NOG

Summary

NOG (noggin, HGNC:7866) is a protein-coding gene on chromosome 17q22, encoding Noggin (Q13253). Inhibitor of bone morphogenetic proteins (BMP) signaling which is required for growth and patterning of the neural tube and somite. It is haploinsufficient (ClinGen: sufficient evidence).

The secreted polypeptide, encoded by this gene, binds and inactivates members of the transforming growth factor-beta (TGF-beta) superfamily signaling proteins, such as bone morphogenetic protein-4 (BMP4). By diffusing through extracellular matrices more efficiently than members of the TGF-beta superfamily, this protein may have a principal role in creating morphogenic gradients. The protein appears to have pleiotropic effect, both early in development as well as in later stages. It was originally isolated from Xenopus based on its ability to restore normal dorsal-ventral body axis in embryos that had been artificially ventralized by UV treatment. The results of the mouse knockout of the ortholog suggest that it is involved in numerous developmental processes, such as neural tube fusion and joint formation. Recently, several dominant human NOG mutations in unrelated families with proximal symphalangism (SYM1) and multiple synostoses syndrome (SYNS1) were identified; both SYM1 and SYNS1 have multiple joint fusion as their principal feature, and map to the same region (17q22) as this gene. All of these mutations altered evolutionarily conserved amino acid residues. The amino acid sequence of this human gene is highly homologous to that of Xenopus, rat and mouse.

Source: NCBI Gene 9241 — RefSeq curated summary.

At a glance

• Gene–disease (curated): NOG-related symphalangism spectrum disorder (Definitive, ClinGen) — +6 more curated relationships
• GWAS associations: 16
• Clinical variants (ClinVar): 251 total — 33 pathogenic, 16 likely-pathogenic
• Phenotypes (HPO): 105
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_005450

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7866
Approved symbol	NOG
Name	noggin
Location	17q22
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000183691
Ensembl biotype	protein_coding
OMIM	602991
Entrez	9241

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000332822

RefSeq mRNA: 1 — MANE Select: NM_005450 NM_005450

CCDS: CCDS11589

Canonical transcript exons

ENST00000332822 — 1 exons

Exon	Start	End
ENSE00001291949	56593699	56595611

Expression profiles

Bgee: expression breadth ubiquitous, 155 present calls, max score 92.31.

FANTOM5 (CAGE): breadth broad, TPM avg 4.0961 / max 376.9462, expressed in 684 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
161804	3.8423	629
161805	0.2538	120

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
pigmented layer of retina	UBERON:0001782	92.31	gold quality
buccal mucosa cell	CL:0002336	82.98	silver quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.02	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	78.67	silver quality
ventricular zone	UBERON:0003053	77.53	gold quality
ganglionic eminence	UBERON:0004023	75.44	gold quality
decidua	UBERON:0002450	74.30	gold quality
placenta	UBERON:0001987	72.96	gold quality
endocervix	UBERON:0000458	71.86	gold quality
nucleus accumbens	UBERON:0001882	70.98	gold quality
stromal cell of endometrium	CL:0002255	70.51	gold quality
hindlimb stylopod muscle	UBERON:0004252	69.02	gold quality
lateral nuclear group of thalamus	UBERON:0002736	69.00	silver quality
caudate nucleus	UBERON:0001873	68.92	gold quality
gastrocnemius	UBERON:0001388	68.84	gold quality
ectocervix	UBERON:0012249	68.34	gold quality
prefrontal cortex	UBERON:0000451	67.81	gold quality
muscle of leg	UBERON:0001383	67.76	gold quality
putamen	UBERON:0001874	67.51	gold quality
tibialis anterior	UBERON:0001385	67.21	silver quality
tibial nerve	UBERON:0001323	67.13	gold quality
amygdala	UBERON:0001876	66.55	gold quality
Brodmann (1909) area 9	UBERON:0013540	65.61	gold quality
anterior cingulate cortex	UBERON:0009835	65.47	gold quality
vagina	UBERON:0000996	63.84	gold quality
granulocyte	CL:0000094	63.37	gold quality
blood	UBERON:0000178	63.11	gold quality
hypothalamus	UBERON:0001898	62.99	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	62.92	gold quality
right frontal lobe	UBERON:0002810	62.25	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-109979	yes	45.89
E-MTAB-6678	yes	16.82
E-GEOD-76312	no	452.84
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

2 targets.

