DMTN

Summary

DMTN (dematin actin binding protein, HGNC:3382) is a protein-coding gene on chromosome 8p21.3, encoding Dematin (Q08495). Membrane-cytoskeleton-associated protein with F-actin-binding activity that induces F-actin bundles formation and stabilization.

The protein encoded by this gene is an actin binding and bundling protein that plays a structural role in erythrocytes, by stabilizing and attaching the spectrin/actin cytoskeleton to the erythrocyte membrane in a phosphorylation-dependent manner. This protein contains a core domain in the N-terminus, and a headpiece domain in the C-terminus that binds F-actin. When purified from erythrocytes, this protein exists as a trimer composed of two 48 kDa polypeptides and a 52 kDa polypeptide. The different subunits arise from alternative splicing in the 3’ coding region, where the headpiece domain is located. Disruption of this gene has been correlated with the autosomal dominant Marie Unna hereditary hypotrichosis disease, while loss of heterozygosity of this gene is thought to play a role in prostate cancer progression. Alternative splicing results in multiple transcript variants encoding different isoforms.

Source: NCBI Gene 2039 — RefSeq curated summary.

At a glance

• GWAS associations: 9
• Clinical variants (ClinVar): 56 total — 1 pathogenic
• MANE Select transcript: NM_001387751

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3382
Approved symbol	DMTN
Name	dematin actin binding protein
Location	8p21.3
Locus type	gene with protein product
Status	Approved
Aliases	DMT
Ensembl gene	ENSG00000158856
Ensembl biotype	protein_coding
OMIM	125305
Entrez	2039

Gene structure

Transcript identifiers

Ensembl transcripts: 23 — 20 protein_coding, 3 retained_intron

ENST00000265800, ENST00000358242, ENST00000381470, ENST00000415253, ENST00000432128, ENST00000443491, ENST00000517305, ENST00000517418, ENST00000517600, ENST00000517804, ENST00000518816, ENST00000519333, ENST00000519850, ENST00000519907, ENST00000519959, ENST00000520174, ENST00000520856, ENST00000522148, ENST00000522340, ENST00000523266, ENST00000523300, ENST00000523623, ENST00000523782

RefSeq mRNA: 53 — MANE Select: NM_001387751 NM_001114135, NM_001114136, NM_001114137, NM_001114138, NM_001114139, NM_001302816, NM_001302817, NM_001323378, NM_001323379, NM_001323380, NM_001323381, NM_001323382, NM_001323383, NM_001323384, NM_001323385, NM_001323387, NM_001323388, NM_001323389, NM_001323390, NM_001323391, NM_001323392, NM_001323393, NM_001323394, NM_001323395, NM_001323396, NM_001323397, NM_001323398, NM_001323399, NM_001323400, NM_001323401, NM_001387723, NM_001387726, NM_001387727, NM_001387728, NM_001387730, NM_001387732, NM_001387734, NM_001387735, NM_001387736, NM_001387737, NM_001387742, NM_001387743, NM_001387744, NM_001387745, NM_001387750, NM_001387751, NM_001387752, NM_001387753, NM_001387754, NM_001387755, NM_001387756, NM_001387757, NM_001978

CCDS: CCDS47820, CCDS47821, CCDS6020, CCDS78311

Canonical transcript exons

ENST00000358242 — 16 exons

Exon	Start	End
ENSE00000980119	22080180	22080244
ENSE00000980120	22080412	22080460
ENSE00001158910	22073730	22073835
ENSE00001158933	22069419	22069518
ENSE00001158939	22069016	22069060
ENSE00001640950	22080618	22080625
ENSE00002709039	22066705	22066893
ENSE00003226793	22080805	22080870
ENSE00003461336	22069881	22069937
ENSE00003498836	22067085	22067159
ENSE00003580897	22067527	22067682
ENSE00003739218	22081113	22081193
ENSE00003784938	22070182	22070334
ENSE00003788515	22072326	22072450
ENSE00003924343	22081350	22082525
ENSE00003934233	22056814	22057136

Expression profiles

Bgee: expression breadth ubiquitous, 269 present calls, max score 99.02.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 27.7359 / max 2782.0234, expressed in 1179 samples.

