CD6

Summary

CD6 (CD6 molecule, HGNC:1691) is a protein-coding gene on chromosome 11q12.2, encoding T-cell differentiation antigen CD6 (P30203). Cell adhesion molecule that mediates cell-cell contacts and regulates T-cell responses via its interaction with ALCAM/CD166.

This gene encodes a protein found on the outer membrane of T-lymphocytes as well as some other immune cells. The encoded protein contains three scavenger receptor cysteine-rich (SRCR) domains and a binding site for an activated leukocyte cell adhesion molecule. The gene product is important for continuation of T cell activation. This gene may be associated with susceptibility to multiple sclerosis (PMID: 19525953, 21849685). Multiple transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 923 — RefSeq curated summary.

At a glance

• GWAS associations: 18
• Clinical variants (ClinVar): 119 total
• Druggable target: yes
• MANE Select transcript: NM_006725

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:1691
Approved symbol	CD6
Name	CD6 molecule
Location	11q12.2
Locus type	gene with protein product
Status	Approved
Aliases	Tp120
Ensembl gene	ENSG00000013725
Ensembl biotype	protein_coding
OMIM	186720
Entrez	923

Gene structure

Transcript identifiers

Ensembl transcripts: 25 — 17 protein_coding, 3 retained_intron, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000313421, ENST00000344931, ENST00000352009, ENST00000419282, ENST00000433107, ENST00000452451, ENST00000505761, ENST00000538288, ENST00000538611, ENST00000541964, ENST00000542157, ENST00000542254, ENST00000545105, ENST00000545320, ENST00000899021, ENST00000899024, ENST00000899026, ENST00000899027, ENST00000899028, ENST00000899029, ENST00000899030, ENST00000899031, ENST00000899032, ENST00000899033, ENST00000899034

RefSeq mRNA: 3 — MANE Select: NM_006725 NM_001254750, NM_001254751, NM_006725

CCDS: CCDS58137, CCDS58138, CCDS7999

Canonical transcript exons

ENST00000313421 — 13 exons

Exon	Start	End
ENSE00000721337	61008534	61008845
ENSE00000721341	61009572	61009874
ENSE00000851452	61007560	61007910
ENSE00001641257	61018289	61018393
ENSE00001644118	61015713	61015835
ENSE00001768072	61013919	61014014
ENSE00001780289	61019254	61020377
ENSE00002252032	60971680	60971914
ENSE00003526256	61013423	61013563
ENSE00003571145	61006574	61006642
ENSE00003654036	61011070	61011135
ENSE00003671262	61017479	61017550
ENSE00003672261	61017759	61018013

Expression profiles

Bgee: expression breadth ubiquitous, 219 present calls, max score 98.02.

FANTOM5 (CAGE): breadth broad, TPM avg 8.5487 / max 539.8701, expressed in 215 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
114538	8.4381	209
114539	0.0983	48
114542	0.0123	6