Target	Regulation
BMP10	Repression
CDKN1C	Activation

Upstream regulators (CollecTRI, top): MBD2, SMAD1, SMAD4

miRNA regulators (miRDB)

72 targeting NOG, 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-340-5P	100.00	72.50	4437
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-8485	100.00	77.57	4731
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-4262	100.00	73.26	3931
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-4789-5P	99.98	70.76	2721
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-144-3P	99.94	73.98	2698
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-9902	99.89	69.15	2250
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-3941	99.86	70.54	2735
HSA-MIR-369-3P	99.85	70.52	2264
HSA-MIR-548AR-3P	99.85	71.26	3889
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-548AZ-3P	99.82	70.56	3549
HSA-MIR-548BC	99.82	70.61	3524
HSA-MIR-548E-3P	99.82	70.59	3514
HSA-MIR-548F-3P	99.82	70.59	3540

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• A novel NOG gene mutation giving rise to the (P35S) amino acid substitution has been identified in an Italian family with symphalangism. (PMID:11857750)
• Autosomal dominant stapes ankylosis with broad thumbs and toes, hyperopia, and skeletal anomalies is caused by heterozygous nonsense and frameshift mutations in NOG, the gene encoding noggin (PMID:12089654)
• crystal structure of the antagonist Noggin bound to BMP-7, which shows that Noggin inhibits BMP signalling by blocking the molecular interfaces of the binding epitopes for both type I and type II receptors (PMID:12478285)
• Nog gene is connected to stapes ankylosis. (PMID:12621334)
• Here, we show that the overexpression of human noggin, by acting to inhibit glial differentiation by subependymal progenitor cells, can potentiate adenoviral BDNF-mediated recruitment of new neurons to the adult rat neostriatum (PMID:14999064)
• Mutations in the nog gene have been identified. (PMID:15264296)
• These studies highlight the critical role played by Cys168 in noggin’s biological activities. (PMID:15756420)
• Overexpression of noggin in PC-3 cells inhibited the expansion of the lesion in vivo. (PMID:16126463)
• Data show calcium-sensing receptor stimulation of T-84 epithelia and colonic myofibroblasts downregulated the BMP family antagonist Noggin. (PMID:17138967)
• Lack of noggin expression by cancer cells may be a relevant mechanism contributing to the osteoblast response in bone metastases (PMID:17200191)
• Antagonism of bone morphogenetic protein signaling by transgenic Noggin plays a critical role in ensuring proper levels of cell proliferation and epithelial-to-mesenchymal transformation during cardiac morphogenesis. (PMID:17218603)
• Expression analysis of additional genes, AKT1, NOG and its antagonist BMP4, which interact downstream to FGFR1, demonstrated expression differences between primary rhabdomyosarcoma tumors and normal skeletal muscles (PMID:17696196)
• NOG is involved in myeloproliferative disease associated with myelofibrosis (PMID:17889703)
• Various mutations may occur in myositis ossificans nuclear families. (PMID:18019378)
• Heterozygous gene mutations in NOGGIN are associated with tall stature in children but not necessarily in adults. (PMID:18204269)
• Transgenic noggin overexpression increases the total number of neurons in the colon; the density of colonic neurons increases significantly in both Nog/+ and Nog/Nog mice, although the two groups of transgenic animals do not differ significantly. (PMID:18537141)
• Advanced melanoma cells may escape from BMP7-induced inhibition through concomitant aberrant expression of Noggin. (PMID:18560367)
• the potential use of bone-morphogenetic protein-6, noggin and sclerostin expression together as a prognostic predictor for metastatic progression of prostate cancer. (PMID:18931653)
• Noggin and chordin were also expressed most intensely in areas of cartilage formation and there was no difference in their expression between the non-hypertrophic and hypertrophic chondrocytes. (PMID:19023570)
• there was no difference in the expression of noggin and chordin between healing and nonhealing fractures (PMID:19058174)
• The analysis suggests that a common variation in the noggin gene is unlikely to have a major impact on BMD among older men of African ancestry. (PMID:19167531)
• NOG & 617G>A activin A type I receptor(ACVRI)mutations in 27 fibrodysplasia ossificans patients; 5 NOG mutations found in 7 patients; 617G>A mutation in ACVR1 gene found in 14 patients; with 1 exception, 617G>A & NOG mutations were mutually exclusive (PMID:19400542)
• Data suggest inhibition of BMP-7, by Drm (Gremlin), follistatin, and Noggin and upregulation of BMP-4 may play an integral role in the development of nonunions. (PMID:19597895)
• This study showed that constitutive and orthotopic Noggin protein expression did not influence cell proliferation, down-regulated BMP-2 expression, and showed no effect on BMP receptor transcripts. (PMID:19692649)
• tumor suppressor activity of the BMPs in skin epithelium depends on the local concentrations of noggin and is mediated at least in part via stage-dependent antagonizing of Wnt and Shh signaling pathways (PMID:19700758)
• Using BMP-6/7 chimeras, we identified lysine 60 as a key residue conferring noggin resistance within the BMP-6 protein. (PMID:20048150)
• study reports on a family with facioaudiosymphalangism syndrome with overgrowth due to a novel heterozygous NOG missense mutation (c.696C > G, p.Cys232Trp) (PMID:20503332)
• This result suggests that there may be population polymorphism, or markers that are seldom polymorphic for our population (PMID:20645637)
• secreted levels of noggin were decreased in untreated patients with relapsing-remitting Multiple sclerosis (PMID:21111488)
• evidence for a model of osteolytic bone metastasis where constitutive secretion of noggin by cancer cells mediates inhibition of bone formation, thereby preventing repair of osteolytic lesions generated by an excess of osteoclast-mediated bone resorption. (PMID:21249149)
• SNPs in the coding region of the NOG gene are identified infrequently in human cases of EA/TEF (PMID:22083168)
• Mutations in the NOG gene are commonly found in congenital stapes ankylosis with symphalangism, but not in otosclerosis. (PMID:22288654)
• high BMP6 activity, defined by strong BMP6 expression with weak noggin or SOST expression, was associated with shorter survival in esophageal SCC patients; results suggest BMP6, noggin and SOST could be used in combination as a prognostic indicator in cancer progression (PMID:22364398)
• we conclude that mutations in the coding region of NOG are rare, and play at most an uncommon role in human Holoprosencephaly (HPE). (PMID:22503063)
• p.G92E represents a rare polymorphism of the NOGGIN gene– causing neither brachydactyly nor fibrodysplasia ossificans progressiva. (PMID:22529972)
• Using genetic approaches, we show that when NOG is expressed in human breast cancer cells, it facilitates bone colonization by fostering osteoclast differentiation and bone degradation and also contributes to metastatic lesions reinitiation. (PMID:22547073)
• Human squamous cell carcinomas and malignant melanomas contain significantly more Myo/Nog cells than basal cell carcinomas. (PMID:22621191)
• BMP2 treatment reduced noggin expression, which resulted in increased expression of apoptotic markers and increased apoptosis of osteoblasts. (PMID:22628200)
• Noggin suppression decreased viability and BMP-2-induced osteogenic differentiation of human mesenchymal stem cells. (PMID:22740073)
• NOggin attenuates BMP4-mediated transdifferentiation of human valve interstitial cells towards an osteogenic-like phenotype in aortic valve sclerosis. (PMID:23483047)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	nog3	ENSDARG00000053528
danio_rerio	nog1	ENSDARG00000058819
mus_musculus	Nog	ENSMUSG00000048616
rattus_norvegicus	Nog	ENSRNOG00000023683