FANTOM5 promoters (25 alternative TSS)

Promoter ID	TPM avg	Samples expressed
87678	7.6300	220
87673	5.5824	845
87684	5.1787	225
87685	1.7262	132
87691	1.4926	37
87697	1.2764	503
87682	1.0473	161
87698	0.9302	269
87695	0.4572	151
87671	0.3558	174

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right frontal lobe	UBERON:0002810	99.02	gold quality
cingulate cortex	UBERON:0003027	98.69	gold quality
anterior cingulate cortex	UBERON:0009835	98.67	gold quality
prefrontal cortex	UBERON:0000451	98.59	gold quality
Brodmann (1909) area 10	UBERON:0013541	98.56	gold quality
nucleus accumbens	UBERON:0001882	98.35	gold quality
amygdala	UBERON:0001876	98.02	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.95	gold quality
frontal cortex	UBERON:0001870	97.80	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.74	gold quality
caudate nucleus	UBERON:0001873	97.70	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.58	gold quality
putamen	UBERON:0001874	97.31	gold quality
cerebellar hemisphere	UBERON:0002245	97.27	gold quality
cerebellar cortex	UBERON:0002129	97.22	gold quality
adenohypophysis	UBERON:0002196	97.19	gold quality
neocortex	UBERON:0001950	97.16	gold quality
frontal pole	UBERON:0002795	96.91	gold quality
pituitary gland	UBERON:0000007	96.82	gold quality
monocyte	CL:0000576	96.26	gold quality
cerebellum	UBERON:0002037	96.25	gold quality
cerebral cortex	UBERON:0000956	96.24	gold quality
telencephalon	UBERON:0001893	96.23	gold quality
type B pancreatic cell	CL:0000169	96.14	gold quality
forebrain	UBERON:0001890	96.13	gold quality
blood	UBERON:0000178	95.98	gold quality
hypothalamus	UBERON:0001898	95.90	gold quality
temporal lobe	UBERON:0001871	95.86	gold quality
mononuclear cell	CL:0000842	95.69	gold quality
brain	UBERON:0000955	95.61	gold quality

Single-cell (SCXA)

Detected in 10 experiment(s), a significant marker in 9.

Experiment	Marker?	Max mean expression
E-CURD-112	yes	42.54
E-MTAB-10042	yes	35.69
E-CURD-122	yes	21.90
E-MTAB-9221	yes	16.52
E-HCAD-10	yes	16.38
E-MTAB-9067	yes	7.96
E-HCAD-9	yes	7.60
E-MTAB-9467	yes	3.62
E-HCAD-5	no	2.14
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

69 targeting DMTN, 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-8485	100.00	77.57	4731
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-10401-5P	99.99	65.79	948
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-6780B-5P	99.96	69.60	2562
HSA-MIR-4725-3P	99.96	69.53	2520
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-6772-5P	99.94	67.01	577
HSA-MIR-6721-5P	99.93	68.92	2981
HSA-MIR-4271	99.88	68.32	2244
HSA-MIR-4492	99.87	68.25	3611
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6842-5P	99.80	67.54	1587
HSA-MIR-7110-5P	99.80	67.84	1712
HSA-MIR-3156-3P	99.76	66.72	939
HSA-MIR-6752-5P	99.59	67.32	1243
HSA-MIR-1207-5P	99.49	69.11	2983
HSA-MIR-6081	99.48	66.07	1446
HSA-MIR-6722-3P	99.45	67.62	1919
HSA-MIR-361-3P	99.19	66.45	1381
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-4763-3P	99.10	67.83	2649
HSA-MIR-485-5P	99.10	64.78	1889

Literature-anchored findings (GeneRIF, showing 9)