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	98.02	gold quality
lymph node	UBERON:0000029	93.54	gold quality
olfactory bulb	UBERON:0002264	93.04	gold quality
blood	UBERON:0000178	92.41	gold quality
thymus	UBERON:0002370	91.39	gold quality
type B pancreatic cell	CL:0000169	90.24	gold quality
pancreatic ductal cell	CL:0002079	90.08	silver quality
vermiform appendix	UBERON:0001154	89.89	gold quality
caecum	UBERON:0001153	88.20	gold quality
endometrium epithelium	UBERON:0004811	88.18	gold quality
spleen	UBERON:0002106	87.51	gold quality
diaphragm	UBERON:0001103	87.35	gold quality
cervix squamous epithelium	UBERON:0006922	86.43	silver quality
cervix epithelium	UBERON:0004801	84.89	silver quality
superficial temporal artery	UBERON:0001614	83.77	gold quality
epithelial cell of pancreas	CL:0000083	83.43	gold quality
bone marrow	UBERON:0002371	83.37	gold quality
endothelial cell	CL:0000115	83.36	silver quality
bone marrow cell	CL:0002092	82.60	gold quality
epithelium of nasopharynx	UBERON:0001951	81.67	gold quality
Brodmann (1909) area 10	UBERON:0013541	81.57	silver quality
right uterine tube	UBERON:0001302	81.54	gold quality
colonic epithelium	UBERON:0000397	81.31	gold quality
small intestine Peyer’s patch	UBERON:0003454	81.20	gold quality
bone element	UBERON:0001474	80.66	gold quality
ileal mucosa	UBERON:0000331	80.64	gold quality
cerebellar vermis	UBERON:0004720	80.50	gold quality
tonsil	UBERON:0002372	80.48	gold quality
small intestine	UBERON:0002108	79.73	gold quality
parotid gland	UBERON:0001831	79.64	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-70580	yes	454.78
E-HCAD-4	yes	111.70
E-CURD-122	yes	50.42
E-MTAB-6678	yes	37.48
E-MTAB-8410	yes	14.76
E-ANND-3	yes	10.98

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ETS1, RUNX1, RUNX3

miRNA regulators (miRDB)

52 targeting CD6, 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-3134	100.00	66.43	777
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4487	99.96	64.58	1252
HSA-MIR-185-3P	99.95	67.01	1743
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-4728-5P	99.85	69.39	4718
HSA-MIR-6785-5P	99.82	68.68	4428
HSA-MIR-6756-5P	99.82	67.97	2466
HSA-MIR-6739-5P	99.80	67.87	2806
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6733-5P	99.74	67.94	2759
HSA-MIR-6752-3P	99.72	66.71	1587
HSA-MIR-149-3P	99.72	68.22	3963
HSA-MIR-6883-5P	99.69	68.05	3785
HSA-MIR-6766-5P	99.68	67.70	2325
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-4328	99.57	71.06	4094
HSA-MIR-6751-5P	99.56	64.99	1145
HSA-MIR-3153	99.55	67.59	2337
HSA-MIR-216A-5P	99.50	68.02	1288
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-4291	99.20	68.88	2969
HSA-MIR-6803-5P	99.19	63.90	1026
HSA-MIR-1286	99.09	66.23	1046
HSA-MIR-1228-3P	99.00	66.53	857
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-330-5P	98.73	67.63	1788
HSA-MIR-6840-3P	98.68	65.95	1923

Literature-anchored findings (GeneRIF, showing 40)