Protein

Protein identifiers

Noggin — Q13253 (reviewed: Q13253)

All UniProt accessions (1): Q13253

UniProt curated annotations — full annotation on UniProt →

Function. Inhibitor of bone morphogenetic proteins (BMP) signaling which is required for growth and patterning of the neural tube and somite. Essential for cartilage morphogenesis and joint formation. Inhibits chondrocyte differentiation through its interaction with GDF5 and, probably, GDF6.

Subunit / interactions. Homodimer. Interacts with GDF5; inhibits chondrocyte differentiation.

Subcellular location. Secreted.

Disease relevance. Symphalangism, proximal 1A (SYM1A) [MIM:185800] A disease characterized by the hereditary absence of the proximal interphalangeal joints. Distal interphalangeal joints are less frequently involved and metacarpophalangeal joints are rarely affected whereas carpal bone malformation and fusion are common. In the lower extremities, tarsal bone coalition is common. Conductive hearing loss is seen and is due to fusion of the stapes to the petrous part of the temporal bone. The disease is caused by variants affecting the gene represented in this entry. Multiple synostoses syndrome 1 (SYNS1) [MIM:186500] A bone disease characterized by multiple progressive joint fusions that commonly involve proximal interphalangeal, tarsal-carpal, humeroradial and cervical spine joints. Additional features can include progressive conductive deafness and facial dysmorphism. The disease is caused by variants affecting the gene represented in this entry. Tarsal-carpal coalition syndrome (TCC) [MIM:186570] Autosomal dominant disorder characterized by fusion of the carpals, tarsals and phalanges, short first metacarpals causing brachydactyly, and humeroradial fusion. TCC is allelic to SYM1, and different mutations in NOG can result in either TCC or SYM1 in different families. The disease is caused by variants affecting the gene represented in this entry. Stapes ankylosis with broad thumb and toes (SABTS) [MIM:184460] An autosomal dominant disorder characterized by hyperopia, a hemicylindrical nose, broad thumbs, great toes, and other minor skeletal anomalies but lacked carpal and tarsal fusion and symphalangism. The disease is caused by variants affecting the gene represented in this entry. Brachydactyly B2 (BDB2) [MIM:611377] A form of brachydactyly characterized by hypoplasia/aplasia of distal phalanges in combination with distal symphalangism, fusion of carpal/tarsal bones and partial cutaneous syndactyly. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the noggin family.

