HCST

Summary

HCST (hematopoietic cell signal transducer, HGNC:16977) is a protein-coding gene on chromosome 19q13.12, encoding Hematopoietic cell signal transducer (Q9UBK5). Transmembrane adapter protein which associates with KLRK1 to form an activation receptor KLRK1-HCST in lymphoid and myeloid cells; this receptor plays a major role in triggering cytotoxicity against target cells expressing cell surface ligands such as MHC class I chain-related M….

This gene encodes a transmembrane signaling adaptor that contains a YxxM motif in its cytoplasmic domain. The encoded protein may form part of the immune recognition receptor complex with the C-type lectin-like receptor NKG2D. As part of this receptor complex, this protein may activate phosphatidylinositol 3-kinase dependent signaling pathways through its intracytoplasmic YxxM motif. This receptor complex may have a role in cell survival and proliferation by activation of NK and T cell responses. Alternative splicing results in two transcript variants encoding different isoforms.

Source: NCBI Gene 10870 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 18 total
• GTEx eGene: eQTL in 9 tissues, sQTL in 5 (q < 0.05)
• Constraint (gnomAD): pLI 0.00 (LoF-tolerant), LOEUF 1.67 (unconstrained)
• MANE Select transcript: NM_014266

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16977
Approved symbol	HCST
Name	hematopoietic cell signal transducer
Location	19q13.12
Locus type	gene with protein product
Status	Approved
Aliases	DAP10, DKFZP586C1522, KAP10
Ensembl gene	ENSG00000126264
Ensembl biotype	protein_coding
OMIM	604089
Entrez	10870

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 15 protein_coding, 2 nonsense_mediated_decay

MANE Select: ENST00000246551

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 2

ENST00000246551, ENST00000437550, ENST00000864003, ENST00000864004, ENST00000930206, ENST00000991377, ENST00001009013, ENST00001009014, ENST00001059589, ENST00001102789, ENST00001102790, ENST00001102791, ENST00001102792, ENST00001102793, ENST00001102794, ENST00001102795, ENST00001136609

RefSeq mRNA: 2 — MANE Select: NM_014266 NM_001007469, NM_014266

CCDS: CCDS32998, CCDS46057

Canonical transcript exons

ENST00000246551 — 4 exons

Exon	Start	End
ENSE00000699089	35903772	35903903
ENSE00000862898	35902529	35902636
ENSE00000862899	35903351	35903416
ENSE00002856716	35904120	35904377

Expression profiles

Bgee: expression breadth ubiquitous, 214 present calls, max score 99.50.

FANTOM5 (CAGE): breadth broad, TPM avg 63.7603 / max 2100.7130, expressed in 652 samples.

Highest expression (Bgee): granulocyte, leukocyte, monocyte, bone marrow, blood.

Genetic regulation across tissues (GTEx eQTL / sQTL)

HCST is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 9 tissues and its splicing (sQTL) in 5 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

14 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Whole Blood	sqtl	3.0e-19	-1.17	19:35905777:A:G
Whole Blood	eqtl	2.8e-08	-0.26	19:35905386:G:A
Cells EBV-transformed lymphocytes	sqtl	2.9e-05	-1.14	19:35901060:T:A
Cells EBV-transformed lymphocytes	eqtl	2.2e-04	-0.55	19:35905386:G:A
Lung	eqtl	9.5e-04	-0.37	19:35900173:CAGCCTCCCA:C
Thyroid	sqtl	4.1e-03	-1.53	19:34990039:T:G
Brain Hippocampus	eqtl	7.6e-03	-1.25	19:35851151:C:T
Brain Cortex	eqtl	1.1e-02	-1.79	19:35128097:C:A
Spleen	sqtl	1.1e-02	-1.57	19:35892561:T:A
Adipose Subcutaneous	sqtl	1.5e-02	-1.24	19:35918137:A:G
Artery Coronary	eqtl	2.3e-02	+0.98	19:36021933:C:T
Brain Caudate basal ganglia	eqtl	2.8e-02	-1.21	19:35863484:A:T
Cells Cultured fibroblasts	eqtl	4.1e-02	-0.41	19:35290621:C:T
Muscle Skeletal	eqtl	4.6e-02	-0.72	19:36013561:A:C