• results suggest that phosphorylation of the dematin headpiece acts as a conformational switch within this headpiece domain (PMID:14660664)
• a crucial role for this proline residue in structural stability and folding potential of HP (sub)domains consistent with Pro-Trp stacking as a more general determinant of protein stability (PMID:16697408)
• study investigated motions in the backbone of dematin headpiece domain and its mutant DHPS74E using several complementary NMR relaxation techniques (PMID:19030997)
• results suggest that the core domain of dematin exhibits properties typical of a natively unfolded protein, while the headpiece domain is folded in a conformation essentially identical to its native structure (PMID:19241372)
• Fast backbone dynamics probed at amide nitrogen versus carbonyl carbon sites for dematin headpiece C-terminal. The reduction of mobility in the loop region upon the S74E mutation can be seen from the (15)N order parameters. (PMID:20396930)
• a novel functional role for dematin in regulating erythrocyte membrane function. (PMID:22927433)
• the headpiece domain of dematin regulates calcium mobilization and signaling in platelets (PMID:23060452)
• When unphosphorylated, dematin’s two F-actin binding domains move independent of one another permitting them to bind different F-actin filaments. (PMID:23355471)
• Dematin inhibits glioblastoma malignancy through RhoA-mediated CDKs downregulation and cytoskeleton remodeling. (PMID:35561787)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	dmtn	ENSDARG00000013110
mus_musculus	Dmtn	ENSMUSG00000022099
rattus_norvegicus	Dmtn	ENSRNOG00000012273
drosophila_melanogaster	Unc-115a	FBGN0051352
drosophila_melanogaster	Unc-115b	FBGN0260463

Paralogs (3): ABLIM1 (ENSG00000099204), ABLIM2 (ENSG00000163995), ABLIM3 (ENSG00000173210)

Protein

Protein identifiers

Dematin — Q08495 (reviewed: Q08495)

Alternative names: Dematin actin-binding protein, Erythrocyte membrane protein band 4.9

All UniProt accessions (10): A0A087WT94, A0A087WUC0, A0A979HLS0, E5RFK4, E5RFK6, E5RGQ0, E5RGQ7, E5RJ61, E5RJC0, Q08495

UniProt curated annotations — full annotation on UniProt →

Function. Membrane-cytoskeleton-associated protein with F-actin-binding activity that induces F-actin bundles formation and stabilization. Its F-actin-bundling activity is reversibly regulated upon its phosphorylation by the cAMP-dependent protein kinase A (PKA). Binds to the erythrocyte membrane glucose transporter-1 SLC2A1/GLUT1, and hence stabilizes and attaches the spectrin-actin network to the erythrocytic plasma membrane. Plays a role in maintaining the functional integrity of PKA-activated erythrocyte shape and the membrane mechanical properties. Also plays a role as a modulator of actin dynamics in fibroblasts; acts as a negative regulator of the RhoA activation pathway. In platelets, functions as a regulator of internal calcium mobilization across the dense tubular system that affects platelet granule secretion pathways and aggregation. Also required for the formation of a diverse set of cell protrusions, such as filopodia and lamellipodia, necessary for platelet cell spreading, motility and migration. Acts as a tumor suppressor and inhibits malignant cell transformation.

Subunit / interactions. Monomeric (isoform 2); under reducing conditions. Self-associates. Exists under oxidizing condition as a trimer of two isoforms 2 and isoform 1 linked by disulfide bonds. Found in a complex with DMTN, F-actin and spectrin. Found in a complex with ADD2, DMTN and SLC2A1. Interacts with F-actin, ITPKB, RASGRF2 and spectrin. Isoform 2 interacts with SLC2A1 (via C-terminus cytoplasmic region). Isoform 1 and isoform 2 interact (phosphorylated form) with plasmodium berghei 14-3-3 protein; the interaction occurs in a PKA-dependent manner.

Subcellular location. Cytoplasm. Cytosol. Perinuclear region. Cytoskeleton. Cell membrane. Membrane. Endomembrane system. Cell projection.

Tissue specificity. Expressed in platelets (at protein level). Expressed in heart, brain, lung, skeletal muscle, and kidney.

Post-translational modifications. Phosphorylated. Phosphorylation at Ser-403 by PKA causes the C-terminal headpiece domain to associate with the N-terminal core domain, and leads to the inhibition of its actin bundling activity. The N-terminus is blocked.

Domain organisation. Both the N-terminal core domain and the C-terminal headpiece domain are sufficient for binding to F-actin and necessary for actin bundling activity.