• Comprehensive profiling of the cell surface proteome provides an effective approach for the identification of commonly occurring proteins as well as proteins with restricted expression patterns in this compartment. (PMID:12493773)
• CD6 associates with the scaffolding PDZ-containing protein syntenin-1 during maturation of the immunological synapse (PMID:16034076)
• Engagement of CD6 with CD166 on tumor cells plays an important role in gammadelta T cell activation by tumor cells sensitized with nonpeptide antigens endogenously or exogenously. (PMID:16818742)
• the CD6-ALCAM interaction results in activation of the three MAP kinase cascades, likely influencing the dynamic balance that determines whether resting or activated lymphocytes survive or undergo apoptosis. (PMID:16818773)
• The costimulatory effect of CD6 is mediated through phosphorylation-dependent binding of a specific tyrosine residue, 662Y, in its cytoplasmic region to the adaptor SLP-76. (PMID:16914752)
• Unprecedented bacterial binding properties of recombinant soluble CD6 support its therapeutic potential for the intervention of septic shock syndrome or other inflammatory diseases of infectious origin. (PMID:17601777)
• A chimpanzee and human conserved CD6 domain 1 epitope recognized by T1 monoclonal antibody. (PMID:18707547)
• Replication in an independent set of 2,215 subjects with multiple sclerosis (MS) and 2,116 control subjects validates new MS susceptibility loci at TNFRSF1A, IRF8 and CD6; TNFRSF1A harbors two independent susceptibility alleles. (PMID:19525953)
• Study reinforces a role for CD6 and TNFRSF1A as risk loci for multiple sclerosis, extending to populations of southern European ancestry. (PMID:20430450)
• Data show that CD6-ALCAM interaction in vitro induced a synergistic co-stimulation of normal peripheral blood mononuclear cells. (PMID:20726988)
• CD6+ B cells are diminished in Sjogren’s syndrome (PMID:20810246)
• CD6 expression on peripheral NK cells marks a novel CD56(dim) subpopulation associated with distinct patterns of cytokine and chemokine secretion. (PMID:21178331)
• association of single nucleotide polymorphisms to multiple sclerosis (PMID:21552549)
• These findings indicate that the multiple sclerosis risk allele in the CD6 locus is associated with altered proliferation of CD4(+) T cells (PMID:21849685)
• Cd6 is a signaling attenuator whose expression alone, i.e. in the absence of ligand engagement, is sufficient to restrain signaling in T cells. (PMID:21956609)
• Data suggest that genetic variations within CD6 and syntaxin binding protein 6 (STXBP6) may influence response to TNFalpha inhibitors in patients with rheumatoid arthritis (RA). (PMID:22685579)
• In a Korean population, one SNP in CD6 was associated with neuromyelitis optica. (PMID:22994200)
• Our findings reveal that this new MS-associated CD6 risk haplotype significantly modifies expression of CD6 on CD4(+) and CD8(+) T cells. (PMID:23638056)
• A novel level of regulation of CD6 function by intracytoplasmic serine phosphorylation. (PMID:23711376)
• The CD6 polymorphism conferred reduced odds of optic neuritis as an attack location (PMID:24130718)
• upon T cell activation, SRSF1 becomes limiting, and its function in CD6 exon 5 splicing is countered by an increase in CD6 transcription, dependent on chromatin acetylation. (PMID:24890719)
• interaction of Galectin-1 and -3 with CD6 (PMID:24945728)
• CD6 regulatory T cells are characterized by CD6 expression and FOXP3 expression. (PMID:25088497)
• Study provides evidence on the role of CD6, a lymphocyte-specific surface receptor from to the ancient and highly conserved Scavenger Receptor Cysteine-Rich (SRCR) superfamily, as a pattern recognition receptor, and the functional consequences this may have on T cell activation and differentiation. [review] (PMID:25777272)
• Data show the multiple aspects that determine the nature of the signals transmitted via CD6 and the context that may define a dual role for this important T cell surface molecule. [review] (PMID:26028048)
• The binding sites on CD6 and CD166 have been characterized to show that a SNP in CD6 causes glycosylation that hinders the CD6/CD166 interaction. (PMID:26146185)
• Data show a role for extracellular and intracellular interactions of CD6 in lateral movement in response to T cell activation. [review] (PMID:26302795)
• Results from recent genetic association studies provide evidence for a role of CD6 in multiple sclerosis and in rheumatoid arthritis pathogenesis. [review] (PMID:26844569)
• This study provides evidence that CD6 is involved in the susceptibility to Behcet’s disease in a Chinese Han population. (PMID:27108704)
• Data indicate that the T cell-specific adaptor protein (TSAd) SH2 domain interacts with CD6 antigen and linker for activation of T cells protein (LAT) phosphotyrosine (pTyr) peptides. (PMID:27896837)
• These results suggest that (i) CD6 is a negative regulator of T-cell activation, (ii) at the same time, CD6 is a positive regulator of activated T-cell survival/proliferation and infiltration; and (iii) CD6 is a potential new target for treating multiple sclerosis (MS)and potentially other T-cell-driven autoimmune conditions. (PMID:28209777)
• These data are consistent with a model in which bivalent recruitment of a GADS/SLP-76 complex is required for costimulation by CD6. (PMID:28289074)
• these results provide new supportive evidence of the contribution of the CD6 lymphocyte receptor in psoriasis at both experimental and clinical levels. (PMID:29225340)
• These data indicate that overexpression of CD6 and ALCAM in the inflamed mucosa of IBD patients accelerates intestinal mucosal immune responses via promoting CD4+ T cell proliferation and differentiation into Th1/Th17 cells. (PMID:30395204)
• Attenuation of Murine Collagen-Induced Arthritis by Targeting CD6. (PMID:32307907)
• Compromised levels of CD6 and reduced T cell activation in the aged immune system. (PMID:33913383)
• Contribution of Evolutionary Selected Immune Gene Polymorphism to Immune-Related Disorders: The Case of Lymphocyte Scavenger Receptors CD5 and CD6. (PMID:34070159)
• The CD6/ALCAM pathway promotes lupus nephritis via T cell-mediated responses. (PMID:34981775)
• Th1 and Th17 cells are resistant towards T cell activation-induced downregulation of CD6. (PMID:35487454)
• Gene variation impact on prostate cancer progression: Lymphocyte modulator, activation, and cell adhesion gene variant contribution. (PMID:35767366)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
mus_musculus	Cd6	ENSMUSG00000024670
rattus_norvegicus	Cd6	ENSRNOG00000020884
drosophila_melanogaster	Loxl2	FBGN0034660