RefSeq proteins (1): NP_005441* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008717	Noggin	Family
IPR029034	Cystine-knot_cytokine	Homologous_superfamily

Pfam: PF05806

UniProt features (43 total): sequence variant 19, strand 8, helix 7, disulfide bond 4, signal peptide 1, chain 1, region of interest 1, glycosylation site 1, turn 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1M4U	X-RAY DIFFRACTION	2.42
7AG0	X-RAY DIFFRACTION	3.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q13253-F1	87.40	0.68

Functional residue map

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

Disulfide bonds (4): 155–192, 178–228, 184–230, 207–215

Glycosylation sites (1): 62

Function

Pathways and Gene Ontology

Reactome pathways

2 pathways

ID	Pathway
R-HSA-201451	Signaling by BMP
R-HSA-9793380	Formation of paraxial mesoderm

MSigDB gene sets: 729 (showing top): GOBP_CARDIAC_CHAMBER_DEVELOPMENT, GOBP_SPINAL_CORD_DEVELOPMENT, GOBP_SMAD_PROTEIN_SIGNAL_TRANSDUCTION, GOBP_MORPHOGENESIS_OF_AN_EPITHELIUM, GOBP_HINDBRAIN_DEVELOPMENT, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_REGULATION_OF_CELLULAR_RESPONSE_TO_GROWTH_FACTOR_STIMULUS, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_NEGATIVE_REGULATION_OF_CELL_DEVELOPMENT, GOBP_BODY_MORPHOGENESIS, GOBP_SOMATIC_STEM_CELL_POPULATION_MAINTENANCE, GOBP_MUSCLE_TISSUE_DEVELOPMENT, GOBP_CARDIAC_SEPTUM_DEVELOPMENT, GOBP_COGNITION

GO Biological Process (87): negative regulation of transcription by RNA polymerase II (GO:0000122), skeletal system development (GO:0001501), osteoblast differentiation (GO:0001649), in utero embryonic development (GO:0001701), endoderm formation (GO:0001706), mesoderm formation (GO:0001707), epithelial to mesenchymal transition (GO:0001837), neural plate morphogenesis (GO:0001839), neural tube closure (GO:0001843), membranous septum morphogenesis (GO:0003149), outflow tract morphogenesis (GO:0003151), ventricular compact myocardium morphogenesis (GO:0003223), endocardial cushion formation (GO:0003272), smoothened signaling pathway (GO:0007224), nervous system development (GO:0007399), mesoderm development (GO:0007498), motor neuron axon guidance (GO:0008045), visual learning (GO:0008542), fibroblast growth factor receptor signaling pathway (GO:0008543), dorsal/ventral pattern formation (GO:0009953), positive regulation of gene expression (GO:0010628), negative regulation of gene expression (GO:0010629), spinal cord development (GO:0021510), cell differentiation in hindbrain (GO:0021533), pituitary gland development (GO:0021983), neural plate anterior/posterior regionalization (GO:0021999), negative regulation of cell migration (GO:0030336), BMP signaling pathway (GO:0030509), negative regulation of BMP signaling pathway (GO:0030514), somatic stem cell population maintenance (GO:0035019), exploration behavior (GO:0035640), nodal signaling pathway (GO:0038092), regulation of fibroblast growth factor receptor signaling pathway (GO:0040036), wound healing (GO:0042060), middle ear morphogenesis (GO:0042474), embryonic digit morphogenesis (GO:0042733), negative regulation of osteoblast differentiation (GO:0045668), positive regulation of transcription by RNA polymerase II (GO:0045944), regulation of neuronal synaptic plasticity (GO:0048168), axial mesoderm development (GO:0048318)

