HCLS1

Summary

HCLS1 (hematopoietic cell-specific Lyn substrate 1, HGNC:4844) is a protein-coding gene on chromosome 3q13.33, encoding Hematopoietic lineage cell-specific protein (P14317). Substrate of the antigen receptor-coupled tyrosine kinase.

Enables RNA polymerase II-specific DNA-binding transcription factor binding activity; protein kinase binding activity; and signaling adaptor activity. Involved in several processes, including granulocyte colony-stimulating factor signaling pathway; positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction; and positive regulation of protein import into nucleus. Located in cytosol; nucleus; and plasma membrane. Part of transcription regulator complex.

Source: NCBI Gene 3059 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 103 total — 1 pathogenic
• Druggable target: yes
• MANE Select transcript: NM_005335

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4844
Approved symbol	HCLS1
Name	hematopoietic cell-specific Lyn substrate 1
Location	3q13.33
Locus type	gene with protein product
Status	Approved
Aliases	HS1, CTTNL
Ensembl gene	ENSG00000180353
Ensembl biotype	protein_coding
OMIM	601306
Entrez	3059

Gene structure

Transcript identifiers

Ensembl transcripts: 18 — 8 protein_coding, 4 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay, 3 retained_intron

ENST00000314583, ENST00000428394, ENST00000464274, ENST00000468693, ENST00000473883, ENST00000479994, ENST00000481314, ENST00000487290, ENST00000488033, ENST00000491824, ENST00000495491, ENST00000497391, ENST00000909628, ENST00000909629, ENST00000909630, ENST00000909631, ENST00000929797, ENST00000962719

RefSeq mRNA: 2 — MANE Select: NM_005335 NM_001292041, NM_005335

CCDS: CCDS3003, CCDS77800

Canonical transcript exons

ENST00000314583 — 14 exons

Exon	Start	End
ENSE00001625394	121631399	121631982
ENSE00001866979	121660820	121660903
ENSE00003472431	121647319	121647448
ENSE00003535984	121637146	121637256
ENSE00003572880	121658264	121658347
ENSE00003582193	121642927	121642981
ENSE00003584897	121657279	121657352
ENSE00003586526	121644818	121644928
ENSE00003589428	121633067	121633171
ENSE00003598698	121634207	121634418
ENSE00003639869	121632101	121632184
ENSE00003641900	121632332	121632563
ENSE00003644723	121635735	121635804
ENSE00003666083	121636434	121636489

Expression profiles

Bgee: expression breadth ubiquitous, 258 present calls, max score 99.45.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 62.6263 / max 2859.9059, expressed in 1093 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
44095	60.3381	1077
44096	2.2883	570

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	99.45	gold quality
leukocyte	CL:0000738	99.44	gold quality
mononuclear cell	CL:0000842	99.44	gold quality
granulocyte	CL:0000094	99.42	gold quality
blood	UBERON:0000178	99.36	gold quality
spleen	UBERON:0002106	99.06	gold quality
vermiform appendix	UBERON:0001154	98.51	gold quality
bone marrow cell	CL:0002092	98.27	gold quality
bone marrow	UBERON:0002371	98.16	gold quality
lymph node	UBERON:0000029	97.23	gold quality
right lung	UBERON:0002167	97.23	gold quality
trabecular bone tissue	UBERON:0002483	96.95	gold quality
upper lobe of left lung	UBERON:0008952	96.20	gold quality
upper lobe of lung	UBERON:0008948	95.98	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.41	gold quality
gall bladder	UBERON:0002110	95.02	gold quality
ileal mucosa	UBERON:0000331	94.93	gold quality
colonic epithelium	UBERON:0000397	94.87	gold quality
lower lobe of lung	UBERON:0008949	94.74	gold quality
omental fat pad	UBERON:0010414	94.64	gold quality
peritoneum	UBERON:0002358	94.56	gold quality
adipose tissue of abdominal region	UBERON:0007808	94.22	gold quality
rectum	UBERON:0001052	93.31	gold quality
right coronary artery	UBERON:0001625	93.25	gold quality
calcaneal tendon	UBERON:0003701	93.11	gold quality
mucosa of stomach	UBERON:0001199	93.00	gold quality
small intestine	UBERON:0002108	92.82	gold quality
descending thoracic aorta	UBERON:0002345	92.63	gold quality
subcutaneous adipose tissue	UBERON:0002190	92.60	gold quality
caecum	UBERON:0001153	92.50	gold quality

Single-cell (SCXA)

Detected in 14 experiment(s), a significant marker in 11.

