HAX1

Summary

HAX1 (HCLS1 associated protein X-1, HGNC:16915) is a protein-coding gene on chromosome 1q21.3, encoding HCLS1-associated protein X-1 (O00165). Recruits the Arp2/3 complex to the cell cortex and regulates reorganization of the cortical actin cytoskeleton via its interaction with KCNC3 and the Arp2/3 complex. It is a selective cancer dependency (DepMap: 11.8% of cell lines).

The protein encoded by this gene is known to associate with hematopoietic cell-specific Lyn substrate 1, a substrate of Src family tyrosine kinases. It also interacts with the product of the polycystic kidney disease 2 gene, mutations in which are associated with autosomal-dominant polycystic kidney disease, and with the F-actin-binding protein, cortactin. It was earlier thought that this gene product is mainly localized in the mitochondria, however, recent studies indicate it to be localized in the cell body. Mutations in this gene result in autosomal recessive severe congenital neutropenia, also known as Kostmann disease. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 10456 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Kostmann syndrome (Definitive, GenCC)
• GWAS associations: 16
• Clinical variants (ClinVar): 692 total — 33 pathogenic, 25 likely-pathogenic
• Phenotypes (HPO): 14
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 11.8% of screened cell lines
• MANE Select transcript: NM_006118

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16915
Approved symbol	HAX1
Name	HCLS1 associated protein X-1
Location	1q21.3
Locus type	gene with protein product
Status	Approved
Aliases	HS1BP1, HCLSBP1, HAX-1
Ensembl gene	ENSG00000143575
Ensembl biotype	protein_coding
OMIM	605998
Entrez	10456

Gene structure

Transcript identifiers

Ensembl transcripts: 34 — 24 protein_coding, 7 retained_intron, 3 nonsense_mediated_decay

ENST00000328703, ENST00000435087, ENST00000447768, ENST00000457918, ENST00000459914, ENST00000471326, ENST00000477780, ENST00000483970, ENST00000492550, ENST00000531435, ENST00000532105, ENST00000696929, ENST00000696930, ENST00000696931, ENST00000696932, ENST00000696933, ENST00000696938, ENST00000696941, ENST00000696944, ENST00000696945, ENST00000696965, ENST00000696966, ENST00000697592, ENST00000697830, ENST00000882498, ENST00000882499, ENST00000882500, ENST00000882501, ENST00000882502, ENST00000919722, ENST00000919723, ENST00000919724, ENST00000919725, ENST00000950411

RefSeq mRNA: 2 — MANE Select: NM_006118 NM_001018837, NM_006118

CCDS: CCDS1064, CCDS44230

Canonical transcript exons

ENST00000328703 — 7 exons

Exon	Start	End
ENSE00001910730	154272629	154272776
ENSE00003968935	154273774	154273961
ENSE00003968941	154275393	154275483
ENSE00003968943	154275154	154275260
ENSE00003968944	154273336	154273598
ENSE00003968945	154274950	154275001
ENSE00003969188	154275616	154275875

Expression profiles

Bgee: expression breadth ubiquitous, 295 present calls, max score 98.67.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 108.3581 / max 1218.7888, expressed in 1822 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
5483	108.3581	1822

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
apex of heart	UBERON:0002098	98.67	gold quality
heart right ventricle	UBERON:0002080	98.53	gold quality
hindlimb stylopod muscle	UBERON:0004252	98.46	gold quality
cardiac ventricle	UBERON:0002082	98.22	gold quality
heart left ventricle	UBERON:0002084	98.21	gold quality
pituitary gland	UBERON:0000007	98.19	gold quality
body of tongue	UBERON:0011876	98.15	gold quality
adenohypophysis	UBERON:0002196	98.13	gold quality
type B pancreatic cell	CL:0000169	98.00	gold quality
islet of Langerhans	UBERON:0000006	98.00	gold quality
diaphragm	UBERON:0001103	97.99	gold quality
biceps brachii	UBERON:0001507	97.88	gold quality
parotid gland	UBERON:0001831	97.87	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.85	gold quality
triceps brachii	UBERON:0001509	97.84	gold quality
body of pancreas	UBERON:0001150	97.83	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	97.74	gold quality
right atrium auricular region	UBERON:0006631	97.59	gold quality
heart	UBERON:0000948	97.58	gold quality
tongue	UBERON:0001723	97.50	gold quality
gastrocnemius	UBERON:0001388	97.38	gold quality
middle frontal gyrus	UBERON:0002702	97.34	gold quality
nucleus accumbens	UBERON:0001882	97.30	gold quality
pancreas	UBERON:0001264	97.24	gold quality
muscle of leg	UBERON:0001383	97.12	gold quality
gluteal muscle	UBERON:0002000	97.10	gold quality
body of stomach	UBERON:0001161	97.06	gold quality
pons	UBERON:0000988	97.05	gold quality
putamen	UBERON:0001874	97.03	gold quality
prefrontal cortex	UBERON:0000451	96.99	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
ATP2A2	Repression

