VSTM1

Summary

VSTM1 (V-set and transmembrane domain containing 1, HGNC:29455) is a protein-coding gene on chromosome 19q13.42, encoding V-set and transmembrane domain-containing protein 1 (Q6UX27). Behaves as a cytokine, promoting IL17A secretion by CD4+ T-cells, and differentiation and activation of IL17 producing helper T-cells (TH17).

Predicted to enable cytokine activity. Predicted to be involved in immune response-regulating signaling pathway. Predicted to be located in extracellular space and membrane. Predicted to be active in plasma membrane.

Source: NCBI Gene 284415 — RefSeq curated summary.

At a glance

• GWAS associations: 1
• Clinical variants (ClinVar): 42 total
• MANE Select transcript: NM_198481

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:29455
Approved symbol	VSTM1
Name	V-set and transmembrane domain containing 1
Location	19q13.42
Locus type	gene with protein product
Status	Approved
Aliases	UNQ3033
Ensembl gene	ENSG00000189068
Ensembl biotype	protein_coding
OMIM	616804
Entrez	284415

Gene structure

Transcript identifiers

Ensembl transcripts: 7 — 6 protein_coding, 1 nonsense_mediated_decay

ENST00000338372, ENST00000366170, ENST00000376626, ENST00000419106, ENST00000425006, ENST00000447872, ENST00000645936

RefSeq mRNA: 4 — MANE Select: NM_198481 NM_001288791, NM_001288792, NM_001288793, NM_198481

CCDS: CCDS12872, CCDS74441, CCDS74442

Canonical transcript exons

ENST00000338372 — 9 exons

Exon	Start	End
ENSE00001371110	54058306	54058590
ENSE00001391066	54051410	54051448
ENSE00001748568	54040825	54041080
ENSE00003489833	54058697	54058732
ENSE00003543808	54042277	54042369
ENSE00003556719	54041779	54041816
ENSE00003588546	54042169	54042196
ENSE00003600235	54041916	54041953
ENSE00003850210	54063744	54063897

Expression profiles

Bgee: expression breadth ubiquitous, 112 present calls, max score 94.36.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 2.7069 / max 531.2266, expressed in 159 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
182584	1.6571	130
182583	0.8079	97
182582	0.2419	80

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	94.36	gold quality
leukocyte	CL:0000738	93.43	gold quality
granulocyte	CL:0000094	93.00	gold quality
bone marrow	UBERON:0002371	92.98	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	90.15	gold quality
blood	UBERON:0000178	89.61	gold quality
bone marrow cell	CL:0002092	88.98	gold quality
pituitary gland	UBERON:0000007	75.79	gold quality
adenohypophysis	UBERON:0002196	75.21	gold quality
spleen	UBERON:0002106	70.83	gold quality
duodenum	UBERON:0002114	64.30	gold quality
gall bladder	UBERON:0002110	62.66	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	59.96	gold quality
right lung	UBERON:0002167	58.65	gold quality
smooth muscle tissue	UBERON:0001135	57.86	gold quality
primary visual cortex	UBERON:0002436	55.89	gold quality
upper lobe of left lung	UBERON:0008952	55.23	gold quality
anterior cingulate cortex	UBERON:0009835	55.12	gold quality
mucosa of transverse colon	UBERON:0004991	54.47	gold quality
substantia nigra	UBERON:0002038	53.89	gold quality
vermiform appendix	UBERON:0001154	53.73	gold quality
placenta	UBERON:0001987	53.05	gold quality
lung	UBERON:0002048	52.02	gold quality
apex of heart	UBERON:0002098	51.61	gold quality
rectum	UBERON:0001052	51.05	gold quality
Ammon’s horn	UBERON:0001954	50.52	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	49.89	gold quality
cerebral cortex	UBERON:0000956	48.78	gold quality
Brodmann (1909) area 9	UBERON:0013540	48.41	gold quality
amygdala	UBERON:0001876	48.35	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	1.43