Similarity. Belongs to the villin/gelsolin family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q08495-1	1, Long	yes
Q08495-2	2, Short
Q08495-3	3
Q08495-4	4

RefSeq proteins (53): NP_001107607, NP_001107608, NP_001107609, NP_001107610, NP_001107611, NP_001289745, NP_001289746, NP_001310307, NP_001310308, NP_001310309, NP_001310310, NP_001310311, NP_001310312, NP_001310313, NP_001310314, NP_001310316, NP_001310317, NP_001310318, NP_001310319, NP_001310320, NP_001310321, NP_001310322, NP_001310323, NP_001310324, NP_001310325, NP_001310326, NP_001310327, NP_001310328, NP_001310329, NP_001310330, NP_001374652, NP_001374655, NP_001374656, NP_001374657, NP_001374659, NP_001374661, NP_001374663, NP_001374664, NP_001374665, NP_001374666, NP_001374671, NP_001374672, NP_001374673, NP_001374674, NP_001374679, NP_001374680, NP_001374681, NP_001374682, NP_001374683, NP_001374684, NP_001374685, NP_001374686, NP_001969 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003128	Villin_headpiece	Domain
IPR032402	AbLIM_anchor	Domain
IPR036886	Villin_headpiece_dom_sf	Homologous_superfamily
IPR051618	Actin-binding_LIM	Family

Pfam: PF02209, PF16182

UniProt features (52 total): modified residue 19, compositionally biased region 6, sequence conflict 6, region of interest 5, helix 5, mutagenesis site 4, splice variant 3, chain 1, domain 1, turn 1, strand 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
1QZP	SOLUTION NMR
1ZV6	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q08495-F1	64.03	0.12

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 (19): 16, 18, 26, 92, 96, 105, 110, 113, 156, 226, 269, 279, 289, 303, 315, 333, 372, 383, 403

Mutagenesis-validated functional residues (4):

Position	Phenotype
124	reduces interaction with plasmodium berghei 14-3-3 protein. inhibits phosphorylation and interaction with plasmodium ber
333	reduces interaction with plasmodium berghei 14-3-3 protein. inhibits phosphorylation and interaction with plasmodium ber
403	inhibits phosphorylation and interaction with plasmodium berghei 14-3-3 protein; when associated with a-124 and a-333.
403	reduces f-actin bundling but not f-actin binding activity.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-5223345	Miscellaneous transport and binding events

MSigDB gene sets: 296 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_CONTAINING_COMPLEX_ASSEMBLY, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_NEGATIVE_REGULATION_OF_PEPTIDYL_TYROSINE_PHOSPHORYLATION, GOBP_ACTIN_FILAMENT_BUNDLE_ORGANIZATION, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_REGULATION_OF_CELL_MORPHOGENESIS, GOBP_REGULATION_OF_WOUND_HEALING, GOBP_REGULATION_OF_PHOSPHORYLATION, GOBP_MYELOID_CELL_DEVELOPMENT, TGCTGCT_MIR15A_MIR16_MIR15B_MIR195_MIR424_MIR497, GOBP_NEGATIVE_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_PEPTIDYL_SERINE_MODIFICATION, GOBP_FOCAL_ADHESION_ASSEMBLY

GO Biological Process (23): cytoskeleton organization (GO:0007010), regulation of cell shape (GO:0008360), regulation of lamellipodium assembly (GO:0010591), positive regulation of fibroblast migration (GO:0010763), negative regulation of peptidyl-threonine phosphorylation (GO:0010801), negative regulation of cell-substrate adhesion (GO:0010812), lamellipodium assembly (GO:0030032), actin cytoskeleton organization (GO:0030036), regulation of actin cytoskeleton organization (GO:0032956), negative regulation of peptidyl-serine phosphorylation (GO:0033137), erythrocyte development (GO:0048821), negative regulation of peptidyl-tyrosine phosphorylation (GO:0050732), actin filament bundle assembly (GO:0051017), regulation of filopodium assembly (GO:0051489), smooth endoplasmic reticulum calcium ion homeostasis (GO:0051563), actin filament capping (GO:0051693), negative regulation of focal adhesion assembly (GO:0051895), protein-containing complex assembly (GO:0065003), cellular response to cAMP (GO:0071320), endoplasmic reticulum tubular network organization (GO:0071786), positive regulation of wound healing (GO:0090303), negative regulation of protein targeting to membrane (GO:0090315), negative regulation of substrate adhesion-dependent cell spreading (GO:1900025)

GO Molecular Function (5): actin binding (GO:0003779), signaling receptor binding (GO:0005102), spectrin binding (GO:0030507), actin filament binding (GO:0051015), protein binding (GO:0005515)