Paralogs (15): CD5L (ENSG00000073754), LGALS3BP (ENSG00000108679), CD5 (ENSG00000110448), LOX (ENSG00000113083), LOXL3 (ENSG00000115318), LOXL1 (ENSG00000129038), LOXL2 (ENSG00000134013), LOXL4 (ENSG00000138131), SSC4D (ENSG00000146700), PRSS12 (ENSG00000164099), CD163 (ENSG00000177575), CD163L1 (ENSG00000177675), SSC5D (ENSG00000179954), DMBT1 (ENSG00000187908), SCART1 (ENSG00000214279)

Protein

Protein identifiers

T-cell differentiation antigen CD6 — P30203 (reviewed: P30203)

Alternative names: T12, TP120

All UniProt accessions (6): P30203, E7ER04, F5H835, F6UFK6, G5E973, H0YGL3

UniProt curated annotations — full annotation on UniProt →

Function. Cell adhesion molecule that mediates cell-cell contacts and regulates T-cell responses via its interaction with ALCAM/CD166. Contributes to signaling cascades triggered by activation of the TCR/CD3 complex. Functions as a costimulatory molecule; promotes T-cell activation and proliferation. Contributes to the formation and maturation of the immunological synapse. Functions as a calcium-dependent pattern receptor that binds and aggregates both Gram-positive and Gram-negative bacteria. Binds both lipopolysaccharide (LPS) from Gram-negative bacteria and lipoteichoic acid from Gram-positive bacteria. LPS binding leads to the activation of signaling cascades and down-stream MAP kinases. Mediates activation of the inflammatory response and the secretion of pro-inflammatory cytokines in response to LPS.

Subunit / interactions. Interacts (via extracellular domain) with ALCAM/CD166 (via extracellular domain). Interacts with the TCR/CD3 complex subunit CD3E. Interacts (via tyrosine phosphorylated C-terminus) with LCP2 (via SH2 domain). Interacts with VAV1. Interacts (via glycosylated extracellular domain) with LGALS1 and LGALS3. Interaction with LGALS1 or LGALS3 inhibits interaction with ALCAM.

Subcellular location. Cell membrane Secreted.

Tissue specificity. Detected on thymocytes. Detected on peripheral blood T-cells. Detected on natural killer (NK) cells. Soluble CD6 is detected in blood serum (at protein level). Detected in spleen, thymus, appendix, lymph node and peripheral blood leukocytes. Expressed by thymocytes, mature T-cells, a subset of B-cells known as B-1 cells, and by some cells in the brain.

