MTDH

Summary

MTDH (metadherin, HGNC:29608) is a protein-coding gene on chromosome 8q22.1, encoding Protein LYRIC (Q86UE4). Down-regulates SLC1A2/EAAT2 promoter activity when expressed ectopically.

Enables NF-kappaB binding activity; double-stranded RNA binding activity; and transcription coactivator activity. Involved in several processes, including lipopolysaccharide-mediated signaling pathway; positive regulation of intracellular signal transduction; and regulation of DNA-templated transcription. Located in endoplasmic reticulum; nuclear lumen; and perinuclear region of cytoplasm. Implicated in hepatocellular carcinoma.

Source: NCBI Gene 92140 — RefSeq curated summary.

At a glance

• GWAS associations: 11
• Clinical variants (ClinVar): 123 total
• Druggable target: yes
• MANE Select transcript: NM_178812

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29608
Approved symbol	MTDH
Name	metadherin
Location	8q22.1
Locus type	gene with protein product
Status	Approved
Aliases	LYRIC, 3D3, AEG-1
Ensembl gene	ENSG00000147649
Ensembl biotype	protein_coding
OMIM	610323
Entrez	92140

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 21 protein_coding, 1 nonsense_mediated_decay, 1 retained_intron

ENST00000336273, ENST00000519293, ENST00000519934, ENST00000521933, ENST00000522104, ENST00000522313, ENST00000887773, ENST00000887774, ENST00000887775, ENST00000915586, ENST00000915587, ENST00000915588, ENST00000915589, ENST00000915590, ENST00000915591, ENST00000915592, ENST00000915593, ENST00000953189, ENST00000953190, ENST00000953191, ENST00000953192, ENST00000953193, ENST00000953194

RefSeq mRNA: 5 — MANE Select: NM_178812 NM_001363136, NM_001363137, NM_001363138, NM_001363139, NM_178812

CCDS: CCDS6274

Canonical transcript exons

ENST00000336273 — 12 exons

Exon	Start	End
ENSE00001088731	97661072	97661173
ENSE00001154648	97706626	97706750
ENSE00001154660	97699754	97699852
ENSE00001154665	97690952	97691188
ENSE00001154672	97689038	97689103
ENSE00001156693	97687429	97687605
ENSE00001156700	97686668	97686752
ENSE00001242762	97724600	97730260
ENSE00001353226	97644184	97644887
ENSE00003515553	97713662	97713769
ENSE00003538906	97722879	97723035
ENSE00003659582	97719049	97719189

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 98.87.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 68.9210 / max 1261.1119, expressed in 1826 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
89892	63.3293	1826
89893	2.3335	1238
89894	1.7838	933
205265	0.8643	510
89891	0.3497	163
89890	0.2605	64

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	98.87	gold quality
secondary oocyte	CL:0000655	98.42	gold quality
pylorus	UBERON:0001166	98.38	gold quality
sural nerve	UBERON:0015488	98.35	gold quality
endometrium epithelium	UBERON:0004811	98.24	gold quality
nipple	UBERON:0002030	98.23	gold quality
corpus callosum	UBERON:0002336	98.08	gold quality
tendon	UBERON:0000043	98.02	gold quality
cardia of stomach	UBERON:0001162	97.86	gold quality
bone marrow cell	CL:0002092	97.85	gold quality
inferior vagus X ganglion	UBERON:0005363	97.75	gold quality
decidua	UBERON:0002450	97.65	gold quality
saphenous vein	UBERON:0007318	97.60	gold quality
pericardium	UBERON:0002407	97.58	gold quality
colonic epithelium	UBERON:0000397	97.45	gold quality
choroid plexus epithelium	UBERON:0003911	97.31	gold quality
dorsal root ganglion	UBERON:0000044	97.13	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.08	gold quality
urethra	UBERON:0000057	97.06	gold quality
tendon of biceps brachii	UBERON:0008188	97.02	gold quality
tonsil	UBERON:0002372	96.92	gold quality
seminal vesicle	UBERON:0000998	96.90	gold quality
trigeminal ganglion	UBERON:0001675	96.85	gold quality
corpus epididymis	UBERON:0004359	96.81	gold quality
bone marrow	UBERON:0002371	96.80	gold quality
renal medulla	UBERON:0000362	96.73	gold quality
synovial joint	UBERON:0002217	96.60	gold quality
parietal pleura	UBERON:0002400	96.60	gold quality
pharyngeal mucosa	UBERON:0000355	96.52	gold quality
superior surface of tongue	UBERON:0007371	96.51	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-HCAD-1	yes	48.56
E-CURD-122	yes	25.60
E-HCAD-9	yes	20.55
E-CURD-46	yes	10.95
E-MTAB-10042	yes	4.18
E-MTAB-3929	no	180.61
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC, NFKB, RELA

