MBTPS2

Summary

MBTPS2 (membrane bound transcription factor peptidase, site 2, HGNC:15455) is a protein-coding gene on chromosome Xp22.12, encoding Membrane-bound transcription factor site-2 protease (O43462). Zinc metalloprotease that mediates intramembrane proteolysis of proteins such as ATF6, ATF6B, SREBF1/SREBP1 and SREBF2/SREBP2. It is a selective cancer dependency (DepMap: 62.2% of cell lines).

This gene encodes a intramembrane zinc metalloprotease, which is essential in development. This protease functions in the signal protein activation involved in sterol control of transcription and the ER stress response. Mutations in this gene have been associated with ichthyosis follicularis with atrichia and photophobia (IFAP syndrome); IFAP syndrome has been quantitatively linked to a reduction in cholesterol homeostasis and ER stress response.

Source: NCBI Gene 51360 — RefSeq curated summary.

At a glance

• Gene–disease (curated): IFAP syndrome 1, with or without BRESHECK syndrome (Definitive, ClinGen) — +7 more curated relationships
• Clinical variants (ClinVar): 387 total — 14 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 197
• Cancer dependency (DepMap): dependent in 62.2% of screened cell lines
• MANE Select transcript: NM_015884

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15455
Approved symbol	MBTPS2
Name	membrane bound transcription factor peptidase, site 2
Location	Xp22.12
Locus type	gene with protein product
Status	Approved
Aliases	S2P
Ensembl gene	ENSG00000012174
Ensembl biotype	protein_coding
OMIM	300294
Entrez	51360

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 protein_coding_CDS_not_defined

ENST00000365779, ENST00000379484, ENST00000465888, ENST00000860793, ENST00000860794, ENST00000860795, ENST00000934337

RefSeq mRNA: 1 — MANE Select: NM_015884 NM_015884

CCDS: CCDS14201

Canonical transcript exons

ENST00000379484 — 11 exons

Exon	Start	End
ENSE00000666765	21878497	21878692
ENSE00000666768	21868467	21868585
ENSE00000870719	21880897	21880972
ENSE00000870720	21878042	21878136
ENSE00001223708	21869498	21869678
ENSE00001481258	21882433	21885423
ENSE00003459802	21839617	21839809
ENSE00003487695	21853376	21853503
ENSE00003517759	21843170	21843318
ENSE00003543829	21851509	21851612
ENSE00003686875	21845171	21845384

Expression profiles

Bgee: expression breadth ubiquitous, 264 present calls, max score 97.29.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.7547 / max 171.8121, expressed in 1805 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
195725	18.0479	1799
195726	4.7069	1633

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	97.29	gold quality
tibia	UBERON:0000979	93.77	gold quality
parietal pleura	UBERON:0002400	92.40	gold quality
pigmented layer of retina	UBERON:0001782	92.03	gold quality
Brodmann (1909) area 23	UBERON:0013554	91.90	gold quality
decidua	UBERON:0002450	90.98	gold quality
germinal epithelium of ovary	UBERON:0001304	90.65	gold quality
visceral pleura	UBERON:0002401	90.65	gold quality
pleura	UBERON:0000977	90.29	gold quality
parotid gland	UBERON:0001831	89.93	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	89.81	gold quality
cartilage tissue	UBERON:0002418	89.57	gold quality
middle temporal gyrus	UBERON:0002771	89.52	gold quality
biceps brachii	UBERON:0001507	88.68	gold quality
upper leg skin	UBERON:0004262	88.32	gold quality
cauda epididymis	UBERON:0004360	88.09	gold quality
heart right ventricle	UBERON:0002080	87.89	gold quality
placenta	UBERON:0001987	87.86	gold quality
caput epididymis	UBERON:0004358	87.44	gold quality
corpus epididymis	UBERON:0004359	87.29	gold quality
esophagus squamous epithelium	UBERON:0006920	87.27	gold quality
seminal vesicle	UBERON:0000998	87.18	gold quality
skin of hip	UBERON:0001554	87.17	gold quality
secondary oocyte	CL:0000655	86.08	gold quality
pons	UBERON:0000988	85.80	gold quality
stromal cell of endometrium	CL:0002255	85.61	gold quality
islet of Langerhans	UBERON:0000006	85.45	gold quality
lateral nuclear group of thalamus	UBERON:0002736	84.85	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	84.83	gold quality
postcentral gyrus	UBERON:0002581	84.75	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.27
E-GEOD-98556	no	1393.71

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
HSPA5	Activation

Upstream regulators (CollecTRI, top): ATF6, ESR1, NFKB1

miRNA regulators (miRDB)

160 targeting MBTPS2, 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-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-4262	100.00	73.26	3931
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-4500	99.99	72.72	2367
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4803	99.98	71.99	3117
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 62.2% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 18)