Post-translational modifications. After T-cell activation, becomes hyperphosphorylated on Ser and Thr residues and phosphorylated on Tyr residues. Glycosylated.

Miscellaneous. Lacks the third SRCR domain and doesn’t bind ALCAM/CD166. Doesn’t localize to the immunological synapse. Lacks the third SRCR domain and doesn’t bind ALCAM/CD166. Doesn’t localize to the immunological synapse. Constitutes the only expressed species in a small percentage of T-cells.

Isoforms (7)

UniProt ID	Names	Canonical?
P30203-1	CD6A	yes
P30203-2	CD6B
P30203-3	CD6C
P30203-4	CD6D
P30203-5	CD6E
P30203-6	6, CD6deltaD3Ex6
P30203-7	7, CD6deltaD3

RefSeq proteins (3): NP_001241679, NP_001241680, NP_006716* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001190	SRCR	Domain
IPR036772	SRCR-like_dom_sf	Homologous_superfamily

Pfam: PF00530

UniProt features (90 total): strand 23, mutagenesis site 12, disulfide bond 11, glycosylation site 8, splice variant 6, sequence variant 6, helix 5, region of interest 3, compositionally biased region 3, domain 3, chain 2, topological domain 2, sequence conflict 2, signal peptide 1, modified residue 1, transmembrane region 1, turn 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
5A2E	X-RAY DIFFRACTION	3.15

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P30203-F1	66.14	0.42

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 (1): 662

Disulfide bonds (11): 54–88, 70–144, 83–155, 129–137, 170–204, 186–249, 199–259, 230–240, 290–350, 303–360, 330–340

Glycosylation sites (8): 28, 49, 112, 118, 229, 339, 345, 368

Mutagenesis-validated functional residues (12):

Position	Phenotype
291	strongly reduces interaction with alcam.
293	reduces interaction with alcam.
295	abolishes interaction with alcam.
298	nearly abolishes interaction with alcam.
314	reduces interaction with alcam.
327	nearly abolishes interaction with alcam.
329	reduces interaction with alcam.
346	strongly reduces interaction with alcam.
349	reduces interaction with alcam.
352	reduces interaction with alcam.
353	reduces interaction with alcam.
662	reduces tyrosine phosphorylation. reduces affinity for lcp2. impairs activation of t-cells.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 276 (showing top): FERRANDO_TAL1_NEIGHBORS, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_LEUKOCYTE_PROLIFERATION, MORF_FLT1, GOBP_HETEROPHILIC_CELL_CELL_ADHESION, GOBP_INFLAMMATORY_RESPONSE, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_CELLULAR_RESPONSE_TO_BIOTIC_STIMULUS, MODULE_45, MODULE_64, GOCC_CELL_SURFACE, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, RACCACAR_AML_Q6, GOBP_VESICLE_MEDIATED_TRANSPORT, MORF_ESR1

GO Biological Process (11): immunological synapse formation (GO:0001771), adaptive immune response (GO:0002250), acute inflammatory response to antigenic stimulus (GO:0002438), heterophilic cell-cell adhesion (GO:0007157), lipopolysaccharide-mediated signaling pathway (GO:0031663), response to lipopolysaccharide (GO:0032496), positive regulation of T cell proliferation (GO:0042102), innate immune response (GO:0045087), positive regulation of cytokine production involved in inflammatory response (GO:1900017), immune system process (GO:0002376), cell adhesion (GO:0007155)

GO Molecular Function (5): lipopolysaccharide binding (GO:0001530), protein kinase binding (GO:0019901), identical protein binding (GO:0042802), lipoteichoic acid binding (GO:0070891), protein binding (GO:0005515)