FANTOM5 promoters

5 alternative TSS:

Promoter ID	TPM avg	Samples expressed
175437	37.1682	577
175436	18.2977	517
175435	6.4201	414
175434	1.7748	339
175433	0.0994	31

Top tissues by expression

showing 100 of 240 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.50	gold quality
leukocyte	CL:0000738	98.44	gold quality
monocyte	CL:0000576	98.38	gold quality
bone marrow	UBERON:0002371	97.05	gold quality
blood	UBERON:0000178	96.90	gold quality
bone marrow cell	CL:0002092	96.84	gold quality
spleen	UBERON:0002106	96.46	gold quality
vermiform appendix	UBERON:0001154	94.61	gold quality
lymph node	UBERON:0000029	92.45	gold quality
thymus	UBERON:0002370	91.74	gold quality
caecum	UBERON:0001153	89.28	gold quality
trabecular bone tissue	UBERON:0002483	89.27	gold quality
right lung	UBERON:0002167	89.22	gold quality
upper lobe of left lung	UBERON:0008952	89.22	gold quality
right coronary artery	UBERON:0001625	89.12	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	88.31	gold quality
upper lobe of lung	UBERON:0008948	88.09	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	87.29	gold quality
omental fat pad	UBERON:0010414	86.93	gold quality
peritoneum	UBERON:0002358	86.88	gold quality
adipose tissue of abdominal region	UBERON:0007808	86.21	gold quality
ileal mucosa	UBERON:0000331	86.02	gold quality
spinal cord	UBERON:0002240	85.65	gold quality
left coronary artery	UBERON:0001626	85.09	gold quality
coronary artery	UBERON:0001621	84.85	gold quality
small intestine Peyer’s patch	UBERON:0003454	84.70	gold quality
thoracic aorta	UBERON:0001515	84.41	gold quality
tibial nerve	UBERON:0001323	84.32	gold quality
subcutaneous adipose tissue	UBERON:0002190	84.31	gold quality
ascending aorta	UBERON:0001496	84.26	gold quality
mucosa of transverse colon	UBERON:0004991	84.17	gold quality
descending thoracic aorta	UBERON:0002345	83.88	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	83.25	gold quality
superficial temporal artery	UBERON:0001614	82.80	gold quality
adipose tissue	UBERON:0001013	82.72	gold quality
lung	UBERON:0002048	82.39	gold quality
small intestine	UBERON:0002108	82.26	gold quality
apex of heart	UBERON:0002098	82.02	gold quality
decidua	UBERON:0002450	81.94	gold quality
aorta	UBERON:0000947	80.74	gold quality
mucosa of stomach	UBERON:0001199	80.56	gold quality
left uterine tube	UBERON:0001303	80.18	gold quality
right lobe of liver	UBERON:0001114	79.37	gold quality
right adrenal gland	UBERON:0001233	79.37	gold quality
muscle layer of sigmoid colon	UBERON:0035805	79.34	gold quality
transverse colon	UBERON:0001157	79.19	gold quality
substantia nigra	UBERON:0002038	79.18	gold quality