Literature-anchored findings (GeneRIF, showing 40)

• 3D3/lyric is localized to the membrane of the endoplasmic reticulum, nuclear envelope, and the nucleolus. (PMID:14980505)
• overexpression of metadherin is associated with metastatic breast cancer (PMID:15093543)
• a novel protein LYRIC is recruited during the maturation of the tight junction complex. (PMID:15383321)
• findings indicate that AEG-1 might play a pivotal role in the pathogenesis, progression and metastasis of diverse cancers (PMID:17397930)
• AEG-1 is an oncogene cooperating with Ha-ras as well as functioning as a downstream target gene of Ha-ras; may perform a central role in Ha-ras-mediated carcinogenesis. (PMID:17704808)
• AEG-1 might function as a coactivator for NF-kappaB, consequently augmenting expression of genes necessary for invasion of glioma cells (PMID:18316612)
• LYRIC/AEG-1 is a negative regulator of BCCIPalpha, promoting proteasomal degradation either through direct interaction, or potentially through an indirect mechanism involving downstream effects of the NF-kappaB signaling pathway. (PMID:18440304)
• AEG-1 protein is a valuable marker of breast cancer progression. (PMID:18519759)
• establish MTDH as an important therapeutic target for simultaneously enhancing chemotherapy efficacy and reducing metastasis risk (PMID:19111877)
• AEG1 plays a central role in regulating diverse aspects of hepatocellular carcinoma pathogenesis and inhibition may lead to an effective therapeutic strategy for this disease. (PMID:19221438)
• Upregulation of AEG-1 plays an important role in the development and pathogenesis of human esophageal squamous cell carcinoma progression and pathogenesis. (PMID:19304953)
• Increased cytoplasmic distribution of LYRIC is associated with prostate cancer. (PMID:19383828)
• AEG-1 may play a crucial role in the pathogenesis of neuroblastoma and could represent a potential target for therapeutic intervention. (PMID:19448665)
• Studies were further confirmed in clinical primary breast cancer specimens, in which high-level expression of AEG-1 was inversely correlated with the expression of FOXO1. (PMID:19633686)
• one mechanism for cells with altered LYRIC/AEG-1 expression to evade apoptosis and increase cell growth during tumourigenesis through the regulation of PLZF repression (PMID:19648967)
• AEG-1 was suggested to be a LPS-responsive gene and involved in LPS-induced inflammatory response. (PMID:19740331)
• findings demonstrate that aberrant AEG-1 expression plays a dominant positive role in regulating oncogenic transformation and angiogenesis (PMID:19940250)
• AEG-1 may play a crucial role in the pathogenesis of glioma. (PMID:20053777)
• AEG-1 gene is clinically significant in human oligodendroglioma. (PMID:20236756)
• AEG-1 may play a role in Wnt/beta-catenin-mediated cancer progression (PMID:20300973)
• Findings show that AEG-1 contributes to glioma progression by enhancing MMP-9 transcription and tumor cell invasiveness, and underscore the importance of AEG-1 in glioma development and progression. (PMID:20388776)