GO Cellular Component (6): immunological synapse (GO:0001772), extracellular region (GO:0005576), plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020), T cell receptor complex (GO:0042101)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
immune response	2
carbohydrate derivative binding	2
cell-cell recognition	1
lymphocyte activation	1
inflammatory response to antigenic stimulus	1
acute inflammatory response	1
cell-cell adhesion	1
cell surface receptor signaling pathway	1
cellular response to lipopolysaccharide	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	1
T cell proliferation	1
regulation of T cell proliferation	1
positive regulation of lymphocyte proliferation	1
positive regulation of T cell activation	1
defense response to symbiont	1
positive regulation of cytokine production	1
cytokine production involved in inflammatory response	1
regulation of cytokine production involved in inflammatory response	1
biological_process	1
cellular process	1
lipid binding	1
kinase binding	1
protein binding	1
binding	1
plasma membrane	1
membrane	1
cell periphery	1
plasma membrane signaling receptor complex	1

Protein interactions and networks

STRING

1810 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CD6	ALCAM	Q13740	999
CD6	CD5	P06127	864
CD6	LCP2	Q13094	840
CD6	SDCBP	O00560	831
CD6	CD2	P06729	825
CD6	CDCP1	Q9H5V8	786
CD6	SLC15A3	Q8IY34	783
CD6	CNTN6	Q9UQ52	773
CD6	CD7	P09564	753
CD6	CD4	P01730	744
CD6	SDCBP2	Q9H190	717
CD6	CD8A	P01732	686
CD6	VAV1	P15498	663
CD6	CD38	P28907	648
CD6	CLEC16A	Q2KHT3	646

IntAct

29 interactions, top by confidence:

A	B	Type	Score
CD6	ALCAM	psi-mi:“MI:0407”(direct interaction)	0.850
ALCAM	CD6	psi-mi:“MI:0407”(direct interaction)	0.850
ALCAM	LGALS1	psi-mi:“MI:0915”(physical association)	0.770
CD6	CD6	psi-mi:“MI:0407”(direct interaction)	0.620
CD6	Sdcbp	psi-mi:“MI:0915”(physical association)	0.620
LGALS1	CD6	psi-mi:“MI:0407”(direct interaction)	0.560
CD6	LGALS3	psi-mi:“MI:0407”(direct interaction)	0.560
UTP4	ANKRD28	psi-mi:“MI:0914”(association)	0.530
LCP2	CD6	psi-mi:“MI:0915”(physical association)	0.500
CD6	LCP2	psi-mi:“MI:0915”(physical association)	0.500
SDCBP	CD6	psi-mi:“MI:0403”(colocalization)	0.460
SDCBP	CD6	psi-mi:“MI:0915”(physical association)	0.460
CD6	GYG1	psi-mi:“MI:0915”(physical association)	0.370
NFE2L1	CD6	psi-mi:“MI:0915”(physical association)	0.370
LCP2	LAT	psi-mi:“MI:0914”(association)	0.350
CUL4B	APBB1	psi-mi:“MI:0914”(association)	0.350
CD6	CIBAR1	psi-mi:“MI:0914”(association)	0.350
CD6	acn	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (153): CD6 (Reconstituted Complex), CD6 (FRET), CD6 (Affinity Capture-Western), POLRMT (Affinity Capture-MS), TRMT1L (Affinity Capture-MS), WDR43 (Affinity Capture-MS), MTMR1 (Affinity Capture-MS), DZIP1 (Affinity Capture-MS), MCRS1 (Affinity Capture-MS), NCAPD3 (Affinity Capture-MS), ARHGEF40 (Affinity Capture-MS), SNX33 (Affinity Capture-MS), TRIM68 (Affinity Capture-MS), USP12 (Affinity Capture-MS), KIF18B (Affinity Capture-MS)

ESM2 similar proteins: A1L0T3, A1L4H1, A6QNY1, D3YZF7, O95428, P28698, P30203, P55068, P55106, P59222, P98162, Q04756, Q14767, Q28019, Q28062, Q28256, Q28343, Q28670, Q3U515, Q4G0T1, Q5F378, Q5HZW5, Q61003, Q61361, Q6H9L7, Q6KF10, Q6PGE4, Q6QNF4, Q7TQH7, Q7Z4F1, Q86T13, Q86VR7, Q86VZ4, Q8BV57, Q8BZE1, Q8CB67, Q8VCP9, Q8WTU2, Q91V98, Q96DN2