left adrenal gland cortex	UBERON:0035825	79.13	gold quality
placenta	UBERON:0001987	79.08	gold quality
smooth muscle tissue	UBERON:0001135	79.05	gold quality
tonsil	UBERON:0002372	79.05	gold quality
gall bladder	UBERON:0002110	78.85	gold quality
intestine	UBERON:0000160	78.57	gold quality
left adrenal gland	UBERON:0001234	78.56	gold quality
hypothalamus	UBERON:0001898	78.50	gold quality
body of stomach	UBERON:0001161	78.24	gold quality
adrenal cortex	UBERON:0001235	78.24	gold quality
layer of synovial tissue	UBERON:0007616	78.22	gold quality
right adrenal gland cortex	UBERON:0035827	78.18	gold quality
tibial artery	UBERON:0007610	78.10	gold quality
popliteal artery	UBERON:0002250	78.08	gold quality
amygdala	UBERON:0001876	78.02	gold quality
large intestine	UBERON:0000059	77.94	gold quality
midbrain	UBERON:0001891	77.93	gold quality
colon	UBERON:0001155	77.81	gold quality
rectum	UBERON:0001052	77.68	gold quality
minor salivary gland	UBERON:0001830	77.57	gold quality
endocervix	UBERON:0000458	77.38	gold quality
myometrium	UBERON:0001296	77.23	gold quality
right ovary	UBERON:0002118	76.94	gold quality
colonic epithelium	UBERON:0000397	76.85	gold quality
ectocervix	UBERON:0012249	76.67	gold quality
body of uterus	UBERON:0009853	76.55	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	76.53	gold quality
lower esophagus	UBERON:0013473	76.45	gold quality
lower esophagus muscularis layer	UBERON:0035833	76.44	gold quality
adenohypophysis	UBERON:0002196	76.43	gold quality
anatomical system	UBERON:0000467	76.33	gold quality
multicellular organism	UBERON:0000468	76.29	gold quality
material anatomical entity	UBERON:0000465	76.26	gold quality
saliva-secreting gland	UBERON:0001044	76.20	gold quality
mouth mucosa	UBERON:0003729	76.17	gold quality
adrenal gland	UBERON:0002369	76.16	gold quality
fundus of stomach	UBERON:0001160	76.04	gold quality
heart left ventricle	UBERON:0002084	76.03	gold quality
anterior cingulate cortex	UBERON:0009835	75.75	gold quality
cardiac ventricle	UBERON:0002082	75.73	gold quality
nucleus accumbens	UBERON:0001882	75.63	gold quality
putamen	UBERON:0001874	75.60	gold quality
skin of hip	UBERON:0001554	75.59	gold quality
epithelium of nasopharynx	UBERON:0001951	75.59	gold quality
vagina	UBERON:0000996	75.49	gold quality
right uterine tube	UBERON:0001302	75.44	gold quality
liver	UBERON:0002107	75.38	gold quality
heart	UBERON:0000948	75.35	gold quality
pituitary gland	UBERON:0000007	75.33	gold quality
synovial joint	UBERON:0002217	75.31	gold quality
duodenum	UBERON:0002114	75.28	gold quality
stomach	UBERON:0000945	75.25	gold quality
seminal vesicle	UBERON:0000998	75.12	gold quality