GO Cellular Component (18): smooth endoplasmic reticulum (GO:0005790), cytosol (GO:0005829), actin filament (GO:0005884), plasma membrane (GO:0005886), postsynaptic density (GO:0014069), spectrin-associated cytoskeleton (GO:0014731), actin cytoskeleton (GO:0015629), cortical cytoskeleton (GO:0030863), platelet dense tubular network membrane (GO:0031095), cell projection membrane (GO:0031253), cytoplasmic vesicle (GO:0031410), perinuclear region of cytoplasm (GO:0048471), cytoplasm (GO:0005737), cytoskeleton (GO:0005856), endomembrane system (GO:0012505), membrane (GO:0016020), cell projection (GO:0042995), synapse (GO:0045202)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	6
negative regulation of protein phosphorylation	3
cytoplasm	3
cytoskeleton	3
regulation of plasma membrane bounded cell projection assembly	2
cellular component assembly	2
cytoskeletal protein binding	2
protein-containing complex binding	2
organelle organization	1
regulation of cell morphogenesis	1
regulation of biological quality	1
lamellipodium assembly	1
regulation of lamellipodium organization	1
fibroblast migration	1
regulation of fibroblast migration	1
positive regulation of cell migration	1
regulation of peptidyl-threonine phosphorylation	1
peptidyl-threonine phosphorylation	1
negative regulation of cell adhesion	1
regulation of cell-substrate adhesion	1
cell-substrate adhesion	1
lamellipodium organization	1
plasma membrane bounded cell projection assembly	1
cytoskeleton organization	1
actin filament-based process	1
actin cytoskeleton organization	1
regulation of actin filament-based process	1
regulation of cytoskeleton organization	1
peptidyl-serine phosphorylation	1
regulation of peptidyl-serine phosphorylation	1
erythrocyte differentiation	1
myeloid cell development	1
peptidyl-tyrosine phosphorylation	1
regulation of peptidyl-tyrosine phosphorylation	1
actin filament bundle organization	1
filopodium assembly	1
smooth endoplasmic reticulum	1
endoplasmic reticulum calcium ion homeostasis	1
negative regulation of actin filament depolymerization	1
negative regulation of actin filament polymerization	1

Protein interactions and networks

STRING

976 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DMTN	ADD2	P35612	993
DMTN	EPB41	P11171	989
DMTN	ADD3	Q9UEY8	987
DMTN	ADD1	P35611	986
DMTN	TMOD1	P28289	905
DMTN	TMOD3	Q9NYL9	894
DMTN	TMOD2	Q9NZR1	890
DMTN	TMOD4	Q9NZQ9	883
DMTN	GYPC	P04921	874
DMTN	ANK1	P16157	844
DMTN	ANK3	Q12955	793
DMTN	ANK2	Q01484	793
DMTN	FSCN1	Q16658	768
DMTN	OPRM1	P35372	692
DMTN	EPB42	P16452	670

IntAct

49 interactions, top by confidence:

A	B	Type	Score
DMTN	YWHAG	psi-mi:“MI:0914”(association)	0.670
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
YWHAB	BLTP3B	psi-mi:“MI:2364”(proximity)	0.610
YWHAB	BLTP3B	psi-mi:“MI:0914”(association)	0.610
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
GOLGA2	DMTN	psi-mi:“MI:0915”(physical association)	0.560
DMTN	GOLGA2	psi-mi:“MI:0915”(physical association)	0.560
DMTN	CEP76	psi-mi:“MI:0915”(physical association)	0.560
DMTN	TEX11	psi-mi:“MI:0915”(physical association)	0.560
DMTN	TRAF2	psi-mi:“MI:0915”(physical association)	0.560
YWHAG	SHTN1	psi-mi:“MI:0914”(association)	0.560
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
YWHAQ	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
DMTN	PKM	psi-mi:“MI:0217”(phosphorylation reaction)	0.440
CPA3	DMTN	psi-mi:“MI:0915”(physical association)	0.400
ECE1	DMTN	psi-mi:“MI:0915”(physical association)	0.370
DMTN	YWHAB	psi-mi:“MI:0914”(association)	0.350
YWHAB	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
YWHAH	SHTN1	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
YWHAB	FOXO6	psi-mi:“MI:0914”(association)	0.350
DMTN	ATE1	psi-mi:“MI:0914”(association)	0.350