Diamond homologs: A1L0T3, A1L1V4, A1L4H1, A5PJQ2, A6H737, A7E3W2, B4F6N6, B5DF27, B8A4W9, E1C3U7, F1QQC3, F1RD85, F7J220, G3V801, M9NDE3, O08762, O43866, O70513, P21757, P21758, P30203, P30204, P30205, P56730, P58022, P58215, P70117, P85521, Q05585, Q07797, Q08380, Q08B63, Q14DK5, Q24JV9, Q2VL90, Q2VLG4, Q2VLG6, Q2VLH6, Q4A3R3, Q4G0T1

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	85
Likely benign	9
Benign	12

Top pathogenic / likely-pathogenic (0)

SpliceAI

1896 predictions. Top by Δscore:

Variant	Effect	Δscore
11:60971911:TCAGG:T	donor_loss	1.0000
11:60971912:CAGG:C	donor_loss	1.0000
11:60971913:AGG:A	donor_loss	1.0000
11:60971915:G:C	donor_loss	1.0000
11:60971916:T:A	donor_loss	1.0000
11:61010825:GGA:G	donor_gain	1.0000
11:61013421:A:AG	acceptor_gain	1.0000
11:61013422:G:GG	acceptor_gain	1.0000
11:61013422:GA:G	acceptor_gain	1.0000
11:61015711:A:AG	acceptor_gain	1.0000
11:61015712:G:GG	acceptor_gain	1.0000
11:61015836:G:GG	donor_gain	1.0000
11:61017755:TTAG:T	acceptor_loss	1.0000
11:61017756:TA:T	acceptor_loss	1.0000
11:61017757:A:AG	acceptor_gain	1.0000
11:61017758:G:GA	acceptor_loss	1.0000
11:61017758:G:GG	acceptor_gain	1.0000
11:61018012:AGG:A	donor_loss	1.0000
11:61018013:GGTA:G	donor_loss	1.0000
11:61018014:G:GG	donor_gain	1.0000
11:61018014:GTA:G	donor_loss	1.0000
11:61018015:T:G	donor_loss	1.0000
11:61013421:A:G	acceptor_loss	0.9900
11:61013422:GAA:G	acceptor_gain	0.9900
11:61013422:GAAT:G	acceptor_gain	0.9900
11:61013422:GAATC:G	acceptor_gain	0.9900
11:61013559:ATATG:A	donor_gain	0.9900
11:61013562:TGG:T	donor_loss	0.9900
11:61013564:G:GG	donor_gain	0.9900
11:61013565:T:A	donor_loss	0.9900

AlphaMissense

4336 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:61008634:G:C	W190C	1.000
11:61008634:G:T	W190C	1.000
11:61009672:G:C	W294C	1.000
11:61009672:G:T	W294C	1.000
11:61008610:G:C	W182C	0.999
11:61008610:G:T	W182C	0.999
11:61008632:T:A	W190R	0.999
11:61008632:T:C	W190R	0.999
11:61009648:G:C	W286C	0.999
11:61009648:G:T	W286C	0.999
11:61009778:T:A	C330S	0.999
11:61009779:G:C	C330S	0.999
11:61008621:G:A	C186Y	0.998
11:61008752:T:A	C230S	0.998
11:61008753:G:C	C230S	0.998
11:61009658:T:A	C290S	0.998
11:61009659:G:A	C290Y	0.998
11:61009659:G:C	C290S	0.998
11:61009670:T:A	W294R	0.998
11:61009670:T:C	W294R	0.998
11:61009697:T:A	C303S	0.998
11:61009698:G:C	C303S	0.998
11:61009779:G:A	C330Y	0.998
11:61009816:G:C	W342C	0.998
11:61009816:G:T	W342C	0.998
11:61009868:T:A	C360S	0.998
11:61009869:G:C	C360S	0.998
11:61007639:G:C	W66C	0.997
11:61007639:G:T	W66C	0.997
11:61007663:G:C	W74C	0.997