GO Molecular Function (4): growth factor binding (GO:0019838), protein homodimerization activity (GO:0042803), receptor ligand inhibitor activity (GO:0141069), protein binding (GO:0005515)

GO Cellular Component (3): extracellular region (GO:0005576), obsolete extracellular space (GO:0005615), presynapse (GO:0098793)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Signaling by TGFB family members	1
Gastrulation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
system development	2
formation of primary germ layer	2
anatomical structure morphogenesis	2
cellular anatomical structure	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
ossification	1
cell differentiation	1
chordate embryonic development	1
endoderm development	1
mesoderm morphogenesis	1
mesenchymal cell differentiation	1
neural plate development	1
morphogenesis of embryonic epithelium	1
primary neural tube formation	1
tube closure	1
ventricular septum morphogenesis	1
heart morphogenesis	1
ventricular cardiac muscle tissue morphogenesis	1
endocardial cushion morphogenesis	1
anatomical structure formation involved in morphogenesis	1
cell surface receptor signaling pathway	1
tissue development	1
axon guidance	1
visual behavior	1
associative learning	1
cell surface receptor protein tyrosine kinase signaling pathway	1
cellular response to fibroblast growth factor stimulus	1
regionalization	1
protein binding	1
identical protein binding	1
protein dimerization activity	1
receptor ligand activity	1
molecular function inhibitor activity	1
binding	1
synapse	1

Protein interactions and networks

STRING

2282 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NOG	BMP7	P18075	997
NOG	BMP2	P12643	996
NOG	BMP4	P12644	993
NOG	GDF5	P43026	968
NOG	SHH	Q15465	935
NOG	RSPO1	Q2MKA7	925
NOG	CHRD	Q9H2X0	909
NOG	BMP6	P22004	905
NOG	WNT3A	P56704	877
NOG	FGF2	P09038	871
NOG	BMPR1B	P78366	865
NOG	BMP5	P22003	864
NOG	BMPR1A	P36894	856
NOG	ACVR1	Q04771	832
NOG	SOST	Q9BQB4	822

IntAct

12 interactions, top by confidence:

A	B	Type	Score
CRP	QSOX1	psi-mi:“MI:0914”(association)	0.530
NOTCH2	ZNF316	psi-mi:“MI:0914”(association)	0.530
BMP7	NOG	psi-mi:“MI:0407”(direct interaction)	0.440
BMP2	NOG	psi-mi:“MI:0407”(direct interaction)	0.440
NOG	BMP2	psi-mi:“MI:0407”(direct interaction)	0.440
GDF5	NOG	psi-mi:“MI:0407”(direct interaction)	0.440
MTDH	NOG	psi-mi:“MI:0915”(physical association)	0.400
NOG	TCAF2	psi-mi:“MI:0914”(association)	0.350
NOG	VGF	psi-mi:“MI:0914”(association)	0.350
NOG	CENPB	psi-mi:“MI:0914”(association)	0.350
ZNF346	ZNF316	psi-mi:“MI:0914”(association)	0.350

BioGRID (44): NOG (Synthetic Lethality), NOG (Co-purification), BMP7 (Co-crystal Structure), BMP7 (Reconstituted Complex), GPC3 (Affinity Capture-MS), ASCC3 (Affinity Capture-MS), AMER1 (Affinity Capture-MS), ZCCHC3 (Affinity Capture-MS), FARP2 (Affinity Capture-MS), NAP1L3 (Affinity Capture-MS), RPS13 (Affinity Capture-MS), NOC2L (Affinity Capture-MS), VWDE (Affinity Capture-MS), DICER1 (Affinity Capture-MS), SULF1 (Affinity Capture-MS)

ESM2 similar proteins: A4IIA2, A5A8Y8, B3F211, P01186, P08833, P10769, P12843, P13384, P15473, P16042, P16229, P17936, P18065, P19336, P21743, P21744, P24591, P24592, P24593, P24594, P24787, P24853, P35455, P35572, P47876, P47877, P47878, P47879, P47880, P49705, P51693, P97466, Q03157, Q05717, Q05718, Q07079, Q13253, Q28985, Q29400, Q32L50

Diamond homologs: O93525, P49011, P97466, Q13253, Q62809, Q9W740, Q9W741, Q9YHT8, Q9YHV3

SIGNOR signaling

12 interactions.