• although AEG-1 does not affect MDR1 gene transcription, it facilitates association of MDR1 mRNA to polysomes, resulting in increased translation (PMID:20388796)
• MTDH overexpression could be identified in proliferative breast lesions and may contribute to breast cancer progression. (PMID:20565850)
• AEG-1 expression in colorectal carcinoma may be associated with tumor progression, and high AEG-1 expression correlates with poor overall survival (PMID:20625905)
• AEG-1 protein is overexpressed in RCC and plays an important role in tumor differentiation and progression. (PMID:20845990)
• miR-26a functionally antagonizes human breast carcinogenesis by targeting MTDH and EZH2. (PMID:20952513)
• Observations link AEG-1 overexpression in glioblastoma with hypoxia and glucose deprivation. (PMID:21084864)
• AEG-1-mediated chemoresistance is because of protective autophagy and inhibition of AEG-1 results in a decrease in protective autophagy and chemosensitization of cancer cells. (PMID:21127263)
• Overexpression of AEG-1 increases cell migration and invasion of glioma cells. (PMID:21150314)
• historical perspective of AEG-1; evaluation of AEG-1 as a novel diagnostic/prognostic biomarker for a variety of cancers; understanding of the molecular and biochemical bases of oncogenic properties of AEG-1 [review] (PMID:21256156)
• AEG-1 expression may be related with tumor angiogenesis and progression and is a valuable prognostic factor in patients with triple-negative breast cancer. (PMID:21259255)
• high AEG-1 expression was associated with progression and prognosis of ovarian carcinoma. (PMID:21293286)
• results suggest that MTDH could promote epithelial-mesenchymal transition in breast cancer cells in driving the progression of their aggressive behavior (PMID:21371176)
• All variants of the MTDH gene were investigated and the association of the variants with breast cancer development, was explored. (PMID:21408129)
• Astrocyte elevated gene-1 activates AMPK in response to cellular metabolic stress and promotes protective autophagy. (PMID:21412050)
• Study revealed a modest gene-based significant association between migraine and the metadherin (MTDH) gene, previously identified in the first clinic-based GWA study (GWAS) for migraine (Bonferroni-corrected gene-based P-value=0.026). (PMID:21448238)
• SND1 as a novel MTDH-interacting protein and shown that it is a functionally and clinically significant mediator of metastasis. (PMID:21478147)
• AEG-1 overexpression is associated with carcinogenesis and tumor progression in endometrial cancer. (PMID:21495225)
• AEG-1 is overexpressed in a great portion of epithelial ovarian cancer (EOC) patients with peritoneal dissemination and/or lymph node metastasis and may be clinically useful for predicting metastasis in EOC. (PMID:21543927)
• The expression of EphA7 and/or MTDH might be closely related to the carcinogenesis, progression, clinical biological behaviors and prognosis of gallbladder adenocarcinoma. (PMID:21609571)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	mtdhb	ENSDARG00000004939
danio_rerio	mtdha	ENSDARG00000014159
mus_musculus	Mtdh	ENSMUSG00000022255
rattus_norvegicus	Mtdh	ENSRNOG00000006870