Experiment	Marker?	Max mean expression
E-GEOD-135922	yes	49.36
E-GEOD-84465	yes	44.16
E-GEOD-134144	yes	30.60
E-MTAB-10287	yes	29.17
E-HCAD-10	yes	28.76
E-HCAD-9	yes	20.15
E-MTAB-8410	yes	13.03
E-MTAB-10042	yes	8.54
E-MTAB-9801	yes	8.24
E-CURD-119	yes	4.92
E-GEOD-106540	no	1417.17
E-CURD-120	no	30.29
E-MTAB-5061	no	3.81
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PTEN

miRNA regulators (miRDB)

31 targeting HCLS1, 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-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-6165	99.44	67.12	1389
HSA-MIR-1206	99.30	69.32	1016
HSA-MIR-4520-2-3P	99.14	69.28	1009
HSA-MIR-4651	99.06	67.57	2002
HSA-MIR-3619-5P	99.00	68.87	2308
HSA-MIR-4801	98.96	69.42	2096
HSA-MIR-608	98.93	67.83	2013
HSA-MIR-129-1-3P	98.86	68.41	779
HSA-MIR-129-2-3P	98.86	68.41	779
HSA-MIR-873-5P	98.84	66.90	1348
HSA-MIR-214-3P	98.71	68.12	2128
HSA-MIR-761	98.71	68.07	2051
HSA-MIR-9500	98.62	66.54	1845
HSA-MIR-4731-3P	98.56	68.60	1860
HSA-MIR-6516-5P	98.42	70.19	1551
HSA-MIR-6819-5P	97.96	66.59	1071
HSA-MIR-3670	97.88	64.39	763
HSA-MIR-6737-5P	97.75	66.54	1044
HSA-MIR-585-5P	97.54	69.02	955
HSA-MIR-938	97.41	68.28	656
HSA-MIR-552-3P	96.68	64.12	1026
HSA-MIR-12128	96.67	66.98	1471
HSA-MIR-3169	96.40	67.58	698
HSA-MIR-4740-5P	96.25	67.96	726

Literature-anchored findings (GeneRIF, showing 17)

• substrate for caspase cleavage during apoptosis (PMID:11689006)
• TBB induces apoptosis and caspase-dependent degradation of haematopoietic lineage cell-specific protein 1 (HS1) in Jurkat cells. (PMID:11988074)
• found in cell types other than hematopoietic cells (PMID:15754022)
• HS1 Tyr phosphorylation catalyzed by Syk and Lyn plays a crucial role in the translocation of the protein to the membrane and is involved in the cytoskeleton rearrangement triggered by thrombin in human platelets (PMID:15795233)
• The HS1 coiled-coil region acts synergistically with the repeat domain in the modulation of the Arp2/3 complex-mediated actin polymerization. (PMID:16157603)
• HS1 may play a role in cytoskeleon organization in B-cells and leukemic B-cells (PMID:17508001)
• HS1 is a central regulator of cytoskeleton remodeling that controls lymphocyte trafficking and homing and significantly influences the tissue invasion and infiltration in chronic lymphocytic leukemia. (PMID:20530793)
• SH3 domain of HS1 protein recognizes lysine-rich polyproline motifs. (PMID:21287358)
• High HS1 expression predicts poor survival of chronic lymphocytic leukemia patients. (PMID:22333038)
• a novel role for HS1 and its phosphorylation during neutrophil directed migration. (PMID:22679023)
• HS1 overexpressed in leukemic as compared to normal B lymphocytes. (PMID:22768161)
• interaction of HCLS1 with LEF-1 is essential for G-CSF-triggered myeloid differentiation; data demonstrate the importance of HCLS1 in myelopoiesis in vitro and in vivo (PMID:23001182)
• Phosphoproteome analyses reveal specific implications of Hcls1, p21-activated kinase 1 and Ezrin in proliferation of a myeloid progenitor cell line downstream of wild-type and ITD mutant Fms-like tyrosine kinase 3 receptors. (PMID:23017497)
• SDF1alpha-induced interaction of the adapter proteins Nck and HS1 facilitates actin polymerization and migration in T cells. (PMID:25359136)
• these studies indicate HS1 plays an important role in ROR1-dependent Wnt5a-enhanced chemokine-directed leukemia-cell migration. (PMID:28465529)
• Hematopoietic cell-specific Lyn substrate, HCLS1, is a versatile actin-binding protein in leukocytes. (Review) (PMID:30537294)
• Correlation between elevated HCLS1 levels and heart failure: A diagnostic biomarker. (PMID:38847679)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	hcls1	ENSDARG00000012729
mus_musculus	Hcls1	ENSMUSG00000022831
rattus_norvegicus	Hcls1	ENSRNOG00000038881