• S2P-mediated ATF6 cleavage is involved in regulating XBP1 in signaling the unfolded protein response. (PMID:11850408)
• S2P cleavage is blocked by the bulky ATF6 luminal domain, which is reduced in size by S1P (PMID:15299016)
• assign the IFAP syndrome locus to the 5.4 Mb region between DXS989 and DXS8019 on Xp22.11-p22.13 and provide evidence that missense mutations of membrane-bound transcription factor protease, site 2 (MBTPS2) are associated with this phenotype (PMID:19361614)
• study presents the largest kindred of ichthyosis follicularis, alopecia and photophobia (IFAP) reported to date clearly demonstrating X-linked inheritance; missense mutations of the gene, MBTPS2 are associated with the IFAP phenotype in this kindred (PMID:19689518)
• Missense mutations in the MBTPS2 gene have been identified as the cause of Follicularis Spinulosa Decalvans (KFSD). (PMID:20672378)
• Chinese family with a mild IFAP phenotype and a novel mutation in the MBTPS2 gene (PMID:20854407)
• We confirm that MBTPS2 mutations cause ichthyosis follicularis atricia and photophobia syndrome in patients of Chinese origin (PMID:21315478)
• Both intronic MBTPS2 c.671-9T>G and c.225-6T>A point mutations are ichthyosis follicularis, alopecia and photophobia syndrome causing mutations. (PMID:21426410)
• We report a fourth pedigree affected with Keratosis Follicularis Spinulosa Decalvans resulting from a recurrent missense mutation in the MBTPS2 gene. (PMID:22816986)
• We demonstrate a novel association between an MBTPS2 mutation and an X-linked form of Olmsted syndrome. (PMID:22931912)
• In male patients, a genotype-phenotype correlation has begun to emerge, linking the site of the mutation in MBTPS2 with the clinical outcome described as IFAP syndrome. (PMID:23316014)
• S2P is essential owing to its activation of the sterol regulatory element binding proteins (SREBPs); in the absence of exogenous lipid, cells lacking S2P cannot survive. (Review) (PMID:23571157)
• MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta. (PMID:27380894)
• This study identified a direct regulatory effect of MBTPS2 on TRPV3 which can partially contribute to the overlapping clinical features of IFAP and Olmsted syndromes under a common signaling pathway. (PMID:28717930)
• Study reports a novel missense mutation c.638C>T (p.Ser213Leu) in MBTPS2 in a large Chinese family with keratosis follicularis spinulosa decalvans. (PMID:29951998)
• Study reports a three-generation Chinese pedigree with a mild phenotype of ichthyosis follicularis with atrichia and photophobia syndrome caused by a novel hemizygous missense mutation c.1494G>T (p.Leu498Phe) in exon 11 of MBTPS2. (PMID:30294811)
• MBTPS2 mutation is associated with Retinal venous tortuosity. (PMID:30589367)
• MBTPS2, a membrane bound protease, underlying several distinct skin and bone disorders. (PMID:33743732)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	mbtps2	ENSDARG00000057577
mus_musculus	Mbtps2	ENSMUSG00000046873
rattus_norvegicus	Yy2	ENSRNOG00000007644
drosophila_melanogaster	S2P	FBGN0033656
caenorhabditis_elegans		WBGENE00013225

Protein

Protein identifiers

Membrane-bound transcription factor site-2 protease — O43462 (reviewed: O43462)

Alternative names: Endopeptidase S2P, Sterol regulatory element-binding proteins intramembrane protease

All UniProt accessions (2): O43462, B9ZVQ3

UniProt curated annotations — full annotation on UniProt →

Function. Zinc metalloprotease that mediates intramembrane proteolysis of proteins such as ATF6, ATF6B, SREBF1/SREBP1 and SREBF2/SREBP2. Catalyzes the second step in the proteolytic activation of the sterol regulatory element-binding proteins (SREBPs) SREBF1/SREBP1 and SREBF2/SREBP2: cleaves SREBPs within the first transmembrane segment, thereby releasing the N-terminal segment with a portion of the transmembrane segment attached. Mature N-terminal SREBP fragments shuttle to the nucleus and activate gene transcription. Also mediates the second step in the proteolytic activation of the cyclic AMP-dependent transcription factor ATF-6 (ATF6 and ATF6B). Involved in intramembrane proteolysis during bone formation. In astrocytes and osteoblasts, upon DNA damage and ER stress, mediates the second step of the regulated intramembrane proteolytic activation of the transcription factor CREB3L1, leading to the inhibition of cell-cycle progression.

Subcellular location. Membrane. Cytoplasm. Golgi apparatus membrane.

Tissue specificity. Expressed in heart, brain, placenta, lung, liver, muscle, kidney and pancreas.