dbSNP variants (sampled 300 via entrez): RS1000084417 (11:60999750 T>C), RS1000090924 (11:60975947 C>A), RS1000231461 (11:60977613 C>T), RS1000232495 (11:61006026 C>T), RS1000254197 (11:60970499 G>C), RS1000274478 (11:60989185 A>G), RS1000284645 (11:61005729 C>G,T), RS1000342752 (11:61012379 G>A,T), RS1000520480 (11:61004984 T>C), RS1000539480 (11:60999461 C>G), RS1000546332 (11:60976173 A>G), RS1000558970 (11:61005352 G>A), RS1000601949 (11:60978008 C>T), RS1000735468 (11:61011564 A>G), RS1000850230 (11:61016368 G>A,T)

Disease associations

OMIM: gene MIM:186720 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

18 associations (top):

Study	Trait	p-value
GCST000424_11	Multiple sclerosis	4.000000e-09
GCST000949_2	Multiple sclerosis	1.000000e-09
GCST001198_8	Multiple sclerosis	2.000000e-11
GCST001725_10	Inflammatory bowel disease	9.000000e-13
GCST003854_12	Gut microbiota (functional units)	2.000000e-07
GCST003854_17	Gut microbiota (functional units)	1.000000e-06
GCST003854_56	Gut microbiota (functional units)	5.000000e-06
GCST003855_19	Gut microbiota (bacterial taxa)	1.000000e-06
GCST003855_20	Gut microbiota (bacterial taxa)	1.000000e-06
GCST003855_21	Gut microbiota (bacterial taxa)	1.000000e-06
GCST004131_121	Inflammatory bowel disease	2.000000e-06
GCST005531_54	Multiple sclerosis	4.000000e-23
GCST005531_76	Multiple sclerosis	2.000000e-07
GCST005537_74	Chronic inflammatory diseases (ankylosing spondylitis, Crohn’s disease, psoriasis, primary sclerosing cholangitis, ulcerative colitis) (pleiotropy)	5.000000e-15
GCST006192_46	Systolic blood pressure x smoking status (ever vs never) interaction (2df test)	3.000000e-06
GCST006195_89	Systolic blood pressure x smoking status (current vs non-current) interaction (2df test)	3.000000e-09
GCST009597_276	Multiple sclerosis	2.000000e-29
GCST90002388_538	Lymphocyte count	1.000000e-12

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0007874	gut microbiome measurement
EFO:0006335	systolic blood pressure
EFO:0006527	smoking status measurement
EFO:0004587	lymphocyte count

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL3712853 (SINGLE PROTEIN)

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other protein — CD molecules

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
itolizumab	Binding	7.22	pKi

CTD chemical–gene interactions

20 total (human), top 20 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, increases methylation	2
Nickel	increases expression	2
GSK-J4	increases expression	1
bisphenol A	affects cotreatment, increases methylation	1
sodium arsenite	affects expression	1
butyraldehyde	increases expression	1
benzo(e)pyrene	increases methylation	1
aflatoxin B2	increases methylation	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, increases methylation	1
Air Pollutants	affects methylation, increases abundance	1
Arsenic	decreases methylation	1
Aspirin	decreases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression, affects response to substance, increases expression	1
Methapyrilene	increases methylation	1
Tamoxifen	decreases expression	1
Tobacco Smoke Pollution	decreases expression	1
Valproic Acid	increases methylation	1
Antirheumatic Agents	decreases expression	1
Particulate Matter	affects methylation, increases abundance	1

Clinical trials (associated diseases)

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