Paralogs (1): MAMSTR (ENSG00000176909)

Protein

Protein identifiers

Protein LYRIC — Q86UE4 (reviewed: Q86UE4)

Alternative names: 3D3/LYRIC, Astrocyte elevated gene-1 protein, Lysine-rich CEACAM1 co-isolated protein, Metadherin, Metastasis adhesion protein

All UniProt accessions (5): Q86UE4, E5RJU9, H0YB56, H0YBE0, H0YBJ8

UniProt curated annotations — full annotation on UniProt →

Function. Down-regulates SLC1A2/EAAT2 promoter activity when expressed ectopically. Activates the nuclear factor kappa-B (NF-kappa-B) transcription factor. Promotes anchorage-independent growth of immortalized melanocytes and astrocytes which is a key component in tumor cell expansion. Promotes lung metastasis and also has an effect on bone and brain metastasis, possibly by enhancing the seeding of tumor cells to the target organ endothelium. Induces chemoresistance.

Subunit / interactions. Interacts with BCCIP, CREBBP/CBP and RELA/p65.

Subcellular location. Endoplasmic reticulum membrane. Nucleus membrane. Cell junction. Tight junction. Nucleus. Nucleolus. Cytoplasm. Perinuclear region.

Tissue specificity. Widely expressed with highest levels in muscle-dominating organs such as skeletal muscle, heart, tongue and small intestine and in endocrine glands such as thyroid and adrenal gland. Overexpressed in various cancers including breast, brain, prostate, melanoma and glioblastoma multiforme.

Induction. By TNF (at protein level). By HIV-1 infection of primary fetal astrocytes.

Miscellaneous. Knockdown significantly reduces the adhesion of cancer cells to lung microvascular endothelial cells and the reciprocal effect is observed following overexpression.

RefSeq proteins (5): NP_001350065, NP_001350066, NP_001350067, NP_001350068, NP_848927* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR031402	LYRIC	Family
IPR052305	TransReg_TumorExp	Family

Pfam: PF15686

UniProt features (48 total): modified residue 21, compositionally biased region 12, region of interest 6, sequence conflict 4, topological domain 2, chain 1, transmembrane region 1, sequence variant 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
4QMG	X-RAY DIFFRACTION	2.7

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q86UE4-F1	51.96	0.01

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 (21): 143, 180, 216, 251, 264, 298, 306, 308, 311, 323, 339, 344, 369, 415, 426, 457, 458, 478, 494, 496 …

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 356 (showing top): MORF_MTA1, SHEPARD_BMYB_MORPHOLINO_UP, FLECHNER_PBL_KIDNEY_TRANSPLANT_REJECTED_VS_OK_UP, GOBP_REGULATION_OF_AUTOPHAGY, MORF_MBD4, GNF2_BNIP2, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, AAGCCAT_MIR135A_MIR135B, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION, GOBP_POSITIVE_REGULATION_OF_VASCULATURE_DEVELOPMENT, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, MORF_HDAC1, MORF_UBE2N, MORF_RAD21

GO Biological Process (10): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of transcription by RNA polymerase II (GO:0006357), positive regulation of autophagy (GO:0010508), lipopolysaccharide-mediated signaling pathway (GO:0031663), negative regulation of apoptotic process (GO:0043066), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), positive regulation of angiogenesis (GO:0045766), obsolete positive regulation of NF-kappaB transcription factor activity (GO:0051092), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (7): transcription coregulator activity (GO:0003712), transcription coactivator activity (GO:0003713), RNA binding (GO:0003723), double-stranded RNA binding (GO:0003725), NF-kappaB binding (GO:0051059), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), protein binding (GO:0005515)

GO Cellular Component (14): fibrillar center (GO:0001650), nucleus (GO:0005634), cytoplasm (GO:0005737), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), bicellular tight junction (GO:0005923), apical plasma membrane (GO:0016324), nuclear body (GO:0016604), nuclear membrane (GO:0031965), intercellular canaliculus (GO:0046581), perinuclear region of cytoplasm (GO:0048471), nucleolus (GO:0005730), membrane (GO:0016020), anchoring junction (GO:0070161)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
transcription by RNA polymerase II	2
regulation of DNA-templated transcription	2
positive regulation of intracellular signal transduction	2
intracellular membrane-bounded organelle	2
cytoplasm	2
organelle membrane	2
intracellular membraneless organelle	2
regulation of transcription by RNA polymerase II	1
negative regulation of DNA-templated transcription	1
autophagy	1
positive regulation of catabolic process	1
regulation of autophagy	1
cell surface receptor signaling pathway	1
cellular response to lipopolysaccharide	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
canonical NF-kappaB signal transduction	1
regulation of canonical NF-kappaB signal transduction	1
angiogenesis	1
regulation of angiogenesis	1
positive regulation of vasculature development	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
transcription regulator activity	1
transcription coregulator activity	1
positive regulation of DNA-templated transcription	1
nucleic acid binding	1
RNA binding	1
RNA polymerase II-specific DNA-binding transcription factor binding	1
DNA-binding transcription factor binding	1
binding	1
nucleolus	1
intracellular anatomical structure	1
endomembrane system	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1