Paralogs (4): CTTN (ENSG00000085733), COTL1 (ENSG00000103187), DBN1 (ENSG00000113758), DBNL (ENSG00000136279)

Protein

Protein identifiers

Hematopoietic lineage cell-specific protein — P14317 (reviewed: P14317)

Alternative names: Hematopoietic cell-specific LYN substrate 1, LckBP1, p75

All UniProt accessions (4): P14317, E7EVW7, F8WDD5, F8WEZ6

UniProt curated annotations — full annotation on UniProt →

Function. Substrate of the antigen receptor-coupled tyrosine kinase. Plays a role in antigen receptor signaling for both clonal expansion and deletion in lymphoid cells. May also be involved in the regulation of gene expression.

Subunit / interactions. Associates with the SH2 and SH3 domains of LCK. Binding to he LCK SH3 domain occurs constitutively, while binding to the LCK SH2 domain occurs only upon TCR stimulation. A similar binding pattern was observed with LYN, but not with FYN in which the FYN SH2 region associates upon TCR stimulation but the FYN SH3 region does not associate regardless of TCR stimulation. Directly associates with HAX1, through binding to its C-terminal region. Interacts with HS1BP3. Interacts with FES/FPS. Interacts (via SH2 domain) with FGR. Forms a multiprotein complex with LYN and ANKRD54.

Subcellular location. Membrane. Cytoplasm. Mitochondrion.

Tissue specificity. Expressed only in tissues and cells of hematopoietic origin.

Post-translational modifications. Phosphorylated by FES. Phosphorylated by LYN, FYN and FGR after cross-linking of surface IgM on B-cells. Phosphorylation by LYN, FYN and FGR requires prior phosphorylation by SYK or FES.

Isoforms (2)

UniProt ID	Names	Canonical?
P14317-1	1	yes
P14317-2	2

RefSeq proteins (2): NP_001278970, NP_005326* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001452	SH3_domain	Domain
IPR003134	Hs1_Cortactin	Repeat
IPR036028	SH3-like_dom_sf	Homologous_superfamily

Pfam: PF00018, PF02218

UniProt features (31 total): modified residue 11, compositionally biased region 5, repeat 4, sequence variant 3, splice variant 2, sequence conflict 2, region of interest 2, chain 1, domain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P14317-F1	64.45	0.17

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 (11): 41, 123, 140, 192, 198, 222, 241, 275, 308, 378, 397

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 355 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, WALLACE_PROSTATE_CANCER_RACE_UP, GNF2_MSN, MCLACHLAN_DENTAL_CARIES_UP, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_MYELOID_CELL_HOMEOSTASIS, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GNF2_BNIP2, GOBP_RESPONSE_TO_PEPTIDE, GOBP_REGULATION_OF_LEUKOCYTE_APOPTOTIC_PROCESS, MODULE_45, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_ERYTHROCYTE_HOMEOSTASIS, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION

GO Biological Process (18): negative regulation of transcription by RNA polymerase II (GO:0000122), regulation of DNA-templated transcription (GO:0006355), actin filament organization (GO:0007015), signal transduction (GO:0007165), positive regulation of cell population proliferation (GO:0008284), response to hormone (GO:0009725), erythrocyte differentiation (GO:0030218), regulation of actin filament polymerization (GO:0030833), positive regulation of granulocyte differentiation (GO:0030854), intracellular signal transduction (GO:0035556), granulocyte colony-stimulating factor signaling pathway (GO:0038158), positive regulation of protein import into nucleus (GO:0042307), positive regulation of macrophage differentiation (GO:0045651), positive regulation of transcription by RNA polymerase II (GO:0045944), nuclear transport (GO:0051169), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), cellular response to cytokine stimulus (GO:0071345), negative regulation of leukocyte apoptotic process (GO:2000107)