Single-cell (SCXA)

Detected in 32 experiment(s), a significant marker in 28.

Experiment	Marker?	Max mean expression
E-GEOD-134144	yes	1854.53
E-MTAB-8530	yes	1672.31
E-MTAB-8495	yes	1585.69
E-MTAB-8410	yes	1523.75
E-HCAD-24	yes	1518.09
E-MTAB-9221	yes	1295.95
E-MTAB-8221	yes	1218.31
E-MTAB-10287	yes	945.06
E-HCAD-4	yes	206.18
E-HCAD-1	yes	160.15
E-MTAB-6701	yes	145.86
E-MTAB-10553	yes	71.69
E-CURD-122	yes	70.18
E-MTAB-9467	yes	64.33
E-HCAD-10	yes	60.15

HPA expression

RNA tissue specificity: Tissue enhanced

showing 60 of 152 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM	Protein (IHC)
Bone marrow	tissue	239.0	high
Spleen	tissue	66.7	high
Lymph node	tissue	63.6	medium
Thymus	tissue	55.5
Appendix	tissue	50.5	medium
Rectum	tissue	44.7
Colon	tissue	37.1
Tonsil	tissue	35.4	medium
Lung	tissue	35.4
Prostate	tissue	34.5
Liver	tissue	30.7
Salivary gland	tissue	29.8
Breast	tissue	29.0
Stomach 1	tissue	27.6
Ovary	tissue	26.4
Cervix	tissue	26.1
Lung	tissue	26.0	medium
Superior colliculi	tissue	24.4
Skin 1	tissue	23.5
Endometrium 1	tissue	23.3
Choroid plexus	tissue	23.3
Placenta	tissue	23.2	high
Adrenal gland	tissue	22.6
Parathyroid gland	tissue	22.3
Septum	tissue	22.1
Spinal cord	tissue	21.9
Cerebellum	tissue	21.4
Hippocampal formation	tissue	21.1
Substantia nigra	tissue	20.9
Epididymis	tissue	20.8
Entorhinal cortex	tissue	20.7
Smooth muscle	tissue	20.6
Amygdala	tissue	20.4
Ventral forebrain	tissue	20.3
Small intestine	tissue	20.2
Midbrain	tissue	20.0
Cerebral cortex	tissue	19.9
Motor cortex	tissue	19.9
Basal ganglia	tissue	19.7
Thalamus	tissue	19.7
Kidney	tissue	19.7
Urinary bladder	tissue	19.6
Hypothalamus	tissue	19.6
Medulla oblongata	tissue	19.5
Putamen	tissue	19.3
Temporal cortex	tissue	19.3
Retrosplenial and cingulate cortex	tissue	19.2
Pons	tissue	19.1
Fallopian tube	tissue	19.0
Caudate putamen	tissue	18.9
Postcentral gyrus	tissue	18.8
Periaqueductal gray	tissue	18.7
Occipital cortex	tissue	18.7
Insular cortex	tissue	18.6
Placenta	tissue	18.5
Prefrontal cortex	tissue	18.3
Gallbladder	tissue	18.3
Retrosplenial cortex	tissue	18.3
Olfactory bulb	tissue	18.0
Pituitary gland	tissue	17.9

Brain sub-regions (HPA Brain Atlas): detected in 378; highest nTPM — Lateral funiculus (white matter) (27.9), Blood vessel (25.0), Cerebellar cortex (22.2), Vermis (22.2), Dorsal spinal cord (21.9).

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

Targeting HCST by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

1 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-1178-5P	95.83	64.12	504

Functional genomics

gnomAD constraint: pLI 3.82e-05, LOEUF 1.67, missense Z 0.762 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD RMC): no regional variation along ENST00000246551 — one region, missense o/e 0.87.

Literature-anchored findings (GeneRIF, showing 13)

• NKG2D-DAP10 triggers human NK cell-mediated killing via a Syk-independent regulatory pathway. (PMID:12740575)
• both activated and expanded CD8+ T cells and NK cells use DAP10 for cytolysis (PMID:16339517)
• Downstream targets of DAP10 and DAP12 are constitutively activated in large granular lymphocyte leukemia cells, and expression of dominant-negative DAP10 and DAP12 dramatically reduces their lytic capacity. (PMID:19075187)
• the rapid degradation of NKG2D/DAP10 observed coincident with recruitment of the receptor to the cytotoxic immune synapse may explain the loss of NKG2D receptor expression after chronic exposure to NKG2D ligands (PMID:19329438)
• A transgenic mouse model demonstrates that induction of tolerance in Ly49H-positive natural killer (NK) cells by chronic exposure to virus-encoded ligand m157 requires signaling through the Ly49H adaptor protein DAP12, not the DAP10 adaptor protein. (PMID:21263069)
• HMBOX1 negatively regulates the expression of NKG2D and the activation of the NKG2D/DAP10 signaling pathway in NK cells. (PMID:21706044)
• TGF-BETA1 down-modulates surface NKG2D expression by controlling the transcriptional and translational levels of DAP10. (PMID:21789015)
• Other gamma(c) cytokines act similarly to IL-2 in up-regulating DAP10 expression and NKG2D-DAP10 surface expression. (PMID:21816829)
• TGF-beta1 may reduce the expression of NKG2D/DAP10 and 2B4/SAPin patients with hepatitis B. (PMID:22438812)
• findings indicate that the functional interaction between RAGE and DAP10 coordinately regulates S100A8/A9-mediated survival and/or apoptotic response of keratinocytes (PMID:25002577)
• These results suggest that NKG2D-DAP10 endocytosis represents a means to decrease cell surface receptor abundance, as well as to control signaling outcome in cytotoxic lymphocytes. (PMID:26508790)
• NKG2D-DAP10 signaling recruits EVL to the cytotoxic synapse to generate F-actin and promote NK cell cytotoxicity. (PMID:31235500)
• CSF1R and HCST: Novel Candidate Biomarkers Predicting the Response to Immunotherapy in Non-Small Cell Lung Cancer. (PMID:33153411)

Cross-species orthologs

2 orthologs

Organism	Symbol	Gene ID
mus_musculus	Hcst	ENSMUSG00000064109
rattus_norvegicus	Hcst	ENSRNOG00000020849

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1344360) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 28 distinct phenotype terms.