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

9 targeting VSTM1, 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-4775	99.98	75.00	6394
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-4496	99.88	68.89	2236
HSA-MIR-4261	99.59	70.30	3415
HSA-MIR-147B-5P	99.45	70.62	2432
HSA-MIR-6830-5P	99.01	68.73	1884
HSA-MIR-4435	95.90	65.47	1201
HSA-MIR-208A-3P	95.87	66.51	397
HSA-MIR-208B-3P	95.87	66.56	396

Literature-anchored findings (GeneRIF, showing 13)

• Signal inhibitory receptor on leukocytes-1 is a member of immunoglobulin superfamily ITIM; expressed by myeloid but not lymphoid cells; requires both of its ITIMs for full inhibition of Fc epsilon receptor type I-mediated mast cell degranulation. (PMID:20375307)
• SIRL-1 negatively regulates the oxidative burst in human phagocytes. (PMID:23436183)
• Signaling via the inhibitory receptor SIRL-1 was induced by ligation with anti-SIRL-1 specific antibodies. (PMID:24205237)
• we report a potential leukocyte differentiation antigen gene VSTM1 (V-set and transmembrane domain-containing 1) that was downregulated in bone marrow cells from leukemia patients and exhibited a higher degree of promoter methylation (PMID:25887911)
• VSTM1-v2 might be a biomarker of rheumatoid arthritis (RA) and a novel factor in the pathogenesis of RA. (PMID:26760041)
• findings show that SIRL-1 attenuates neutrophil extracellular traps (NET) release by neutrophils in response to distinct triggers, including opsonized Staphylococcus aureus and inflammatory danger signals; define SIRL-1 as an intervention point of benefit to suppress neutrophil extracellular trap formation in disease while preserving intracellular antimicrobial defense (PMID:27016607)
• VSTM1 rs612529T is associated with a complete demethylation of the VSTM1 promoter and allele-specific upregulation of SIRL-1 expression in monocytes. (PMID:28219444)
• Signal inhibitory receptor on leukocytes (SIRL)-1 and leukocyte- associated immunoglobulin-like receptor (LAIR)-1 regulate neutrophil function in infants. (PMID:31843567)
• Signal Inhibitory Receptor on Leukocytes-1 is highly expressed on lung monocytes, but absent on mononuclear phagocytes in skin and colon. (PMID:32942189)
• Recognition of S100 proteins by Signal Inhibitory Receptor on Leukocytes-1 negatively regulates human neutrophils. (PMID:34145909)
• VSTM1-v2 does not drive human Th17 cell differentiation: A replication study. (PMID:37053248)
• Oxidized galectin-1 in SLE fails to bind the inhibitory receptor VSTM1 and increases reactive oxygen species levels in neutrophils. (PMID:37737309)
• New insights into the role of the immune inhibitory receptor VSTM1 in autoimmune disease. (PMID:37935837)

Cross-species orthologs

0 orthologs

Paralogs (25): GP6 (ENSG00000088053), LILRB1 (ENSG00000104972), LILRA1 (ENSG00000104974), LILRB5 (ENSG00000105609), A1BG (ENSG00000121410), KIR2DL1 (ENSG00000125498), LILRB2 (ENSG00000131042), IGSF1 (ENSG00000147255), LAIR2 (ENSG00000167618), KIR3DL1 (ENSG00000167633), OSCAR (ENSG00000170909), FCAR (ENSG00000186431), LILRB4 (ENSG00000186818), LILRA5 (ENSG00000187116), KIR2DL4 (ENSG00000189013), NCR1 (ENSG00000189430), LILRB3 (ENSG00000204577), KIR2DS4 (ENSG00000221957), LILRA4 (ENSG00000239961), LILRA2 (ENSG00000239998), KIR3DL2 (ENSG00000240403), KIR3DL3 (ENSG00000242019), KIR2DL3 (ENSG00000243772), LILRA6 (ENSG00000244482), TARM1 (ENSG00000248385)

Protein

Protein identifiers

V-set and transmembrane domain-containing protein 1 — Q6UX27 (reviewed: Q6UX27)

Alternative names: Signal inhibitory receptor on leukocytes-1

All UniProt accessions (5): A0A2R8Y636, D2DJS5, G8JLN4, Q6UX27, H7C340

UniProt curated annotations — full annotation on UniProt →

Function. Behaves as a cytokine, promoting IL17A secretion by CD4+ T-cells, and differentiation and activation of IL17 producing helper T-cells (TH17). Inhibitory immune receptor involved in the regulation of phagocytes.