GO Molecular Function (7): SH3 domain binding (GO:0017124), protein kinase binding (GO:0019901), signaling adaptor activity (GO:0035591), actin filament binding (GO:0051015), RNA polymerase II-specific DNA-binding transcription factor binding (GO:0061629), protein binding (GO:0005515), protein-containing complex binding (GO:0044877)

GO Cellular Component (8): nucleus (GO:0005634), transcription regulator complex (GO:0005667), cytoplasm (GO:0005737), mitochondrion (GO:0005739), cytosol (GO:0005829), plasma membrane (GO:0005886), endocytic vesicle (GO:0030139), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
regulation of transcription by RNA polymerase II	2
transcription by RNA polymerase II	2
positive regulation of myeloid leukocyte differentiation	2
intracellular anatomical structure	2
binding	2
intracellular membrane-bounded organelle	2
cytoplasm	2
negative regulation of DNA-templated transcription	1
DNA-templated transcription	1
regulation of gene expression	1
regulation of RNA biosynthetic process	1
actin cytoskeleton organization	1
supramolecular fiber organization	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
response to endogenous stimulus	1
response to chemical	1
myeloid cell differentiation	1
erythrocyte homeostasis	1
regulation of actin polymerization or depolymerization	1
actin filament polymerization	1
regulation of protein polymerization	1
granulocyte differentiation	1
regulation of granulocyte differentiation	1
signal transduction	1
cytokine-mediated signaling pathway	1
protein import into nucleus	1
regulation of protein import into nucleus	1
positive regulation of nucleocytoplasmic transport	1
positive regulation of intracellular protein transport	1
positive regulation of protein localization to nucleus	1
macrophage differentiation	1
regulation of macrophage differentiation	1

Protein interactions and networks

STRING

4566 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HCLS1	WASL	O00401	997
HCLS1	CFL2	Q9Y281	995
HCLS1	CFL1	P23528	995
HCLS1	WAS	P42768	995
HCLS1	PXN	P49023	994
HCLS1	SRC	P12931	994
HCLS1	HDAC6	Q9UBN7	989
HCLS1	SCIN	Q9Y6U3	986
HCLS1	TJP1	Q07157	986
HCLS1	GSN	P06396	985
HCLS1	DNM2	P50570	983
HCLS1	CTTNBP2	Q8WZ74	976
HCLS1	SH3PXD2A	Q5TCZ1	971
HCLS1	HAX1	O00165	958
HCLS1	VCL	P18206	955
HCLS1	NCK1	P16333	955

IntAct

56 interactions, top by confidence:

A	B	Type	Score
PIK3CA	PIK3R2	psi-mi:“MI:0914”(association)	0.900
HCLS1	SH2D4A	psi-mi:“MI:0915”(physical association)	0.830
SH2D4A	HCLS1	psi-mi:“MI:0915”(physical association)	0.830
CFTR	XPO1	psi-mi:“MI:0914”(association)	0.710
HCLS1		psi-mi:“MI:0915”(physical association)	0.560
	HCLS1	psi-mi:“MI:0915”(physical association)	0.560
HCLS1	SH3BP2	psi-mi:“MI:0915”(physical association)	0.560
HCLS1	SNX1	psi-mi:“MI:0914”(association)	0.530
KCNS3	UPK3BL1	psi-mi:“MI:0914”(association)	0.530
HCLS1	WIPF1	psi-mi:“MI:0915”(physical association)	0.520
WIPF1	HCLS1	psi-mi:“MI:0915”(physical association)	0.520
TERF1	HCLS1	psi-mi:“MI:0915”(physical association)	0.510
HCLS1	LYN	psi-mi:“MI:0915”(physical association)	0.500
LYN	HCLS1	psi-mi:“MI:0914”(association)	0.500
ADAM10	HCLS1	psi-mi:“MI:0407”(direct interaction)	0.440
Dlg4	HCLS1	psi-mi:“MI:0407”(direct interaction)	0.440
HCLS1	WAS	psi-mi:“MI:0915”(physical association)	0.400
HCLS1	Mbp	psi-mi:“MI:0915”(physical association)	0.400
HCLS1	SSBP3	psi-mi:“MI:0915”(physical association)	0.370
HCLS1	TRIM29	psi-mi:“MI:0915”(physical association)	0.370
HCLS1	ZBTB25	psi-mi:“MI:0915”(physical association)	0.370
HCLS1	LZTR1	psi-mi:“MI:0915”(physical association)	0.370
HCLS1	IKBKG	psi-mi:“MI:0915”(physical association)	0.370
HCLS1	BLZF1	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (96): SH2D4A (Two-hybrid), SH2D4A (Two-hybrid), HCLS1 (Co-localization), HCLS1 (Co-localization), KCNA3 (Co-localization), HCLS1 (Affinity Capture-MS), SNX1 (Affinity Capture-MS), HCLS1 (Affinity Capture-MS), SNX5 (Affinity Capture-MS), HCLS1 (Two-hybrid), HCLS1 (Affinity Capture-MS), HCLS1 (Proximity Label-MS), HCLS1 (Affinity Capture-MS), HCLS1 (Two-hybrid), HCLS1 (Two-hybrid)