Disease relevance. IFAP syndrome 1, with or without Bresheck syndrome (IFAP1) [MIM:308205] An X-linked syndrome characterized by a peculiar triad of follicular ichthyosis, total or subtotal atrichia, and photophobia of varying degree. Histopathologically, the epidermal granular layer is generally well-preserved or thickened at the infundibulum. Hair follicles are poorly developed and tend to be surrounded by an inflammatory infiltrate. A subgroup of patients is described with lamellar rather than follicular ichthyosis. Non-consistent features may include growth and psychomotor retardation, aganglionic megacolon, seizures and nail dystrophy. The disease is caused by variants affecting the gene represented in this entry. Olmsted syndrome, X-linked (OLMSX) [MIM:300918] A rare congenital disorder characterized by bilateral mutilating palmoplantar keratoderma and periorificial keratotic plaques with severe itching at all lesions. Diffuse alopecia, constriction of digits, and onychodystrophy have also been reported. Infections and squamous cell carcinomas can arise on the keratotic areas. The digital constriction may progress to autoamputation of fingers and toes. The disease is caused by variants affecting the gene represented in this entry. Keratosis follicularis spinulosa decalvans X-linked (KFSDX) [MIM:308800] A rare disorder affecting the skin and the eye. Affected men show thickening of the skin of the neck, ears, and extremities, especially the palms and soles, loss of eyebrows, eyelashes and beard, thickening of the eyelids with blepharitis and ectropion, and corneal degeneration. The disease is caused by variants affecting the gene represented in this entry. Osteogenesis imperfecta 19 (OI19) [MIM:301014] An X-linked form of osteogenesis imperfecta, a disorder of bone formation characterized by low bone mass, bone fragility and susceptibility to fractures after minimal trauma. Disease severity ranges from very mild forms without fractures to intrauterine fractures and perinatal lethality. Extraskeletal manifestations, which affect a variable number of patients, are dentinogenesis imperfecta, hearing loss, and blue sclerae. OI19 is characterized by prenatal fractures, short stature, white sclerae, variable scoliosis and pectal deformity, striking tibial anterior angulation and generalized osteopenia. The disease is caused by variants affecting the gene represented in this entry.

Cofactor. Binds 1 zinc ion per subunit.

Similarity. Belongs to the peptidase M50A family.

RefSeq proteins (1): NP_056968* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001193	MBTPS2	Family
IPR008915	Peptidase_M50	Domain
IPR036034	PDZ_sf	Homologous_superfamily

Pfam: PF02163

Enzyme classification (BRENDA):

• EC 3.4.24.85 — S2P endopeptidase (BRENDA: 37 organisms, 52 substrates, 14 inhibitors, 0 Km, 0 kcat entries)

UniProt features (36 total): transmembrane region 10, sequence variant 9, topological domain 6, mutagenesis site 5, binding site 2, chain 1, region of interest 1, active site 1, glycosylation site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O43462-F1	87.78	0.67

Functional residue map

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

Catalytic / active sites (1): 172

Ligand- & substrate-binding residues (2): 171; 175

Glycosylation sites (1): 337

Mutagenesis-validated functional residues (5):

Position	Phenotype
171	loss of activity.
172	loss of activity.
172	partial loss of activity.
175	loss of activity.
467	loss of activity.

Function

Pathways and Gene Ontology

Reactome pathways

14 pathways

ID	Pathway
R-HSA-1655829	Regulation of cholesterol biosynthesis by SREBP (SREBF)
R-HSA-381033	ATF6 (ATF6-alpha) activates chaperones
R-HSA-8874177	ATF6B (ATF6-beta) activates chaperones
R-HSA-8874211	CREB3 factors activate genes
R-HSA-8963889	Assembly of active LPL and LIPC lipase complexes
R-HSA-1430728	Metabolism
R-HSA-174824	Plasma lipoprotein assembly, remodeling, and clearance
R-HSA-2262752	Cellular responses to stress
R-HSA-381119	Unfolded Protein Response (UPR)
R-HSA-382551	Transport of small molecules
R-HSA-556833	Metabolism of lipids
R-HSA-8953897	Cellular responses to stimuli
R-HSA-8957322	Metabolism of steroids
R-HSA-8963899	Plasma lipoprotein remodeling