A	Effect	B	Mechanism
NOG	down-regulates	BMP2	binding
NOG	down-regulates	BMP4	binding
NOG	“down-regulates activity”	BMPR1A	binding
NOG	“down-regulates activity”	BMPR1B	binding
NOG	“down-regulates activity”	BMPR2	binding
NOG	down-regulates	BMPR1A/1B/2	binding
NOG	“down-regulates activity”	GDF5	binding
NOG	“down-regulates activity”	BMP7	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	33
Likely pathogenic	16
Uncertain significance	147
Likely benign	38
Benign	8

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1196412	NM_005450.6(NOG):c.509C>T (p.Pro170Leu)	Pathogenic
1342879	NM_005450.6(NOG):c.635_636delinsT (p.Gly212fs)	Pathogenic
1522426	NM_005450.6(NOG):c.355G>T (p.Glu119Ter)	Pathogenic
2672716	GRCh37/hg19 17q22(chr17:54671585-54672283)x1	Pathogenic
2699744	NM_005450.6(NOG):c.621T>A (p.Cys207Ter)	Pathogenic
2972864	NM_005450.6(NOG):c.613T>G (p.Trp205Gly)	Pathogenic
30290	NM_005450.6(NOG):c.696C>G (p.Cys232Trp)	Pathogenic
3237153	NM_005450.6(NOG):c.666C>G (p.Tyr222Ter)	Pathogenic
3250390	NM_005450.6(NOG):c.613dup (p.Trp205fs)	Pathogenic
3642991	NM_005450.6(NOG):c.551G>C (p.Cys184Ser)	Pathogenic
3648554	NM_005450.6(NOG):c.449G>A (p.Trp150Ter)	Pathogenic
3768446	NM_005450.6(NOG):c.461del (p.Phe154fs)	Pathogenic
4711977	NM_005450.6(NOG):c.581dup (p.Ser195fs)	Pathogenic
4731822	NM_005450.6(NOG):c.343del (p.Ala115fs)	Pathogenic
6692	NM_005450.6(NOG):c.664T>G (p.Tyr222Asp)	Pathogenic
6693	NM_005450.6(NOG):c.649T>G (p.Trp217Gly)	Pathogenic
6694	NM_005450.6(NOG):c.668C>T (p.Pro223Leu)	Pathogenic
6695	NM_005450.6(NOG):c.565G>T (p.Gly189Cys)	Pathogenic
6696	NM_005450.6(NOG):c.611G>T (p.Arg204Leu)	Pathogenic
6699	NM_005450.6(NOG):c.551G>A (p.Cys184Tyr)	Pathogenic
6700	NM_005450.6(NOG):c.386T>A (p.Leu129Ter)	Pathogenic
6701	NM_005450.6(NOG):c.58del (p.Leu20fs)	Pathogenic
6702	NM_005450.6(NOG):c.499C>G (p.Arg167Gly)	Pathogenic
6703	NM_005450.6(NOG):c.103C>T (p.Pro35Ser)	Pathogenic
6704	NM_005450.6(NOG):c.328C>T (p.Gln110Ter)	Pathogenic
6705	NM_005450.6(NOG):c.252dup (p.Glu85fs)	Pathogenic
6706	NM_005450.6(NOG):c.614G>A (p.Trp205Ter)	Pathogenic
6707	NM_005450.6(NOG):c.615G>C (p.Trp205Cys)	Pathogenic
6708	NM_005450.6(NOG):c.103C>G (p.Pro35Ala)	Pathogenic
827845	NM_005450.6(NOG):c.64dup (p.Ala22fs)	Pathogenic

SpliceAI

98 predictions. Top by Δscore:

Variant	Effect	Δscore
17:56593791:G:T	donor_gain	0.5800
17:56593791:G:GT	donor_gain	0.5400
17:56594762:G:GG	donor_gain	0.5100
17:56594392:A:AC	acceptor_gain	0.5000
17:56595304:A:AG	acceptor_gain	0.4900
17:56595305:G:GG	acceptor_gain	0.4900
17:56594761:A:AG	donor_gain	0.4700
17:56594393:A:G	acceptor_gain	0.4100
17:56594396:A:T	donor_gain	0.4000
17:56594395:G:GT	donor_gain	0.3800
17:56593859:G:GT	donor_gain	0.3500
17:56594391:CAAGG:C	acceptor_gain	0.3400
17:56594392:AAGGA:A	acceptor_gain	0.3400
17:56594393:AGGAA:A	acceptor_gain	0.3400
17:56593866:G:T	donor_gain	0.3300
17:56594389:CCCAA:C	acceptor_loss	0.3300
17:56594390:CCAA:C	acceptor_loss	0.3300
17:56594391:CAA:C	acceptor_loss	0.3300
17:56594393:AG:A	acceptor_loss	0.3300
17:56594394:GGA:G	acceptor_loss	0.3300
17:56594743:AAGG:A	donor_loss	0.3300
17:56594744:AG:A	donor_loss	0.3300
17:56594745:GGTG:G	donor_loss	0.3300
17:56594746:G:GG	donor_loss	0.3300
17:56594747:T:G	donor_loss	0.3300
17:56595305:GT:G	acceptor_gain	0.3300
17:56594043:C:CA	acceptor_gain	0.3200
17:56594380:ATCTT:A	acceptor_loss	0.3200
17:56594381:TCTTT:T	acceptor_loss	0.3200
17:56594385:T:A	acceptor_loss	0.3200