ESM2 similar proteins: A0MZ66, A2APB8, A4IG59, A4IH24, A5A6J4, A6H6Z7, B0BM24, E2RYF8, E7F7X0, F4I2H7, O13024, O43683, O60566, O95990, P13505, P14317, P92204, Q0IHP2, Q28E45, Q2KI00, Q32N93, Q3B820, Q3TGF2, Q5EAW4, Q5NVP3, Q5RAF2, Q5U4F3, Q62736, Q659C4, Q66KE9, Q68FU8, Q6AY14, Q6DDV8, Q6NUF4, Q6PKG0, Q78TU8, Q7L590, Q84ZT9, Q8CB59, Q8CH02

Diamond homologs: A3LXQ8, A6H7G2, A6ZR73, A7MBI0, B3LRN4, B5VHP4, B8R1V5, C4Y1G1, C7GKW5, E7KBW4, E7KMS3, E7LTJ6, E7Q311, E7QE10, G5EC32, O13154, O35179, O35180, O42287, O60861, O74749, O75886, O76041, O77506, O88811, P08487, P10569, P10686, P14317, P18302, P19174, P20929, P34121, P34416, P40073, P49710, P70297, Q01406, Q07266, Q09822

SIGNOR signaling

9 interactions.

A	Effect	B	Mechanism
CSNK2A1	unknown	HCLS1	phosphorylation
LYN	“up-regulates activity”	HCLS1	phosphorylation
PTEN	“up-regulates quantity by expression”	HCLS1	“transcriptional regulation”
SYK	up-regulates	HCLS1	phosphorylation
FGR	unknown	HCLS1	phosphorylation
LYN	unknown	HCLS1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 43 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
Cytokine Signaling in Immune system	6	9.4×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	1
Likely pathogenic	0
Uncertain significance	74
Likely benign	7
Benign	1

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
562809	GRCh37/hg19 3q13.31-21.1(chr3:115518341-122129283)x1	Pathogenic

SpliceAI

1850 predictions. Top by Δscore:

Variant	Effect	Δscore
3:121631983:C:CC	acceptor_gain	1.0000
3:121632325:CACT:C	donor_loss	1.0000
3:121632326:ACTC:A	donor_loss	1.0000
3:121632328:TCA:T	donor_loss	1.0000
3:121632329:CAC:C	donor_loss	1.0000
3:121632330:A:AC	donor_gain	1.0000
3:121632330:ACCAG:A	donor_gain	1.0000
3:121632331:C:CC	donor_gain	1.0000
3:121632331:CCAG:C	donor_gain	1.0000
3:121632331:CCAGC:C	donor_gain	1.0000
3:121632376:T:TA	donor_gain	1.0000
3:121632559:TTGTC:T	acceptor_gain	1.0000
3:121632560:TGTC:T	acceptor_gain	1.0000
3:121632562:TC:T	acceptor_gain	1.0000
3:121632563:CC:C	acceptor_gain	1.0000
3:121632564:C:CC	acceptor_gain	1.0000
3:121632564:C:CG	acceptor_loss	1.0000
3:121633167:CAGGC:C	acceptor_gain	1.0000
3:121634201:GCTCA:G	donor_loss	1.0000
3:121634202:CTCAC:C	donor_loss	1.0000
3:121634203:TCA:T	donor_loss	1.0000
3:121634204:CACCT:C	donor_loss	1.0000
3:121634205:A:AC	donor_gain	1.0000
3:121634205:A:AG	donor_loss	1.0000
3:121634206:C:CC	donor_gain	1.0000
3:121634206:CCT:C	donor_gain	1.0000
3:121634253:T:TA	donor_gain	1.0000
3:121634414:AGAAG:A	acceptor_gain	1.0000
3:121634415:GAAG:G	acceptor_gain	1.0000
3:121634416:AAG:A	acceptor_gain	1.0000