Subcellular location. Membrane Secreted.

Tissue specificity. Expressed on myeloid (neutrophils, eosinophils and monocytes) but not on lymphoid cells.

Post-translational modifications. Isoform 2 is N-glycosylated.

Domain organisation. Contains 2 copies of a cytoplasmic motif that is referred to as the immunoreceptor tyrosine-based inhibitor motif (ITIM). This motif is involved in modulation of cellular responses. The phosphorylated ITIM motif can bind the SH2 domain of several SH2-containing phosphatases. Both motives are required for full inhibition of FCER1A-mediated degranulation.

Miscellaneous. Mainly detected in immune tissues and cells. May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Isoforms (3)

UniProt ID	Names	Canonical?
Q6UX27-1	1	yes
Q6UX27-2	2, VSTM1-v2
Q6UX27-3	3

RefSeq proteins (4): NP_001275720, NP_001275721, NP_001275722, NP_940883* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003599	Ig_sub	Domain
IPR007110	Ig-like_dom	Domain
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR050412	Ig-like_Receptors_ImmuneReg	Family

Pfam: PF13895

UniProt features (17 total): splice variant 3, glycosylation site 2, topological domain 2, region of interest 2, short sequence motif 2, signal peptide 1, chain 1, disulfide bond 1, sequence variant 1, transmembrane region 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q6UX27-F1	77.00	0.49

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 (1): 49–96

Glycosylation sites (2): 44, 55

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 27 (showing top): GOMF_CYTOKINE_ACTIVITY, TAKEDA_TARGETS_OF_NUP98_HOXA9_FUSION_16D_DN, GOMF_SIGNALING_RECEPTOR_BINDING, SENESE_HDAC3_TARGETS_DN, GOMF_TRANSMEMBRANE_SIGNALING_RECEPTOR_ACTIVITY, GOMF_SIGNALING_RECEPTOR_REGULATOR_ACTIVITY, HMGA1_TARGET_GENES, GSE11057_PBMC_VS_MEM_CD4_TCELL_UP, GSE15659_NAIVE_VS_PTPRC_NEG_CD4_TCELL_DN, GSE15659_NAIVE_CD4_TCELL_VS_RESTING_TREG_DN, GSE15659_NAIVE_CD4_TCELL_VS_NONSUPPRESSIVE_TCELL_DN, HAY_BONE_MARROW_NEUTROPHIL, DESCARTES_FETAL_LUNG_MYELOID_CELLS, ZAK_PBMC_MRKAD5_HIV_1_GAG_POL_NEF_AGE_20_50YO_AD5_NAB_TITERS_GT_200_VS_LTE_200_1DY_DN, NAKAYA_PBMC_IMUVAC_MALE_AGE_14_27YO_1D_POSTBOOST_VS_0DY_PREIMM_TIV_UP

GO Biological Process (3): immune system process (GO:0002376), immune response-regulating signaling pathway (GO:0002764), cell surface receptor signaling pathway (GO:0007166)

GO Molecular Function (2): cytokine activity (GO:0005125), protein binding (GO:0005515)

GO Cellular Component (4): obsolete extracellular space (GO:0005615), plasma membrane (GO:0005886), extracellular region (GO:0005576), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
signal transduction	2
cellular anatomical structure	2
biological_process	1
regulation of immune response	1
receptor ligand activity	1
binding	1
membrane	1
cell periphery	1