Mouse phenotype (MP)	Records
impaired natural killer cell mediated cytotoxicity	2
abnormal NK T cell physiology	2
decreased interferon-gamma secretion	2
increased bone mineral density	1
osteopetrosis	1
abnormal trabecular bone morphology	1
abnormal long bone metaphysis morphology	1
decreased metastatic potential	1
abnormal osteoclast physiology	1
reduced fertility	1
decreased tumor growth/size	1
abnormal maternal decidual layer morphology	1
enlarged placenta	1
decreased incidence of tumors by chemical induction	1
increased susceptibility to experimental autoimmune encephalomyelitis	1
increased spleen weight	1
decreased osteoclast cell number	1
abnormal response to infection	1
ascites	1
decreased CD8-positive, alpha-beta T cell number	1
abnormal osteoclast differentiation	1
increased interferon-gamma secretion	1
increased interleukin-4 secretion	1
decreased uterine NK cell number	1
increased susceptibility to induced morbidity/mortality	1

+3 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Macaca fascicularis	Q70RD5	97.5%	Diamond
Macaca mulatta	Q8WNQ9	97.5%	Diamond
Bos taurus	Q1XF11	88.6%	Diamond
Sus scrofa	Q9GJR5	88.6%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
APLP1	protein-coding	333
NPHS1	protein-coding	4868
KIRREL2	protein-coding	84063
NFKBID	protein-coding	84807
TYROBP	protein-coding	7305
LRFN3	protein-coding	79414
SDHAF1	protein-coding	644096

Protein

Protein identifiers

Hematopoietic cell signal transducer — Q9UBK5 (reviewed: Q9UBK5)

Alternative names: DNAX-activation protein 10, Membrane protein DAP10, Transmembrane adapter protein KAP10

All UniProt accessions (1): Q9UBK5

UniProt curated annotations — full annotation on UniProt →

Function. Transmembrane adapter protein which associates with KLRK1 to form an activation receptor KLRK1-HCST in lymphoid and myeloid cells; this receptor plays a major role in triggering cytotoxicity against target cells expressing cell surface ligands such as MHC class I chain-related MICA and MICB, and UL16-binding proteins (ULBPs); these ligands are up-regulated by stress conditions and pathological state such as viral infection and tumor transformation. Functions as a docking site for PI3-kinase PIK3R1 and GRB2. Interaction of ULBPs with KLRK1-HCST triggers calcium mobilization and activation of the PIK3R1, MAP2K/ERK, and JAK2/STAT5 signaling pathways. Both PIK3R1 and GRB2 are required for full KLRK1-HCST-mediated activation and ultimate killing of target cells. In NK cells, KLRK1-HCST signaling directly induces cytotoxicity and enhances cytokine production initiated via DAP12/TYROBP-associated receptors. In T-cells, it provides primarily costimulation for TCR-induced signals. KLRK1-HCST receptor plays a role in immune surveillance against tumors and is required for cytolysis of tumors cells; indeed, melanoma cells that do not express KLRK1 ligands escape from immune surveillance mediated by NK cells.

Subunit / interactions. Interacts with CLEC5A. Forms an CLEC5A/TYROBP/HCST trimolecular complex depending almost solely on TYROBP. Homodimer; Disulfide-linked. Heterohexamer composed of four subunits of HCST/DAP10 and two subunits of KLRK1. Interacts (via transmembrane domain) with KLRK1 (via transmembrane domain); the interaction is required for KLRK1 NK cell surface and induces NK cell-mediated cytotoxicity. Interacts with PIK3R1 and GRB2. Interacts with CD300H.

Subcellular location. Membrane.

Tissue specificity. Predominantly expressed in hemopoietic cells such as NK cells, subset of T-cells and monocytes. Detected in leukocytes, spleen, and thymus.

Post-translational modifications. Phosphorylated; PIK3R1 and GRB2 associate specifically with tyrosine-phosphorylated HCST. O-glycosylated.

Induction. By T-cell receptor (TCR) ligation, which leads to enhanced KLRK1-HCST cell surface expression. Down-regulated by IL21/interleukin-21 in T-cells and NK cells.