Upstream regulators (CollecTRI, top): NFKB1, NFKB

miRNA regulators (miRDB)

23 targeting HAX1, 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-4493	99.90	66.48	977
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-6134	99.63	65.68	1537
HSA-MIR-21-5P	99.46	70.54	1035
HSA-MIR-329-5P	99.27	68.11	1597
HSA-MIR-590-5P	99.25	70.76	930
HSA-MIR-6744-3P	99.22	64.41	972
HSA-MIR-4757-5P	99.12	64.51	981
HSA-MIR-4504	99.10	69.14	1328
HSA-MIR-12135	98.99	70.26	1814
HSA-MIR-6769B-5P	98.73	64.91	1092
HSA-MIR-31-5P	98.58	68.35	1239
HSA-MIR-210-5P	98.57	64.37	832
HSA-MIR-1262	98.17	66.52	757
HSA-MIR-4701-3P	98.17	66.25	788
HSA-MIR-6736-5P	98.17	66.43	760
HSA-MIR-6769A-5P	97.99	64.16	851
HSA-MIR-874-5P	96.93	63.92	1014
HSA-MIR-1236-5P	96.62	66.38	856
HSA-MIR-541-3P	96.07	66.11	1271
HSA-MIR-654-5P	96.07	66.18	1280
HSA-MIR-6815-5P	96.05	65.55	662
HSA-MIR-6865-5P	96.05	65.58	675