BioGRID (60): GOLGA2 (Two-hybrid), DMTN (Affinity Capture-RNA), DMTN (Affinity Capture-RNA), DMTN (Affinity Capture-RNA), YWHAE (Affinity Capture-MS), YWHAZ (Affinity Capture-MS), TRAPPC10 (Affinity Capture-MS), NUP188 (Affinity Capture-MS), UBR1 (Affinity Capture-MS), DPP9 (Affinity Capture-MS), DPP9 (Affinity Capture-MS), YWHAZ (Affinity Capture-MS), UBR1 (Affinity Capture-MS), YWHAG (Affinity Capture-MS), YWHAB (Affinity Capture-MS)

ESM2 similar proteins: A2A7S8, A5D7K1, A5PK23, B1AXH1, F1QGH6, O94885, O95402, Q08495, Q08DM1, Q3T044, Q499V8, Q5HYW2, Q5PQP4, Q5R4B6, Q5R8Q8, Q5SYE7, Q5T0Z8, Q5U2R6, Q6PDH0, Q6PFX7, Q6PGN9, Q6ZVC0, Q7TT28, Q80U35, Q80VC9, Q80Z38, Q86UU1, Q86WR7, Q8BI29, Q8C5R2, Q8CAF4, Q8JZX9, Q8K4J6, Q8N1G1, Q8TF72, Q91Z58, Q969V6, Q96A73, Q9BW04, Q9D0P7

Diamond homologs: A0JNI8, A1ZA47, A2I8Z7, A2PZF9, A9LS46, O14639, O35652, O60711, O75112, O94929, O97581, P25800, P29673, P36198, P36200, P49023, P49024, P50211, P50212, P50458, P50480, P50481, P53405, P53406, P53407, P53408, P53409, P53410, P53412, P53666, P53667, P53668, P53669, P53671, P53776, P61371, P61372, P61373, P61374, Q08495

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 25 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
Activation of BAD and translocation to mitochondria	6	207.6×	1e-11
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	183.2×	1e-11
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	183.2×	1e-11
Activation of BH3-only proteins	6	135.4×	9e-11
RHO GTPases activate PKNs	6	86.5×	1e-09
Intrinsic Pathway for Apoptosis	6	79.9×	2e-09
Apoptosis	7	53.4×	8e-10
SARS-CoV-1-host interactions	6	47.9×	3e-08

GO biological processes:

GO term	Partners	Fold	FDR
intracellular protein localization	6	25.1×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	39
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
3063027	GRCh37/hg19 8p23.3-11.21(chr8:158048-41600696)x3	Pathogenic

SpliceAI

2109 predictions. Top by Δscore:

Variant	Effect	Δscore
8:22067523:TCAGG:T	acceptor_gain	1.0000
8:22067524:CAGGC:C	acceptor_gain	1.0000
8:22067525:A:AC	acceptor_loss	1.0000
8:22067525:A:AG	acceptor_gain	1.0000
8:22067525:AG:A	acceptor_gain	1.0000
8:22067525:AGGCC:A	acceptor_gain	1.0000
8:22067526:G:GT	acceptor_gain	1.0000
8:22067526:GG:G	acceptor_gain	1.0000
8:22067526:GGC:G	acceptor_gain	1.0000
8:22067526:GGCC:G	acceptor_gain	1.0000
8:22067526:GGCCA:G	acceptor_gain	1.0000
8:22067678:GCGAG:G	donor_gain	1.0000
8:22067680:GAG:G	donor_gain	1.0000
8:22067681:AGGTG:A	donor_loss	1.0000
8:22067682:GGTG:G	donor_loss	1.0000
8:22067683:G:GC	donor_loss	1.0000
8:22067683:G:GG	donor_gain	1.0000
8:22067684:T:A	donor_loss	1.0000
8:22069879:A:AG	acceptor_gain	1.0000
8:22069880:G:GG	acceptor_gain	1.0000
8:22069880:GA:G	acceptor_gain	1.0000
8:22069880:GAGAC:G	acceptor_gain	1.0000
8:22069933:GAGAG:G	donor_gain	1.0000
8:22069934:AGAGG:A	donor_loss	1.0000
8:22069935:GAG:G	donor_gain	1.0000
8:22069937:GGTGA:G	donor_loss	1.0000
8:22069938:GT:G	donor_loss	1.0000
8:22069939:T:A	donor_loss	1.0000
8:22070177:TGCA:T	acceptor_loss	1.0000
8:22070180:A:AG	acceptor_gain	1.0000