AlphaMissense

1485 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:56594389:C:A	P56T	1.000
17:56594389:C:T	P56S	1.000
17:56594390:C:A	P56H	1.000
17:56594420:T:C	L66P	1.000
17:56594669:T:C	L149P	1.000
17:56594686:T:A	C155S	1.000
17:56594686:T:C	C155R	1.000
17:56594687:G:A	C155Y	1.000
17:56594687:G:C	C155S	1.000
17:56594687:G:T	C155F	1.000
17:56594688:C:G	C155W	1.000
17:56594704:T:A	W161R	1.000
17:56594704:T:C	W161R	1.000
17:56594706:G:C	W161C	1.000
17:56594706:G:T	W161C	1.000
17:56594714:T:C	L164P	1.000
17:56594716:G:C	G165R	1.000
17:56594716:G:T	G165C	1.000
17:56594717:G:T	G165V	1.000
17:56594722:C:A	R167S	1.000
17:56594725:T:C	F168L	1.000
17:56594726:T:C	F168S	1.000
17:56594726:T:G	F168C	1.000
17:56594727:T:A	F168L	1.000
17:56594727:T:G	F168L	1.000
17:56594728:T:A	W169R	1.000
17:56594728:T:C	W169R	1.000
17:56594730:G:C	W169C	1.000
17:56594730:G:T	W169C	1.000
17:56594731:C:A	P170T	1.000

dbSNP variants (sampled 300 via entrez): RS1000562643 (17:56596030 G>C), RS1001069469 (17:56592693 C>A), RS1001099316 (17:56592490 G>C), RS1001164330 (17:56594646 G>A,T), RS1002125473 (17:56593304 G>T), RS1002199008 (17:56593087 C>G,T), RS1003152912 (17:56594636 G>A,T), RS1003339140 (17:56595738 C>T), RS1003967890 (17:56592908 G>A,C,T), RS1005139237 (17:56592169 A>G,T), RS1005211314 (17:56591862 C>T), RS1006091121 (17:56593843 C>G), RS1007025494 (17:56592471 T>C), RS1007134702 (17:56594115 G>A,C,T), RS1007508658 (17:56592274 G>A)

Disease associations

OMIM: gene MIM:602991 | disease phenotypes: MIM:185800, MIM:611377, MIM:184460, MIM:186500, MIM:186570, MIM:616471

GenCC curated gene-disease

Disease	Classification	Inheritance
NOG-related symphalangism spectrum disorder	Definitive	Autosomal dominant
multiple synostoses syndrome 1	Definitive	Autosomal dominant
brachydactyly type B2	Supportive	Autosomal dominant
stapes ankylosis with broad thumbs and toes	Supportive	Autosomal dominant
tarsal-carpal coalition syndrome	Supportive	Autosomal dominant
multiple synostoses syndrome	Supportive	Autosomal dominant
proximal symphalangism	Supportive	Autosomal dominant

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
NOG-related symphalangism spectrum disorder	Definitive	AD

Mondo (9): proximal symphalangism 1A (MONDO:0020733), brachydactyly type B2 (MONDO:0012658), stapes ankylosis with broad thumbs and toes (MONDO:0008484), multiple synostoses syndrome 1 (MONDO:0008519), tarsal-carpal coalition syndrome (MONDO:0008521), Bethlem myopathy 2 (MONDO:0034022), NOG-related symphalangism spectrum disorder (MONDO:0100521), multiple synostoses syndrome (MONDO:0017923), proximal symphalangism (MONDO:0008511)

Orphanet (7): Proximal symphalangism (Orphanet:3250), Brachydactyly type B2 (Orphanet:140908), Stapes ankylosis with broad thumbs and toes (Orphanet:140917), Multiple synostoses syndrome (Orphanet:3237), Tarsal-carpal coalition syndrome (Orphanet:1412), Myopathic Ehlers-Danlos syndrome (Orphanet:536516), Bethlem muscular dystrophy (Orphanet:610)