MSigDB gene sets: 575 (showing top): HORIUCHI_WTAP_TARGETS_DN, REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, GOBP_SKELETAL_SYSTEM_DEVELOPMENT, GOMF_METALLOPEPTIDASE_ACTIVITY, GOBP_RESPONSE_TO_ENDOPLASMIC_RETICULUM_STRESS, GOBP_CELL_CYCLE_PHASE_TRANSITION, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, GOBP_POSITIVE_REGULATION_OF_ALCOHOL_BIOSYNTHETIC_PROCESS, GOBP_MITOTIC_G2_M_TRANSITION_CHECKPOINT, GOBP_CELLULAR_RESPONSE_TO_TOPOLOGICALLY_INCORRECT_PROTEIN, GOBP_REGULATION_OF_CELL_CYCLE_G2_M_PHASE_TRANSITION, GOBP_REGULATION_OF_LIPID_BIOSYNTHETIC_PROCESS, GOBP_REGULATION_OF_CHOLESTEROL_BIOSYNTHETIC_PROCESS, GOBP_SMALL_MOLECULE_BIOSYNTHETIC_PROCESS

GO Biological Process (16): mitotic G2 DNA damage checkpoint signaling (GO:0007095), cholesterol metabolic process (GO:0008203), endoplasmic reticulum unfolded protein response (GO:0030968), membrane protein intracellular domain proteolysis (GO:0031293), response to endoplasmic reticulum stress (GO:0034976), ATF6-mediated unfolded protein response (GO:0036500), regulation of cholesterol biosynthetic process (GO:0045540), positive regulation of cholesterol biosynthetic process (GO:0045542), positive regulation of transcription by RNA polymerase II (GO:0045944), protein maturation (GO:0051604), bone maturation (GO:0070977), regulation of response to endoplasmic reticulum stress (GO:1905897), proteolysis (GO:0006508), NLS-bearing protein import into nucleus (GO:0006607), lipid metabolic process (GO:0006629), steroid metabolic process (GO:0008202)

GO Molecular Function (7): metalloendopeptidase activity (GO:0004222), metal ion binding (GO:0046872), transcription regulator activator activity (GO:0140537), protein binding (GO:0005515), peptidase activity (GO:0008233), metallopeptidase activity (GO:0008237), hydrolase activity (GO:0016787)

GO Cellular Component (5): Golgi membrane (GO:0000139), cytoplasm (GO:0005737), membrane (GO:0016020), Golgi apparatus (GO:0005794), endomembrane system (GO:0012505)

Reactome top-level categories

Rollup of top-9 pathways:

Category	Pathways
Unfolded Protein Response (UPR)	3
Metabolism of steroids	1
Plasma lipoprotein remodeling	1
Transport of small molecules	1
Cellular responses to stimuli	1
Cellular responses to stress	1
Metabolism	1
Metabolism of lipids	1
Plasma lipoprotein assembly, remodeling, and clearance	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
response to endoplasmic reticulum stress	2
cholesterol biosynthetic process	2
protein metabolic process	2
mitotic G2 phase	1
mitotic DNA damage checkpoint signaling	1
mitotic G2/M transition checkpoint	1
sterol metabolic process	1
secondary alcohol metabolic process	1
cellular response to unfolded protein	1
intracellular signal transduction	1
membrane protein proteolysis	1
cellular response to stress	1
ER-nucleus signaling pathway	1
endoplasmic reticulum unfolded protein response	1
regulation of cholesterol metabolic process	1
regulation of sterol biosynthetic process	1
regulation of alcohol biosynthetic process	1
regulation of cholesterol biosynthetic process	1
positive regulation of cholesterol metabolic process	1
positive regulation of sterol biosynthetic process	1
positive regulation of alcohol biosynthetic process	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	1
gene expression	1
animal organ maturation	1
bone development	1
regulation of cellular response to stress	1
protein import into nucleus	1
primary metabolic process	1
lipid metabolic process	1
endopeptidase activity	1
metallopeptidase activity	1
cation binding	1
regulation of gene expression	1
transcription regulator activity	1
molecular function activator activity	1
binding	1
hydrolase activity	1

Protein interactions and networks

STRING

2024 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MBTPS2	MBTPS1	Q14703	978
MBTPS2	SCAP	Q12770	918
MBTPS2	ATF6	P18850	915
MBTPS2	ATF6B	Q99941	825
MBTPS2	CREB3L3	Q68CJ9	823
MBTPS2	HSPA5	P11021	786
MBTPS2	HSP90B1	P14625	738
MBTPS2	CREB3L1	Q96BA8	719
MBTPS2	TMEM38B	Q9NVV0	718
MBTPS2	SREBF2	Q12772	715
MBTPS2	XBP1	P17861	709
MBTPS2	HM13	Q8TCT9	708
MBTPS2	SEC24D	O94855	683
MBTPS2	FKBP10	Q96AY3	681
MBTPS2	SREBF1	P36956	674

IntAct

13 interactions, top by confidence:

A	B	Type	Score
MBTPS2	SARAF	psi-mi:“MI:0915”(physical association)	0.400
MBTPS2	FAM8A1	psi-mi:“MI:0915”(physical association)	0.400
MBTPS2	SLC26A6	psi-mi:“MI:0915”(physical association)	0.400
IL17RC	C2CD2L	psi-mi:“MI:0914”(association)	0.350
BSCL2	TMEM223	psi-mi:“MI:0914”(association)	0.350
NKAIN1	GPR89A	psi-mi:“MI:0914”(association)	0.350
OR6T1	PSMD11	psi-mi:“MI:0914”(association)	0.350
ADAM30	MBTPS2	psi-mi:“MI:0914”(association)	0.350
C15orf32	NPC1	psi-mi:“MI:0914”(association)	0.350
SLC18A2	LGALS8	psi-mi:“MI:0914”(association)	0.350
SLC19A2	TMEM223	psi-mi:“MI:0914”(association)	0.350
SLC44A1	UPK3BL1	psi-mi:“MI:0914”(association)	0.350

BioGRID (99): SYVN1 (Affinity Capture-MS), SARAF (Affinity Capture-MS), FAM8A1 (Affinity Capture-MS), SARAF (Affinity Capture-MS), MBTPS2 (Affinity Capture-MS), MBTPS2 (Positive Genetic), MBTPS2 (Negative Genetic), MBTPS2 (Negative Genetic), MBTPS2 (Negative Genetic), MBTPS2 (Negative Genetic), MBTPS2 (Negative Genetic), MBTPS2 (Negative Genetic), MBTPS2 (Negative Genetic), MBTPS2 (Negative Genetic), MBTPS2 (Negative Genetic)

ESM2 similar proteins: B0S4Q1, B9EN89, O43462, O54862, O75915, Q0III2, Q0IIK4, Q15041, Q1LZE6, Q28H54, Q3SWT5, Q4G019, Q4KLV1, Q4R4R4, Q502G2, Q56P28, Q5BJC1, Q5E978, Q5E9M1, Q5NV96, Q5R454, Q5R4X8, Q5RAC8, Q5ZLL0, Q66H21, Q66J05, Q66J44, Q68EQ9, Q6AXM5, Q6DFT6, Q6GPZ5, Q6IFY7, Q6INE8, Q7ZYQ3, Q80TA1, Q8BGS7, Q8C025, Q8CHX6, Q8LEQ4, Q8NFR3

Diamond homologs: O43462, O54862, Q0III2, Q5RAC8, Q8CHX6

SIGNOR signaling

3 interactions.

A	Effect	B	Mechanism
MBTPS2	up-regulates	CREB3L1	cleavage
MBTPS2	“up-regulates activity”	SREBF2	cleavage
MBTPS2	“up-regulates activity”	SREBF1	cleavage

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	14
Likely pathogenic	3
Uncertain significance	139
Likely benign	59
Benign	28

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
11402	NM_015884.4(MBTPS2):c.680A>T (p.His227Leu)	Pathogenic
11403	NM_015884.4(MBTPS2):c.261G>A (p.Met87Ile)	Pathogenic
11404	NM_015884.4(MBTPS2):c.1286G>A (p.Arg429His)	Pathogenic
11405	NM_015884.4(MBTPS2):c.1424T>C (p.Phe475Ser)	Pathogenic
11406	NM_015884.4(MBTPS2):c.677G>T (p.Trp226Leu)	Pathogenic
1215609	NM_015884.4(MBTPS2):c.758G>C (p.Gly253Ala)	Pathogenic
126904	NM_015884.4(MBTPS2):c.671-9T>G	Pathogenic
126905	NM_015884.4(MBTPS2):c.1391T>C (p.Phe464Ser)	Pathogenic
1369817	NC_000023.10:g.(?21755681)(22266301_?)del	Pathogenic
29956	NM_015884.4(MBTPS2):c.1523A>G (p.Asn508Ser)	Pathogenic
4070962	NM_015884.4(MBTPS2):c.1313C>T (p.Pro438Leu)	Pathogenic
4528364	NM_015884.4(MBTPS2):c.970+5G>A	Pathogenic
558767	NM_015884.4(MBTPS2):c.1376A>G (p.Asn459Ser)	Pathogenic
558768	NM_015884.4(MBTPS2):c.1515G>C (p.Leu505Phe)	Pathogenic
3773854	NM_015884.4(MBTPS2):c.1165C>T (p.Pro389Ser)	Likely pathogenic
392629	NM_015884.4(MBTPS2):c.1523A>T (p.Asn508Ile)	Likely pathogenic
427134	NM_015884.4(MBTPS2):c.661T>A (p.Phe221Ile)	Likely pathogenic

SpliceAI

1798 predictions. Top by Δscore:

Variant	Effect	Δscore
X:21839809:GGT:G	donor_loss	1.0000
X:21839810:GTG:G	donor_loss	1.0000
X:21843168:A:AG	acceptor_gain	1.0000
X:21843169:G:GA	acceptor_gain	1.0000
X:21843169:GT:G	acceptor_gain	1.0000
X:21843169:GTC:G	acceptor_gain	1.0000
X:21843169:GTCAT:G	acceptor_gain	1.0000
X:21843304:G:GT	donor_gain	1.0000
X:21845168:CAG:C	acceptor_loss	1.0000
X:21845169:A:AT	acceptor_loss	1.0000
X:21845380:TTGTG:T	donor_gain	1.0000
X:21845382:GTG:G	donor_gain	1.0000
X:21845385:G:GG	donor_gain	1.0000
X:21845386:TAAG:T	donor_loss	1.0000
X:21853370:TCTTA:T	acceptor_loss	1.0000
X:21853371:CTTA:C	acceptor_loss	1.0000
X:21853372:TTAG:T	acceptor_loss	1.0000
X:21853373:TAGGG:T	acceptor_loss	1.0000
X:21853374:A:AG	acceptor_gain	1.0000
X:21853374:AG:A	acceptor_gain	1.0000
X:21853374:AGGGA:A	acceptor_loss	1.0000
X:21853375:G:GG	acceptor_gain	1.0000
X:21853375:GG:G	acceptor_gain	1.0000
X:21853485:C:G	donor_gain	1.0000
X:21869660:T:G	donor_gain	1.0000
X:21878494:TA:T	acceptor_loss	1.0000
X:21878495:A:AG	acceptor_gain	1.0000
X:21878496:G:GG	acceptor_gain	1.0000
X:21878496:GC:G	acceptor_gain	1.0000
X:21878496:GCA:G	acceptor_gain	1.0000

AlphaMissense

3374 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:21845181:G:A	G79R	1.000
X:21845181:G:C	G79R	1.000
X:21845182:G:A	G79E	1.000
X:21845182:G:T	G79V	1.000
X:21845193:G:C	G83R	1.000
X:21845194:G:A	G83D	1.000
X:21851569:A:C	S167R	1.000
X:21851571:T:A	S167R	1.000
X:21851571:T:G	S167R	1.000
X:21851572:G:C	G168R	1.000
X:21851581:C:G	H171D	1.000
X:21851581:C:T	H171Y	1.000
X:21851585:A:C	E172A	1.000
X:21851585:A:G	E172G	1.000
X:21851585:A:T	E172V	1.000
X:21851586:A:C	E172D	1.000
X:21851586:A:T	E172D	1.000
X:21851590:G:A	G174R	1.000
X:21851590:G:C	G174R	1.000
X:21851591:G:A	G174E	1.000
X:21851591:G:T	G174V	1.000
X:21851593:C:G	H175D	1.000
X:21851595:T:A	H175Q	1.000
X:21851595:T:G	H175Q	1.000
X:21851596:G:A	G176R	1.000
X:21851596:G:C	G176R	1.000
X:21851597:G:A	G176E	1.000
X:21851603:C:A	A178E	1.000
X:21851605:G:C	A179P	1.000
X:21851606:C:A	A179D	1.000

dbSNP variants (sampled 300 via entrez): RS1000090214 (X:21877555 C>T), RS1000154465 (X:21854777 G>A), RS1000318793 (X:21844420 G>A), RS1000567402 (X:21882849 A>G), RS1000572689 (X:21885381 T>A), RS1000733546 (X:21838442 C>T), RS1000765023 (X:21838072 G>A), RS1000884611 (X:21866311 G>A), RS1000902216 (X:21876061 G>A), RS1001176948 (X:21843759 A>T), RS1001196669 (X:21854646 C>A), RS1001248297 (X:21866025 A>T), RS1001350953 (X:21865467 T>C), RS1001396861 (X:21848601 A>T), RS1001507375 (X:21885833 T>C)

Disease associations

OMIM: gene MIM:300294 | disease phenotypes: MIM:300918, MIM:308205, MIM:166200, MIM:619681, MIM:308800, MIM:301014, MIM:143890

GenCC curated gene-disease

Disease	Classification	Inheritance
IFAP syndrome 1, with or without BRESHECK syndrome	Definitive	X-linked
keratosis follicularis spinulosa decalvans	Definitive	X-linked
Olmsted syndrome, X-linked	Strong	X-linked
osteogenesis imperfecta, type 19	Strong	X-linked
mutilating palmoplantar keratoderma with periorificial keratotic plaques	Supportive	Autosomal dominant
osteogenesis imperfecta	Supportive	Autosomal dominant
BRESEK syndrome	Supportive	X-linked
keratosis follicularis spinulosa decalvans, X-linked	Limited	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
IFAP syndrome 1, with or without BRESHECK syndrome	Definitive	XL