AlphaMissense

2619 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
8:22070304:T:A	W192R	1.000
8:22070304:T:C	W192R	1.000
8:22073755:T:C	I252T	1.000
8:22081442:G:C	K399N	1.000
8:22081442:G:T	K399N	1.000
8:22067564:T:C	L44P	0.999
8:22067615:T:C	L61P	0.999
8:22070247:T:C	F173L	0.999
8:22070249:T:A	F173L	0.999
8:22070249:T:G	F173L	0.999
8:22070306:G:C	W192C	0.999
8:22070306:G:T	W192C	0.999
8:22073743:T:C	L248S	0.999
8:22073755:T:A	I252N	0.999
8:22073755:T:G	I252S	0.999
8:22081132:T:A	L348Q	0.999
8:22081189:T:A	L367H	0.999
8:22081357:T:C	L371P	0.999
8:22081372:T:C	F376S	0.999
8:22081422:T:A	W393R	0.999
8:22081422:T:C	W393R	0.999
8:22067591:T:A	I53N	0.998
8:22070248:T:C	F173S	0.998
8:22070248:T:G	F173C	0.998
8:22070257:C:A	A176D	0.998
8:22070310:T:C	C194R	0.998
8:22073745:G:A	G249R	0.998
8:22073745:G:C	G249R	0.998
8:22073746:G:A	G249E	0.998
8:22073746:G:T	G249V	0.998

dbSNP variants (sampled 300 via entrez): RS1000000099 (8:22069287 A>C,G), RS1000016377 (8:22075835 A>G), RS1000130844 (8:22074567 G>A,C), RS1000221634 (8:22053546 G>C), RS1000268784 (8:22058888 G>A), RS1000377739 (8:22058652 G>A), RS1000444411 (8:22064400 A>G), RS1000455067 (8:22060203 A>G), RS1000682212 (8:22065747 A>G), RS1000699400 (8:22054587 C>T), RS1000732216 (8:22064573 C>G), RS1000736098 (8:22050432 A>C,T), RS1000936553 (8:22049836 C>G), RS1000941718 (8:22054609 G>A), RS1000982970 (8:22059890 G>A)

Disease associations

OMIM: gene MIM:125305 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

9 associations (top):

Study	Trait	p-value
GCST006612_21	LDL cholesterol	2.000000e-10
GCST006614_136	Total cholesterol levels	9.000000e-12
GCST010204_184	Low density lipoprotein cholesterol levels	8.000000e-13
GCST010243_25	Apolipoprotein B levels	5.000000e-13
GCST010245_10	LDL cholesterol levels	9.000000e-10
GCST011349_11	Gamma glutamyl transferase levels	7.000000e-09
GCST90011898_111	Alanine aminotransferase levels	3.000000e-12
GCST90013405_73	Liver enzyme levels (alanine transaminase)	5.000000e-15
GCST90013407_28	Liver enzyme levels (gamma-glutamyl transferase)	5.000000e-78

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004574	total cholesterol measurement
EFO:0004615	apolipoprotein B measurement
EFO:0004532	serum gamma-glutamyl transferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	increases abundance, increases expression	2
Air Pollutants	increases abundance, increases expression	2
Aflatoxin B1	decreases methylation	2
Particulate Matter	increases abundance, increases expression	2
GSK-J4	decreases expression	1
afuresertib	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
cinnamaldehyde	increases expression	1
butyraldehyde	decreases expression	1
tetrabromobisphenol A	decreases expression	1
CGP 52608	affects binding, increases reaction	1
ICG 001	decreases expression	1
abrine	decreases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	decreases expression	1
Acetaminophen	decreases expression	1
Arsenic	increases abundance, increases expression	1
Atrazine	increases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Cadmium	decreases expression, increases abundance	1
Caffeine	affects phosphorylation	1
Diazinon	increases methylation	1
Doxorubicin	decreases expression	1
Estradiol	affects cotreatment, decreases expression	1
Lead	affects splicing	1
Silicon Dioxide	decreases expression	1
Smoke	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	decreases expression, increases methylation	1

Clinical trials (associated diseases)

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