HPO phenotypes

105 total (30 of 105 shown, HPO-id order):

HPO	Term
HP:0000002	Abnormality of body height
HP:0000006	Autosomal dominant inheritance
HP:0000215	Thick upper lip vermilion
HP:0000219	Thin upper lip vermilion
HP:0000275	Narrow face
HP:0000322	Short philtrum
HP:0000324	Facial asymmetry
HP:0000364	Hearing abnormality
HP:0000381	Stapes ankylosis
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0000430	Underdeveloped nasal alae
HP:0000431	Wide nasal bridge
HP:0000466	Limited neck range of motion
HP:0000483	Astigmatism
HP:0000486	Strabismus
HP:0000508	Ptosis
HP:0000540	Hypermetropia
HP:0000582	Upslanted palpebral fissure
HP:0000646	Amblyopia
HP:0000767	Pectus excavatum
HP:0000879	Short sternum
HP:0000920	Enlargement of the costochondral junction
HP:0000954	Single transverse palmar crease
HP:0001156	Brachydactyly
HP:0001204	Distal finger symphalangism
HP:0001387	Joint stiffness
HP:0001597	Abnormal nail morphology
HP:0001770	Toe syndactyly
HP:0001773	Short foot

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST000175_3	Height	1.000000e-07
GCST000547_3	Orofacial clefts	7.000000e-06
GCST000547_4	Orofacial clefts	1.000000e-08
GCST000817_18	Height	2.000000e-08
GCST000817_94	Height	7.000000e-15
GCST002112_6	Celiac disease	4.000000e-06
GCST002337_162	Amyotrophic lateral sclerosis (sporadic)	2.000000e-06
GCST004166_28	Nonsyndromic cleft lip with cleft palate	9.000000e-09
GCST006291_37	Spherical equivalent or myopia (age of diagnosis)	2.000000e-12
GCST008839_301	Height	4.000000e-17
GCST008839_534	Height	1.000000e-08
GCST009391_1541	Metabolite levels	3.000000e-06
GCST010002_126	Refractive error	7.000000e-42
GCST012226_798	Waist circumference adjusted for body mass index	3.000000e-08
GCST012226_799	Waist circumference adjusted for body mass index	4.000000e-11
GCST90020029_488	Waist circumference adjusted for body mass index	3.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0003959	cleft lip
EFO:0004847	age at onset
EFO:0010510	NG-monomethyl-arginine measurement
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C536223	Cushing’s symphalangism (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases methylation, affects cotreatment, affects expression, decreases expression, increases expression	6
trichostatin A	affects cotreatment, affects expression, decreases expression, increases expression	3
Air Pollutants	decreases expression, increases abundance, increases expression	3
Estradiol	affects cotreatment, increases expression, decreases expression, increases reaction	3
Tretinoin	affects cotreatment, increases expression, decreases expression, affects expression	3
entinostat	decreases expression, affects cotreatment, affects expression, increases expression	2
belinostat	affects cotreatment, decreases expression, increases expression	2
Vorinostat	increases expression, affects cotreatment, decreases expression	2
Panobinostat	affects cotreatment, decreases expression, increases expression	2
Benzo(a)pyrene	increases expression, increases methylation	2
Oxygen	increases expression	2
Phenylmercuric Acetate	affects cotreatment, affects expression, decreases expression, increases expression	2
Progesterone	decreases abundance, decreases reaction, increases expression, increases reaction	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	decreases expression	1
bisphenol F	increases expression	1
sotorasib	decreases expression, affects cotreatment	1
methylmercuric chloride	increases expression, affects cotreatment, decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
O,O-diethyl O-3,5,6-trichloro-2-pyridyl phosphate	affects response to substance, affects expression	1
sulforaphane	decreases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	increases expression	1
ferrous chloride	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	affects cotreatment, decreases expression	1
mercuric bromide	affects cotreatment, affects expression, decreases expression, increases expression	1
polyhexamethyleneguanidine	increases expression	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04671407	PHASE2	UNKNOWN	The Aim of This Study is to Compare the Efficacy of Perioperative Hypertonic Saline 3% Versus Normal Saline (0.9%) in Decreasing Recurrence Risk in Non-muscle Invasive Bladder Cancer
NCT04147182	PHASE1	UNKNOWN	Perioperative Intravesical Instilation of Hypertonic Saline Following Bladder Tumor Resection