Mondo (13): Olmsted syndrome, X-linked (MONDO:0010486), IFAP syndrome 1, with or without BRESHECK syndrome (MONDO:0100213), intellectual disability (MONDO:0001071), osteogenesis imperfecta (MONDO:0019019), dystonia, early-onset, and/or spastic paraplegia (MONDO:0859215), keratosis follicularis spinulosa decalvans, X-linked (MONDO:0010637), osteogenesis imperfecta, type 19 (MONDO:0049223), hypercholesterolemia, familial, 1 (MONDO:0007750), congenital heart disease (MONDO:0005453), skeletal dysplasia (MONDO:0018230), keratosis follicularis spinulosa decalvans (MONDO:0000136), (MONDO:0019014), BRESEK syndrome (MONDO:0019414)

Orphanet (8): Mutilating palmoplantar keratoderma with periorificial keratotic plaques (Orphanet:659), Ichthyosis follicularis-alopecia-photophobia syndrome (Orphanet:2273), BRESEK syndrome (Orphanet:85284), Osteogenesis imperfecta (Orphanet:666), Keratosis follicularis spinulosa decalvans (Orphanet:2340), Homozygous familial hypercholesterolemia (Orphanet:391665), Primary bone dysplasia (Orphanet:364526), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

197 total (30 of 197 shown, HPO-id order):

HPO	Term
HP:0000003	Multicystic kidney dysplasia
HP:0000023	Inguinal hernia
HP:0000028	Cryptorchidism
HP:0000047	Hypospadias
HP:0000072	Hydroureter
HP:0000076	Vesicoureteral reflux
HP:0000077	Abnormality of the kidney
HP:0000089	Renal hypoplasia
HP:0000104	Renal agenesis
HP:0000110	Renal dysplasia
HP:0000122	Unilateral renal agenesis
HP:0000126	Hydronephrosis
HP:0000157	Abnormality of the tongue
HP:0000164	Abnormality of the dentition
HP:0000168	Abnormality of the gingiva
HP:0000175	Cleft palate
HP:0000238	Hydrocephalus
HP:0000252	Microcephaly
HP:0000365	Hearing impairment
HP:0000369	Low-set ears
HP:0000400	Macrotia
HP:0000407	Sensorineural hearing impairment
HP:0000411	Protruding ear
HP:0000444	Convex nasal ridge
HP:0000452	Choanal stenosis
HP:0000453	Choanal atresia
HP:0000483	Astigmatism
HP:0000491	Keratitis
HP:0000492	Abnormal eyelid morphology
HP:0000495	Recurrent corneal erosions

GWAS associations

0 associations (top):

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D006330	Heart Defects, Congenital	C14.240.400; C14.280.400; C16.131.240.400
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D010013	Osteogenesis Imperfecta	C05.116.099.708.685; C16.320.737; C17.300.200.540
C564519	Brain Anomalies, Retardation, Ectodermal Dysplasia, Skeletal Malformations, Hirschsprung Disease, Ear-Eye Anomalies, Cleft Palate-Cryptorchidism, And Kidney Dysplasia-Hypoplasia (supp.)
C536085	Ichthyosis follicularis atrichia photophobia syndrome (supp.)
C536159	Keratosis Follicularis Spinulosa Decalvans, X-Linked (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

18 total (human), top 18 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects methylation, decreases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
1,10-phenanthroline	decreases activity, decreases cleavage, affects localization	1
Sunitinib	increases expression	1
Zoledronic Acid	increases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Doxorubicin	decreases expression	1
Thiram	decreases expression	1
Tobacco Smoke Pollution	increases expression	1
Tunicamycin	increases expression	1
Valproic Acid	decreases methylation	1
Cyclosporine	decreases expression	1
Cadmium Chloride	decreases expression	1
Copper Sulfate	decreases expression	1
Nelfinavir	decreases reaction, increases activity, increases cleavage	1