Protein interactions and networks

STRING

1766 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MTDH	SND1	Q7KZF4	991
MTDH	BCCIP	Q9P287	925
MTDH	DPYD	Q12882	820
MTDH	AGO2	Q9UKV8	808
MTDH	TYMS	P04818	784
MTDH	TFCP2	Q12800	770
MTDH	CRISP3	P54108	758
MTDH	FMR1	Q06787	738
MTDH	AKT1	P31749	691
MTDH	HRAS	P01112	646
MTDH	SLC1A2	P43004	600
MTDH	RRS1	Q15050	594
MTDH	CEACAM1	P13688	579
MTDH	FOXO3	O43524	567
MTDH	ZBTB16	Q05516	543

IntAct

150 interactions, top by confidence:

A	B	Type	Score
MTDH	SND1	psi-mi:“MI:0914”(association)	0.840
MTDH	SND1	psi-mi:“MI:0915”(physical association)	0.840
SND1	MTDH	psi-mi:“MI:0915”(physical association)	0.840
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
INSR	PIK3R2	psi-mi:“MI:2364”(proximity)	0.570
SNN	MTDH	psi-mi:“MI:0914”(association)	0.530
RPS3	ZNF316	psi-mi:“MI:0914”(association)	0.530
AGO2	MTDH	psi-mi:“MI:0915”(physical association)	0.500
MTDH	CSNK2A1	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
RELA	MTDH	psi-mi:“MI:0915”(physical association)	0.400
CREBBP	MTDH	psi-mi:“MI:0915”(physical association)	0.400
MNS1	MTDH	psi-mi:“MI:0915”(physical association)	0.400
MTDH	NOG	psi-mi:“MI:0915”(physical association)	0.400
SDC1	ILVBL	psi-mi:“MI:0915”(physical association)	0.400
MTDH		psi-mi:“MI:0915”(physical association)	0.370
Rpl35	RPS6	psi-mi:“MI:0914”(association)	0.350
EXOSC4	RPS3	psi-mi:“MI:0914”(association)	0.350
JUN	TPM3	psi-mi:“MI:0914”(association)	0.350
MME		psi-mi:“MI:0914”(association)	0.350
MTDH		psi-mi:“MI:0914”(association)	0.350
HIF1AN	ARID1A	psi-mi:“MI:0914”(association)	0.350
		psi-mi:“MI:0914”(association)	0.350

BioGRID (623): MTDH (Affinity Capture-MS), MTDH (Affinity Capture-MS), MTDH (Affinity Capture-MS), MTDH (Affinity Capture-MS), MTDH (Affinity Capture-MS), MTDH (Affinity Capture-MS), MTDH (Proximity Label-MS), MTDH (Proximity Label-MS), MTDH (Proximity Label-MS), MTDH (Proximity Label-MS), MTDH (Affinity Capture-MS), MTDH (Affinity Capture-MS), MTDH (Affinity Capture-Western), CREBBP (Affinity Capture-Western), MTDH (Affinity Capture-MS)

ESM2 similar proteins: A7XYH5, B2RRE7, G5CEW6, O15014, O15265, Q01804, Q0JDM0, Q0P5K1, Q14966, Q3KR53, Q3UHI0, Q3UHK8, Q56A10, Q5F2E7, Q5R4E9, Q5R9C3, Q5ZM88, Q61464, Q6AI39, Q6IMN6, Q6NXH3, Q6NZP2, Q6ZQ03, Q76L83, Q7TPM1, Q7Z417, Q80WJ7, Q86UE4, Q86WP2, Q8BKI2, Q8BZ47, Q8IH18, Q8IZQ8, Q8N3X1, Q8NDV7, Q8SY33, Q93ZJ9, Q9C658, Q9D0P5, Q9ESC8

Diamond homologs: Q80WJ7, Q86UE4, Q9Z1W6

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 169 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
SARS-CoV-1 modulates host translation machinery	8	21.7×	9e-08
Eukaryotic Translation Initiation	7	18.9×	2e-06
Cap-dependent Translation Initiation	7	18.9×	2e-06
Eukaryotic Translation Elongation	7	17.1×	4e-06
Formation of the ternary complex, and subsequently, the 43S complex	9	17.0×	9e-08
Activation of the mRNA upon binding of the cap-binding complex and eIFs, and subsequent binding to 43S	7	16.7×	4e-06
SRP-dependent cotranslational protein targeting to membrane	18	15.8×	3e-14
SARS-CoV-1-host interactions	10	15.4×	4e-08