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 11.8% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• In psoriasis, the epidermal differentiation could be disturbed due to the increased expression of HAX-1 and hence a prolonged resistance to terminal differentiation (PMID:12787133)
• HAX-1 binds bile salt export protein (BSEP), cortactin, MDR1, and MDR2. HAX-1 and cortactin regulate BSEP abundance in the apical membrane of cells. (PMID:15159385)
• Interacts with the alpha subunit of G protein G13 to promote cell migration. (PMID:15339924)
• HAX-1 is a newly identified anti-apoptotic factor and its mechanism of action is through caspase-9 inhibition. (PMID:16857965)
• These findings reveal that nuclear localization of pre-IL-1alpha depends on the binding to HAX-1 and that biological activities might be elicited by the binding to both HAX-1 and IL-1RII in SSc fibroblasts. (PMID:16971486)
• HAX1 is a major regulator of myeloid homeostasis and mutant proteins cause autosomal recessive severe congenital neutropenia. (PMID:17187068)
• HAX1, an anti-apoptotic protein, inhibits the HIV-1 rev function by altering is subcellular localization. (PMID:17929250)
• important role of HAX1 on neural development as well as myelopoiesis. (PMID:18055975)
• Results suggest that HAX-1, a substrate of CASP3, inhibits the apoptotic process by inhibiting CASP3 activity. (PMID:18319618)
• Severe congenital neutropenia caused by a homozygous mutation (R86X) in the antiapoptotic molecule HAX1. (PMID:18330843)
• identified 6 additional patients with HAX1 mutations carrying 4 novel mutations; mutations of transcript variants are characterized by phenotype and localization (PMID:18337561)
• HAX-1 deficiency or overexpression leads to hereditary or systemic diseases (Kostmann disease, lesional psoriasis, systemic sclerosis) (PMID:18399350)
• alternative splice variants, encoded by the chromosome 1 gene, produce a family of transcripts composed of up to eight members (PMID:18472110)
• neurological and neuropsychological abnormalities in the central nervous system symptoms appear to be associated with specific HAX1 mutations in Kostmann disease patients. (PMID:18513342)
• the R86X mutation in the HAX1 gene is an abnormality in Japanese Severe congenital neutropenia patients with HAX1 deficiency and may lead to neurodevelopmental abnormalities and severe myelopoietic defects (PMID:18611981)
• These findings suggest that HAX-1 may promote cell survival through modulation of SERCA2 protein levels and thus endoplasmic reticulum calcium stores. (PMID:18971376)
• The data indicate that Hax-1 plays a role in suppression of apoptosis and promotion of melanoma cell growth, suggesting that this Hax-1 siRNA has a therapeutic indication in control of melanoma. (PMID:19254774)
• HAX-1 has been shown to bind to the 3’ untranslated regions of certain mRNAs and could therefore contribute to the regulation of transport and/or stability of such transcripts. (PMID:19524642)
• there is an an association between HCV core and HAX-1, which promotes 5-FU mediated p53-dependent caspase-7 activation and hepatocyte growth inhibition (PMID:19605487)
• Data demonstrate that TPCK induces apoptosis in human B cell lines and exerts multiple effects on pro- and anti-apoptotic factors, including HAX-1. (PMID:19679660)
• results indicate a different function and mechanism of Hax1 in apoptosis and re-opens the question of whether mammalian PARL, in addition to apoptosis, regulates mitochondrial stress response through Omi/HtrA2 processing. (PMID:19680265)
• study suggests that the novel missense c.421T>C mutation in the HAX1 gene produces a milder form of severe congenital neutropenia without apparent developmental or neurological manifestations (PMID:19796188)
• HAX-1 is a multifaceted antiapoptotic protein localizing in the mitochondria and the sarcoplasmic reticulum of striated muscle cells (PMID:19913549)
• Neurological symptoms were found in HAX1-deficient patients with mutations in the HAX1 gene affecting both transcript variants, while they were not found in those affecting isoform a only. (PMID:19928538)
• Novel HAX1 gene mutations are associated with neurodevelopmental abnormalities in two Italian patients with severe congenital neutropenia. (PMID:20065084)
• HAX-1 suppresses the polyubiquitination of XIAP; formation of the HAX-1-XIAP complex inhibits apoptosis by enhancing the stability of XIAP against proteosomal degradation. (PMID:20171186)
• analysis of HAX-1 overexpression, splicing and cellular localization in tumors (PMID:20196840)
• describe congenital neutropenia patients with mutations in two candidate genes each,HAX1 and G6PC3, including 6 novel mutations (PMID:20220065)
• This study is the first to demonstrate GrB activity within the mitochondrion and to identify Hax-1 cleavage as a novel mechanism for GrB-mediated mitochondrial depolarization. (PMID:20388708)
• PELO is subcellularly localized at the actin cytoskeleton, interacts with HAX1, EIF3G and SRPX proteins and that this interaction occurs at the cytoskeleton; this interaction may facilitate PELO to detect and degrade aberrant mRNAs. (PMID:20406461)
• The N(pro)-HAX-1 interaction was confirmed using co-precipitation assays. (PMID:20631090)
• Full-length Grb7 and Hax-1 interact in mammalian cells and Grb7 is tyrosine phosphorylated. (PMID:20665473)
• hSpry1 and HAX1 proteins are putative candidate proteins that interact with uPAR. (PMID:20696135)
• identified consanguineous family with 2 patients with severe congenital neutropenia and neurological disease caused by novel, homozygous genomic deletion including exons 4-7 of the HAX1 gene; quantitative MRI showed alteration in cerebral proton density (PMID:21108402)
• Our resultsvindicate that HAX-1 may not be a candidate gene for psoriasis susceptibility in the Chinese Han population. (PMID:21109726)
• Biallelic mutations in the antiapoptotic gene HAX1 were identified in patients with autosomal recessive severe congenital neutropenia. (PMID:21206270)
• Data suggest that Hax-1 is a new PrP-interacting partner that may play role in cell oxidative stress and anti-apoptosis physiologically and cell damage pathologically. (PMID:21301993)
• Hax1 is a novel regulator of neutrophil uropod detachment and chemotaxis through RhoA (PMID:21518791)
• hSav1 interacts with HAX1 and attenuates its protective role against apoptosis in MCF-7 breast cancer cells. (PMID:21567072)
• We also confirmed the interaction of HAX-1 and hSav1 in mammalian cells. (PMID:22570112)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	hax1	ENSDARG00000036764
mus_musculus	Hax1	ENSMUSG00000027944
rattus_norvegicus	Hax1	ENSRNOG00000045647
drosophila_melanogaster	CG4230	FBGN0031683