Protein interactions and networks

STRING

378 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VSTM1	TFPT	P0C1Z6	488
VSTM1	LENG8	Q96PV6	477
VSTM1	PTPN11	Q06124	455
VSTM1	LAMP1	P11279	403
VSTM1	GP6	Q9HCN6	401
VSTM1	CDC42EP5	Q6NZY7	373
VSTM1	FAM228A	Q86W67	370
VSTM1	TTYH1	Q9H313	363
VSTM1	NDUFA3	O95167	331
VSTM1	PRPF31	Q8WWY3	317
VSTM1	ZNF512	Q96ME7	317
VSTM1	EFCAB7	A8K855	311
VSTM1	LAIR1	Q6GTX8	279
VSTM1	ARHGAP40	Q5TG30	274
VSTM1	LENG9	Q96B70	264

IntAct

3 interactions, top by confidence:

A	B	Type	Score
VSTM1	FADS1	psi-mi:“MI:0914”(association)	0.350
VSTM1	ACOT8	psi-mi:“MI:0914”(association)	0.350

BioGRID (55): VSTM1 (Two-hybrid), VSTM1 (Two-hybrid), VSTM1 (Two-hybrid), VSTM1 (Two-hybrid), VSTM1 (Two-hybrid), VSTM1 (Two-hybrid), VSTM1 (Two-hybrid), VSTM1 (Two-hybrid), VSTM1 (Two-hybrid), VSTM1 (Two-hybrid), VSTM1 (Two-hybrid), VSTM1 (Two-hybrid), VSTM1 (Two-hybrid), VSTM1 (Two-hybrid), VSTM1 (Two-hybrid)

ESM2 similar proteins: A0A0G2KBC9, A1YIY0, B6A8R8, C0HJX2, C0HJX3, D3ZQX2, P08101, P0C1X9, P0DTI4, P12314, P12318, P26151, P43626, P43627, P43628, P43629, P43630, P43631, P43632, P83555, P83556, P97484, Q01965, Q13291, Q14943, Q14952, Q14953, Q14954, Q28942, Q3B8P2, Q60513, Q61450, Q63203, Q64281, Q68SN8, Q6UX27, Q7TQA1, Q7Z6M3, Q8BG84, Q8BHK6

Diamond homologs: B6A8C7, B6A8R8, O75022, O75023, P04217, P0C191, P24071, P43628, P43629, P43630, P59901, P83555, P97484, Q14943, Q2KJF1, Q6GTX8, Q6ISS4, Q6PI73, Q6UX27, Q7TQA1, Q8IYS5, Q8MJZ2, Q8MJZ7, Q8N109, Q8N149, Q8N423, Q8N6C5, Q8N6C8, Q8N743, Q8NHJ6, Q8NHK3, Q8NHL6, Q8VBT3, Q925N6, Q9H7L2, Q9HCN6, A6NI73, C0HJX2, C0HJX3, O75019

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	35
Likely benign	2
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

1458 predictions. Top by Δscore:

Variant	Effect	Δscore
19:54041083:T:C	acceptor_gain	1.0000
19:54042275:A:AC	donor_gain	1.0000
19:54042276:C:CC	donor_gain	1.0000
19:54042276:CTGTG:C	donor_gain	1.0000
19:54042370:C:CC	acceptor_gain	1.0000
19:54058589:CT:C	acceptor_gain	1.0000
19:54041077:CCGT:C	acceptor_gain	0.9900
19:54041078:CGT:C	acceptor_gain	0.9900
19:54041078:CGTC:C	acceptor_gain	0.9900
19:54041079:GT:G	acceptor_gain	0.9900
19:54041081:C:CC	acceptor_gain	0.9900
19:54041082:T:C	acceptor_gain	0.9900
19:54041083:T:TC	acceptor_gain	0.9900
19:54041902:C:A	donor_gain	0.9900
19:54041952:TTCTG:T	acceptor_loss	0.9900
19:54041954:C:CC	acceptor_gain	0.9900
19:54041955:T:A	acceptor_loss	0.9900
19:54042245:C:A	donor_gain	0.9900
19:54042254:C:CA	donor_gain	0.9900
19:54058300:TCTCA:T	donor_loss	0.9900
19:54058301:CTCA:C	donor_loss	0.9900
19:54058302:TCA:T	donor_loss	0.9900
19:54058303:CA:C	donor_loss	0.9900
19:54058304:A:C	donor_loss	0.9900
19:54058305:C:CG	donor_loss	0.9900
19:54058384:T:TA	donor_gain	0.9900
19:54058385:C:A	donor_gain	0.9900
19:54058586:TTTCT:T	acceptor_gain	0.9900
19:54058587:TTCT:T	acceptor_gain	0.9900
19:54058590:TC:T	acceptor_loss	0.9900