GO biological processes:

GO term	Partners	Fold	FDR
cytoplasmic translation	16	20.0×	1e-13
ribosomal small subunit biogenesis	10	15.4×	3e-07
ribosomal large subunit biogenesis	5	15.0×	3e-03
negative regulation of translation	11	14.6×	9e-08
translational initiation	5	12.1×	7e-03
positive regulation of translation	7	10.8×	8e-04
translation	15	10.4×	9e-09
rRNA processing	9	8.6×	3e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	90
Likely benign	2
Benign	3

Top pathogenic / likely-pathogenic (0)

SpliceAI

1739 predictions. Top by Δscore:

Variant	Effect	Δscore
8:97644883:CCAAA:C	donor_gain	1.0000
8:97644884:CAAA:C	donor_gain	1.0000
8:97644885:AAA:A	donor_gain	1.0000
8:97644886:AA:A	donor_gain	1.0000
8:97644886:AAGT:A	donor_loss	1.0000
8:97644887:AG:A	donor_loss	1.0000
8:97644888:GT:G	donor_loss	1.0000
8:97644888:GTGA:G	donor_gain	1.0000
8:97644892:G:GG	donor_gain	1.0000
8:97661058:T:TA	acceptor_gain	1.0000
8:97661061:T:TA	acceptor_gain	1.0000
8:97661065:T:TA	acceptor_gain	1.0000
8:97661067:T:TA	acceptor_gain	1.0000
8:97661067:TGCA:T	acceptor_loss	1.0000
8:97661070:A:AC	acceptor_loss	1.0000
8:97661070:A:AG	acceptor_gain	1.0000
8:97661071:G:GG	acceptor_gain	1.0000
8:97661071:GC:G	acceptor_gain	1.0000
8:97661071:GCC:G	acceptor_gain	1.0000
8:97661071:GCCA:G	acceptor_gain	1.0000
8:97661071:GCCAA:G	acceptor_gain	1.0000
8:97661169:AAAAG:A	donor_gain	1.0000
8:97661170:AAAG:A	donor_gain	1.0000
8:97661170:AAAGG:A	donor_loss	1.0000
8:97661171:AAG:A	donor_gain	1.0000
8:97661171:AAGGT:A	donor_loss	1.0000
8:97661172:AG:A	donor_gain	1.0000
8:97661172:AGGTA:A	donor_loss	1.0000
8:97661173:GG:G	donor_gain	1.0000
8:97661174:G:GG	donor_gain	1.0000

AlphaMissense

3769 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:97687434:T:A	W192R	1.000
8:97687434:T:C	W192R	1.000
8:97687436:G:C	W192C	1.000
8:97687436:G:T	W192C	1.000
8:97687449:A:C	S197R	1.000
8:97687451:T:A	S197R	1.000
8:97687451:T:G	S197R	1.000
8:97706658:T:A	W394R	1.000
8:97706658:T:C	W394R	1.000
8:97706679:T:A	W401R	1.000
8:97706679:T:C	W401R	1.000
8:97706681:G:C	W401C	1.000
8:97706681:G:T	W401C	1.000
8:97687435:G:C	W192S	0.999
8:97687457:A:C	R199S	0.999
8:97687457:A:T	R199S	0.999
8:97687465:G:C	R202P	0.999
8:97687473:C:A	R205S	0.999
8:97699840:T:A	W379R	0.999
8:97699840:T:C	W379R	0.999
8:97706660:G:C	W394C	0.999
8:97706660:G:T	W394C	0.999
8:97724657:G:C	R579T	0.999
8:97724658:A:C	R579S	0.999
8:97724658:A:T	R579S	0.999
8:97686752:G:A	G190R	0.998
8:97686752:G:C	G190R	0.998
8:97687459:A:T	E200V	0.998
8:97687461:A:G	K201E	0.998
8:97687463:A:C	K201N	0.998

