
3,4-dichloroaniline	increases expression	1
beta-lapachone	increases expression	1
sulforaphane	increases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
aflatoxin B2	decreases methylation	1
lei gong teng	increases expression	1
epigallocatechin gallate	increases expression	1
avobenzone	increases expression	1
exemestane	increases expression	1
di-n-butylphosphoric acid	affects expression	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
bisphenol B	increases expression	1

Clinical trials (associated diseases)

18 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00004402	PHASE3	COMPLETED	Phase III Randomized Study of Interferon Gamma in Children With Severe, Congenital Osteopetrosis
NCT00638820	PHASE2	TERMINATED	Reduced Intensity AlloTransplant For Osteopetrosis
NCT00968864	PHASE2	TERMINATED	T-cell Depleted Alternative Donor Transplantation
NCT02171104	PHASE2	ACTIVE_NOT_RECRUITING	MT2013-31: Allo HCT for Metabolic Disorders and Severe Osteopetrosis
NCT02666768	PHASE2	COMPLETED	ACTIMMUNE in Intermediate Osteopetrosis
NCT00145886	PHASE1	TERMINATED	rhPTH Therapy for Low Turnover Bone Fragility
NCT00775931	PHASE2/PHASE3	COMPLETED	Allogeneic Transplantation For Severe Osteopetrosis
NCT01019876	PHASE2/PHASE3	COMPLETED	Risk-Adapted Allogeneic Stem Cell Transplantation For Mixed Donor Chimerism In Patients With Non-Malignant Diseases
NCT01087398	PHASE2/PHASE3	UNKNOWN	Hematopoietic Stem Cell Transplantation for Malignant Infantile Osteopetrosis
NCT00730314	PHASE1/PHASE2	COMPLETED	Unrelated Hematopoietic Stem Cell Transplantation(HSCT) for Genetic Diseases of Blood Cells
NCT02065869	PHASE1/PHASE2	TERMINATED	Safety Study of Gene Modified Donor T-cells Following TCRαβ+ Depleted Stem Cell Transplant
NCT03301168	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Study of Gene Modified Donor T-cells Following TCR Alpha Beta Positive Depleted Stem Cell Transplant
NCT00043329	Not specified	COMPLETED	Post Marketing Surveillance Study of Actimmune in Patients With Severe, Malignant Osteopetrosis
NCT00145587	Not specified	TERMINATED	Stem Cell Transplantation for Children Affected With Osteopetrosis
NCT01199094	Not specified	COMPLETED	Clinical Assessment of Patients With High Bone Mass Due to Mutation in Lrp5
NCT01200017	Not specified	NO_LONGER_AVAILABLE	Expanded Access Protocol (EAP) Using the CliniMACS® Device for Pediatric Haplocompatible Donor Stem Cell Transplant
NCT03333200	Not specified	RECRUITING	Longitudinal Study of Neurodegenerative Disorders
NCT06521580	Not specified	COMPLETED	Outcomes of Patients With Osteopetrosis Weight-bearing Bone Fractures