Miscellaneous. Silencing of HCST suppresses cytolytic activity of T-cells and NK cells.

Similarity. Belongs to the DAP10 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9UBK5-1	1	yes
Q9UBK5-2	2

RefSeq proteins (2): NP_001007470, NP_055081* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR009861	HCST	Family

Pfam: PF07213

UniProt features (12 total): mutagenesis site 3, topological domain 2, region of interest 2, signal peptide 1, chain 1, transmembrane region 1, modified residue 1, splice variant 1

Structure

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9UBK5-F1	66.95	0.07

Human Protein Atlas

Protein class: Predicted membrane proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): golgi apparatus; plasma membrane; vesicles

Antibody reliability (HPA): IH enhanced · IF uncertain

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)

Type	Positions
Phosphotyrosine	86

Mutagenesis-validated functional residues (3)

Position	Phenotype
88	abrogates cell killing and interaction with grb2. no effect on interaction with pik3r1.
89	abrogates cell killing and interaction with pik3r1. no effect on interaction with grb2.
57	abolishes stable interaction with klrk1.

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

ID	Pathway	Evidence
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	curated
R-HSA-1280218	Adaptive Immune System	—
R-HSA-168256	Immune System	—

MSigDB gene sets: 161 (showing top): CREL_01, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOCC_CELL_SURFACE, GOBP_LEUKOCYTE_MEDIATED_CYTOTOXICITY, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, GOBP_LYMPHOCYTE_MEDIATED_IMMUNITY, GOBP_PHOSPHATIDYLINOSITOL_3_KINASE_PROTEIN_KINASE_B_SIGNAL_TRANSDUCTION, ZIC1_01, GOBP_NATURAL_KILLER_CELL_MEDIATED_IMMUNITY, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_SIGNAL_TRANSDUCTION, ATF4_Q2, GOBP_POSITIVE_REGULATION_OF_PHOSPHATIDYLINOSITOL_3_KINASE_PROTEIN_KINASE_B_SIGNAL_TRANSDUCTION

GO Biological Process (4): protein phosphorylation (GO:0006468), natural killer cell mediated cytotoxicity (GO:0042267), regulation of immune response (GO:0050776), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897)

GO Molecular Function (4): signaling receptor binding (GO:0005102), protein-macromolecule adaptor activity (GO:0030674), phosphatidylinositol 3-kinase binding (GO:0043548), protein binding (GO:0005515)

GO Cellular Component (3): plasma membrane (GO:0005886), cell surface (GO:0009986), membrane (GO:0016020)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Adaptive Immune System	1
Immune System	1

GO top-level categories

16 GO namespaces:

Category	Terms
protein binding	3
cellular anatomical structure	2
phosphorylation	1
protein modification process	1
leukocyte mediated cytotoxicity	1
natural killer cell mediated immunity	1
regulation of immune system process	1
immune response	1
regulation of response to stimulus	1
phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	1
positive regulation of intracellular signal transduction	1
molecular adaptor activity	1
binding	1
membrane	1
cell periphery	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 8 of 11 annotations. The rest are phylogenetic / computational / electronic (IEA).

8 experimentally-supported GO terms:

GO term	NS	Evidence
natural killer cell mediated cytotoxicity	BP	direct assay
positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction	BP	direct assay
protein phosphorylation	BP	genetic interaction
cell surface	CC	direct assay
plasma membrane	CC	direct assay
phosphatidylinositol 3-kinase binding	MF	direct assay
protein-macromolecule adaptor activity	MF	direct assay
signaling receptor binding	MF	physical interaction

Protein interactions and networks

STRING

showing 15 of 1,254 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HCST	KLRK1	P26718	937
HCST	TYROBP	O43914	930
HCST	MICB	P79525	877
HCST	CD247	P20963	850
HCST	ULBP1	Q9BZM6	848
HCST	ULBP2	Q9BZM5	838
HCST	ULBP3	Q9BZM4	837
HCST	FCER1G	P30273	830
HCST	NCR2	O95944	765
HCST	NCR1	O76036	749
HCST	KLRD1	Q13241	747
HCST	IL15	P40933	723
HCST	VAV1	P15498	716
HCST	SYK	P43405	715
HCST	FCGR3A	P08637	710