AlphaMissense

3176 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:121631862:A:T	V482D	0.998
3:121631877:A:G	F477S	0.998
3:121631912:C:A	W465C	0.998
3:121631912:C:G	W465C	0.998
3:121631914:A:G	W465R	0.998
3:121631914:A:T	W465R	0.998
3:121631943:A:C	I455S	0.998
3:121631943:A:G	I455T	0.998
3:121632121:G:T	A435D	0.998
3:121658285:C:A	W21C	0.998
3:121658285:C:G	W21C	0.998
3:121658287:A:G	W21R	0.998
3:121658287:A:T	W21R	0.998
3:121631876:G:C	F477L	0.997
3:121631876:G:T	F477L	0.997
3:121631878:A:G	F477L	0.997
3:121631904:C:T	G468E	0.997
3:121631943:A:T	I455N	0.997
3:121631961:A:G	F449S	0.997
3:121636473:A:C	F194L	0.996
3:121636473:A:T	F194L	0.996
3:121636475:A:G	F194L	0.996
3:121658344:A:G	W2R	0.996
3:121658344:A:T	W2R	0.996
3:121631877:A:C	F477C	0.995
3:121631883:C:T	G475E	0.995
3:121631905:C:G	G468R	0.995
3:121631905:C:T	G468R	0.995
3:121631911:A:G	W466R	0.995
3:121631911:A:T	W466R	0.995

dbSNP variants (sampled 300 via entrez): RS1000048902 (3:121639000 G>A), RS1000067413 (3:121645235 C>G,T), RS1000113737 (3:121662459 G>A), RS1000276262 (3:121662016 A>G), RS1000352366 (3:121630909 T>A,C), RS1000378986 (3:121658520 C>A), RS1000573524 (3:121639743 T>C,G), RS1000763813 (3:121650126 G>A), RS1000798200 (3:121633321 T>A), RS1001107067 (3:121646750 A>T), RS1001166808 (3:121633644 C>T), RS1001170936 (3:121646867 T>C), RS1001202084 (3:121657839 A>C), RS1001259104 (3:121653935 T>C), RS1001405863 (3:121646953 A>G)

Disease associations

OMIM: gene MIM:601306 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066407 (SINGLE PROTEIN)

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

ChEMBL bioactivities

2 potent at pChembl≥5 of 3 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.52	Kd	29.91	nM	CHEMBL3752910
7.52	ED50	29.91	nM	CHEMBL3752910

PubChem BioAssay actives

1 with measured affinity, of 4 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148494: Binding affinity to human HCLS1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0299	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects expression, increases expression	3
aristolochic acid I	increases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
ethyl-p-hydroxybenzoate	increases expression	1
butyraldehyde	increases expression	1
potassium chromate(VI)	decreases expression	1
Resveratrol	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Arsenic Trioxide	increases expression	1
Acetaminophen	increases expression	1
Air Pollutants	increases abundance, affects expression	1
Arsenicals	increases expression	1
Aspirin	decreases expression	1
Benzo(a)pyrene	affects methylation	1
Clozapine	affects cotreatment, decreases expression	1
Cuprizone	affects cotreatment, decreases expression	1
Doxorubicin	affects response to substance	1
Lead	decreases expression	1
Mustard Gas	increases expression	1
Nickel	increases expression	1
Ozone	affects expression, increases abundance	1
Plant Extracts	affects cotreatment, increases expression	1
Plant Oils	increases expression	1
Progesterone	increases expression	1
Quercetin	increases expression	1
Smoke	increases expression	1
Sodium Dodecyl Sulfate	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651536	Binding	Binding affinity to human HCLS1 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

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