AlphaMissense

1541 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
19:54058419:A:C	F81C	0.986
19:54058515:C:G	C49S	0.983
19:54058516:A:T	C49S	0.983
19:54042338:G:C	S142R	0.982
19:54042338:G:T	S142R	0.982
19:54042340:T:G	S142R	0.982
19:54058374:C:G	C96S	0.982
19:54058375:A:T	C96S	0.982
19:54058380:T:C	Y94C	0.979
19:54058418:G:C	F81L	0.978
19:54058418:G:T	F81L	0.978
19:54058420:A:G	F81L	0.978
19:54058374:C:T	C96Y	0.976
19:54058380:T:G	Y94S	0.974
19:54058381:A:C	Y94D	0.973
19:54058419:A:G	F81S	0.971
19:54058516:A:G	C49R	0.969
19:54058375:A:G	C96R	0.967
19:54058373:A:C	C96W	0.966
19:54058381:A:G	Y94H	0.966
19:54058487:A:C	F58L	0.961
19:54058487:A:T	F58L	0.961
19:54058489:A:G	F58L	0.961
19:54058331:A:C	S110R	0.960
19:54058331:A:T	S110R	0.960
19:54058333:T:G	S110R	0.960
19:54058482:A:G	L60P	0.953
19:54058514:A:C	C49W	0.952
19:54058521:A:G	L47P	0.951
19:54058387:C:A	G92W	0.950

dbSNP variants (sampled 300 via entrez): RS1000190942 (19:54051059 T>C), RS1000200496 (19:54043307 T>G), RS1000258457 (19:54048425 T>C), RS1000289807 (19:54048212 C>T), RS1000564452 (19:54041701 G>T), RS1000634677 (19:54042967 C>T), RS1000897672 (19:54059050 T>A,G), RS1000929853 (19:54058707 C>T), RS1000935133 (19:54041845 G>C), RS1001208432 (19:54064339 A>G), RS1001412394 (19:54064251 A>C,G), RS1001580984 (19:54064512 C>T), RS1001702678 (19:54043629 C>T), RS1001742477 (19:54048524 A>G), RS1002055037 (19:54047565 A>G)

Disease associations

OMIM: gene MIM:616804 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST004746_50	Small cell lung carcinoma	2.000000e-07

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
sodium arsenite	decreases expression	1
butyraldehyde	increases expression	1
aflatoxin B2	increases methylation	1
pentanal	increases expression	1
2-palmitoylglycerol	increases expression	1
jinfukang	affects cotreatment, decreases expression	1
Air Pollutants	affects expression, increases abundance	1
Aldehydes	increases expression	1
Allergens	affects cotreatment, increases abundance, increases expression	1
Vehicle Emissions	affects cotreatment, increases abundance, increases expression	1
Benzo(a)pyrene	affects methylation, decreases methylation	1
Cisplatin	decreases expression, affects cotreatment	1
Formaldehyde	decreases expression	1
Methylcholanthrene	affects binding, increases reaction	1
Ozone	affects expression, increases abundance	1
Particulate Matter	affects cotreatment, increases abundance, increases expression	1

Clinical trials (associated diseases)

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