IntAct

Human interaction partners of HCST in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

8 partners by confidence:

Partner	Interaction type	MIscore	Records
BDNF	physical association	0.560	3
SEC22A	physical association	0.560	3
STARD3NL	physical association	0.560	3
VSTM1	physical association	0.560	3
KLRK1	physical association	0.400	1
FCN1	physical association	0.370	1
B3GAT3	association	0.350	1
TMEM120B	association	0.350	1

BioGRID (203 interactions; top human partners by supporting records): ACAD10 (Affinity Capture-MS), ADCK1 (Affinity Capture-MS), ADCK4 (Affinity Capture-MS), AGPAT5 (Affinity Capture-MS), AGPAT9 (Affinity Capture-MS), ALG11 (Affinity Capture-MS), AP5B1 (Affinity Capture-MS), ARID1A (Negative Genetic), ARL15 (Affinity Capture-MS), ARV1 (Affinity Capture-MS), ATL2 (Affinity Capture-MS), ATL3 (Affinity Capture-MS), ATM (Affinity Capture-MS), ATP12A (Affinity Capture-MS), ATP13A3 (Affinity Capture-MS)

Protein complexes (CORUM) (5)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

5 complexes by size:

Complex	Subunits	Members
MICB-KLRK1-HCST complex	3	HCST, KLRK1, MICB
ULBP3-KLRK1-HCST complex	3	HCST, KLRK1, ULBP3
MICA-KLRK1-HCST complex	3	MICA, HCST, KLRK1
ULBP2-KLRK1-HCST complex	3	ULBP2, HCST, KLRK1
ULBP1-KLRK1-HCST complex	3	KLRK1, ULBP1, HCST

Disease & clinical

Genetic variants

Variant evidence for HCST: 18 ClinVar records (0 pathogenic / likely pathogenic).

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	9
Likely benign	0
Benign	1

AlphaMissense

96 missense substitutions predicted likely pathogenic (of 571 scored), across 36 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
D57	8	0.842	0.920
N88	7	0.798	0.944
C42	6	0.667	0.741
Y86	5	0.863	0.897
G66	4	0.837	0.935
F69	4	0.814	0.829
M89	4	0.812	0.851
L63	3	0.892	0.928
L62	3	0.885	0.919
L53	3	0.863	0.925
S61	3	0.826	0.902
I87	3	0.790	0.835
R92	3	0.698	0.702
L50	3	0.677	0.697
V85	3	0.675	0.762
A58	2	0.948	0.950
A56	2	0.922	0.944
G52	2	0.919	0.935
A55	2	0.917	0.968
I64	2	0.852	0.950

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	unfavorable	0.000155
Skin Cutaneous Melanoma (TCGA)	unfavorable	0.000354
Kidney Renal Clear Cell Carcinoma (validation)	favorable	0.000743

Disease associations

OMIM: gene MIM:604089 | disease phenotypes:

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

CTD chemical–gene interactions

25 total (human), top 25 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Nickel	increases expression	2
Cyclosporine	increases expression	2
propionaldehyde	increases expression	1
butyraldehyde	increases expression	1
CGP 52608	affects binding, increases reaction	1
fenpyroximate	increases expression	1
pyrimidifen	increases expression	1
abrine	increases expression	1
2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazophenyl)amide	decreases expression, decreases reaction	1
(+)-JQ1 compound	decreases expression	1
2,3,5-trichloro-6-phenyl-(1,4)benzoquinone	increases expression	1
Sunitinib	decreases expression	1
Arsenic Trioxide	decreases expression	1
Vehicle Emissions	decreases reaction, decreases expression	1
Benzo(a)pyrene	increases expression	1
Diethylhexyl Phthalate	increases expression	1
Diuron	decreases expression	1
Menthol	decreases expression	1
Rotenone	increases expression	1
Dronabinol	decreases expression	1
Tretinoin	increases expression	1
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	increases expression	1
Okadaic Acid	increases expression	1
Genistein	decreases expression	1
Particulate Matter	decreases expression, decreases reaction	1

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.