Cellosaurus cell lines

7 cell lines: 2 spontaneously immortalized cell line, 2 transformed cell line, 2 induced pluripotent stem cell, 1 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_2H49	CHO/pS2P	Spontaneously immortalized cell line	Female
CVCL_2H50	SRD-12A	Transformed cell line	Female
CVCL_2H51	SRD-12B	Transformed cell line	Female
CVCL_2H52	SRD-13A	Spontaneously immortalized cell line	Female
CVCL_SX56	HAP1 MBTPS2 (-)	Cancer cell line	Male
CVCL_XI89	MDCUi001-A	Induced pluripotent stem cell	Male
CVCL_XI90	MDCUi001-B	Induced pluripotent stem cell	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00131469	PHASE4	COMPLETED	Study of Teriparatide (FORTEO) to Treat Adults With Osteogenesis Imperfecta
NCT00159419	PHASE4	COMPLETED	Bisphosphonate Therapy for Osteogenesis Imperfecta
NCT01713231	PHASE4	COMPLETED	Effect of High-Dose Vitamin D on Bone Density in Osteogenesis Imperfecta
NCT02303873	PHASE4	COMPLETED	Efficacy and Safety of Alendronate in Chinese Children or Adolescents With Osteogenesis Imperfecta
NCT03735537	PHASE4	COMPLETED	Treatment of Osteogenesis Imperfecta With Parathyroid Hormone and Zoledronic Acid
NCT04152551	PHASE4	RECRUITING	Effects of Bisphosphonates on OI-Related Hearing Loss
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT00001305	PHASE3	COMPLETED	Growth Hormone Therapy in Osteogenesis Imperfecta
NCT00005901	PHASE3	COMPLETED	Pamidronate to Treat Osteogenesis Imperfecta in Children
NCT00106028	PHASE3	COMPLETED	Safety and Efficacy of Risedronate in the Treatment of Osteogenesis Imperfecta in Children
NCT00982124	PHASE3	COMPLETED	An Efficacy and Safety Trial of Intravenous Zoledronic Acid in Infants Less Than One Year of Age, With Severe Osteogenesis Imperfecta
NCT02352753	PHASE3	TERMINATED	Multicenter,Single-arm Study to Evaluate Efficacy, Safety, & Pharmacokinetics of Denosumab in Children w/ OI
NCT03638128	PHASE3	TERMINATED	Open-label Extension of Study 20130173 of Denosumab in Children and Young Adults With Osteogenesis Imperfecta
NCT05768854	PHASE3	ACTIVE_NOT_RECRUITING	Setrusumab vs Bisphosphonates in Pediatric Subjects With Osteogenesis Imperfecta
NCT05972551	PHASE3	ACTIVE_NOT_RECRUITING	Study to Evaluate Efficacy and Safety of Romosozumab Compared With Bisphosphonates in Children and Adolescents With Osteogenesis Imperfecta
NCT06636071	PHASE3	ACTIVE_NOT_RECRUITING	Setrusumab in Pediatric Japanese Subjects With Osteogenesis Imperfecta
NCT07366086	PHASE3	RECRUITING	Pediatric Safety Follow-up Study of Prior Treatment With Romosozumab for Osteogenesis Imperfecta
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00063479	PHASE2	COMPLETED	Bisphosphonate Treatment of Osteogenesis Imperfecta
NCT00131118	PHASE2	COMPLETED	Zoledronic Acid in Children (1 -17 Years) With Severe Osteogenesis Imperfecta
NCT01417091	PHASE2	COMPLETED	Safety, Pharmacokinetics and Pharmacodynamics of BPS804 in Osteogenesis Imperfecta
NCT01679080	PHASE2	TERMINATED	The Effect of Treatment With Teriparatide and Zoledronic Acid in Patients With Osteogenesis Imperfecta
NCT01799798	PHASE2	COMPLETED	Translational Therapy in Patients With Osteogenesis Imperfecta - A Pilot Trial on Treatment With the Rankl-Antibody Denosumab
NCT03208582	PHASE2	COMPLETED	Do Bisphosphonates Alter the Skeletal Response to Mechanical Stimulation in Children With Osteogenesis Imperfecta?
NCT03216486	PHASE2	WITHDRAWN	An Exploratory Study of BPS804 Treatment in Adult Patients With Type I, III or IV Osteogenesis Imperfecta
NCT05312697	PHASE2	TERMINATED	Long-term Extension Study of Setrusumab in Adults With Type I, III, or IV Osteogenesis Imperfecta
NCT07062588	PHASE2	RECRUITING	Osteogenesis Imperfecta Trial of AGA2115 for ADUlts With COL1A1 and/or COL1A2 GeNetic Variations (IDUN)
NCT07557446	PHASE2	NOT_YET_RECRUITING	A Dose REgimen-Finding Study of AGA2115 in Chinese Patients With Osteogenesis ImpeRfecta (EIR)
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00705120	PHASE1	COMPLETED	Treatment of Severe Osteogenesis Imperfecta by Allogeneic Bone Marrow Transplantation
NCT02172885	PHASE1	COMPLETED	Mesenchymal Stem Cell Based Therapy for the Treatment of Osteogenesis Imperfecta
NCT03064074	PHASE1	COMPLETED	Safety of Fresolimumab in the Treatment of Osteogenesis Imperfecta
NCT04545554	PHASE1	COMPLETED	Study to Evaluate Romosozumab in Children and Adolescents With Osteogenesis Imperfecta
NCT05231668	PHASE1	TERMINATED	Single Ascending Dose Study of SAR439459 in Adults With Osteogenesis Imperfecta (OI)