dbSNP variants (sampled 300 via entrez): RS1000027040 (8:97707180 CTTG>C), RS1000140275 (8:97725623 A>G), RS1000157366 (8:97644271 C>T), RS1000160072 (8:97718915 C>T), RS1000161862 (8:97665276 G>A), RS1000168979 (8:97683408 T>C,G), RS1000196306 (8:97728867 G>A), RS1000197953 (8:97683616 A>G), RS1000238689 (8:97697544 C>T), RS1000359937 (8:97648570 T>G), RS1000373131 (8:97716114 C>A,T), RS1000411953 (8:97650397 C>G), RS1000420459 (8:97694815 C>G,T), RS1000436069 (8:97671898 A>G,T), RS1000512463 (8:97684369 G>A)

Disease associations

OMIM: gene MIM:610323 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST000782_1	Migraine	2.000000e-11
GCST003629_14	Nicotine metabolite ratio in current smokers	3.000000e-08
GCST004621_123	Red cell distribution width	2.000000e-16
GCST005993_42	Mean corpuscular hemoglobin	4.000000e-08
GCST006431_9	Plasma parathyroid hormone levels	5.000000e-06
GCST006804_96	Red cell distribution width	7.000000e-22
GCST010572_9	Sweet taste preference	3.000000e-06
GCST90002390_607	Mean corpuscular hemoglobin	5.000000e-31
GCST90002391_188	Mean corpuscular hemoglobin concentration	1.000000e-24
GCST90002392_588	Mean corpuscular volume	6.000000e-17
GCST90002404_321	Red cell distribution width	6.000000e-60

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0007794	nicotine metabolite ratio
EFO:0009188	Red cell distribution width
EFO:0004527	mean corpuscular hemoglobin
EFO:0010156	sweet liking measurement
EFO:0004528	mean corpuscular hemoglobin concentration

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066346 (SINGLE PROTEIN)

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

ChEMBL bioactivities

4 potent at pChembl≥5 of 4 total, top 4 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.35	Kd	4506	nM	CHEMBL3752910
5.35	ED50	4506	nM	CHEMBL3752910
5.17	Kd	6820	nM	CHEMBL5653589
5.17	ED50	6820	nM	CHEMBL5653589

PubChem BioAssay actives

2 with measured affinity, of 4 total; 2 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148793: Binding affinity to human MTDH incubated for 45 mins by Kinobead based pull down assay	kd	4.5058	uM
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148793: Binding affinity to human MTDH incubated for 45 mins by Kinobead based pull down assay	kd	6.8205	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Cyclosporine	increases expression	5
Valproic Acid	increases expression, affects expression, affects cotreatment	4
trichostatin A	affects cotreatment, increases expression	3
Cadmium Chloride	decreases expression, increases expression, decreases reaction, increases abundance, increases palmitoylation	3
Lead	affects splicing, decreases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	2
Particulate Matter	decreases expression, increases abundance, affects cotreatment, increases expression	2
aristolochic acid I	decreases expression	1
FR900359	affects phosphorylation	1
triphenyl phosphate	affects expression	1
bisphenol A	increases expression	1
sodium arsenite	affects binding, increases reaction	1
2-bromopalmitate	decreases reaction, increases abundance, increases palmitoylation	1
coumarin	increases phosphorylation	1
dibenzo(a,l)pyrene	decreases expression	1
beta-methylcholine	affects expression	1
ovatodiolide	decreases 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
abrine	decreases expression	1
dorsomorphin	increases expression, affects cotreatment	1
bisphenol S	affects expression	1
bisphenol AF	increases expression	1
4-(4-((5-(4,5-dimethyl-2-nitrophenyl)-2-furanyl)methylene)-4,5-dihydro-3-methyl-5-oxo-1H-pyrazol-1-yl)benzoic acid	decreases expression	1
Sunitinib	increases expression	1
Cidofovir	decreases expression	1
Acetaminophen	decreases expression	1
Air Pollutants	decreases expression, increases abundance	1
Benztropine	affects cotreatment, decreases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651835	Binding	Binding affinity to human MTDH incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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