Protein

Protein identifiers

HCLS1-associated protein X-1 — O00165 (reviewed: O00165)

Alternative names: HS1-associating protein X-1, HS1-binding protein 1

All UniProt accessions (12): O00165, A0A0S2Z565, A0A0S2Z591, A0A8V8TKG3, A0A8V8TKG6, A0A8V8TKH7, A0A8V8TKI6, A0A8V8TKI8, A0A8V8TLX9, A0A8V8TLZ3, E9PIQ7, Q5VYD6

UniProt curated annotations — full annotation on UniProt →

Function. Recruits the Arp2/3 complex to the cell cortex and regulates reorganization of the cortical actin cytoskeleton via its interaction with KCNC3 and the Arp2/3 complex. Slows down the rate of inactivation of KCNC3 channels. Promotes GNA13-mediated cell migration. Involved in the clathrin-mediated endocytosis pathway. May be involved in internalization of ABC transporters such as ABCB11. May inhibit CASP9 and CASP3. Promotes cell survival. May regulate intracellular calcium pools.

Subunit / interactions. Interacts with ABCB1, ABCB4 and ABCB11. Directly associates with HCLS1/HS1, through binding to its N-terminal region. Interacts with CTTN. Interacts with PKD2. Interacts with GNA13. Interacts with CASP9. Interacts with ITGB6. Interacts with PLN and ATP2A2; these interactions are inhibited by calcium. Interacts with GRB7. Interacts (via C-terminus) with XIAP/BIRC4 (via BIR 2 domain and BIR 3 domain) and this interaction blocks ubiquitination of XIAP/BIRC4. Interacts with TPC2. Interacts with KCNC3. Interacts with XPO1. Interacts with RNF217. Interacts with UCP3; the interaction is direct and calcium-dependent. Interacts with MAPRE2; this interaction regulates cell migration in keratinocytes.

Subcellular location. Mitochondrion matrix. Endoplasmic reticulum. Nucleus membrane. Cytoplasmic vesicle. Cytoplasm. Cell cortex. Cell membrane. Sarcoplasmic reticulum. P-body Cytoplasm. Nucleus Cytoplasm.

Tissue specificity. Ubiquitous. Up-regulated in oral cancers.

Post-translational modifications. Proteolytically cleaved by caspase-3 during apoptosis.

Disease relevance. Neutropenia, severe congenital 3, autosomal recessive (SCN3) [MIM:610738] A disorder of hematopoiesis characterized by maturation arrest of granulopoiesis at the level of promyelocytes with peripheral blood absolute neutrophil counts below 0.5 x 10(9)/l and early onset of severe bacterial infections. Some patients affected by severe congenital neutropenia type 3 have neurological manifestations such as psychomotor retardation and seizures. The disease is caused by variants affecting the gene represented in this entry. The clinical phenotype due to HAX1 deficiency appears to depend on the localization of the mutations and their influence on the transcript variants. Mutations affecting exclusively isoform 1 are associated with isolated congenital neutropenia, whereas mutations affecting both isoform 1 and isoform 5 are associated with additional neurologic symptoms.

Similarity. Belongs to the HAX1 family.

Isoforms (6)

UniProt ID	Names	Canonical?
O00165-1	1	yes
O00165-2	2
O00165-3	3
O00165-4	4
O00165-5	5
O00165-6	6

RefSeq proteins (2): NP_001018238, NP_006109* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR017248	HAX-1	Family

UniProt features (38 total): region of interest 12, splice variant 7, sequence variant 6, compositionally biased region 4, modified residue 3, sequence conflict 3, initiator methionine 1, chain 1, site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O00165-F1	60.06	0.10

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 127–128 (cleavage; by caspase-3)

Post-translational modifications (3): 2, 189, 192

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 306 (showing top): GOBP_MYELOID_CELL_DIFFERENTIATION, GOBP_REGULATION_OF_AUTOPHAGY, GOBP_REGULATION_OF_PROTEIN_POLYMERIZATION, GOBP_POSITIVE_REGULATION_OF_HEMOPOIESIS, GOBP_RESPONSE_TO_PEPTIDE, MORF_HDAC1, DITTMER_PTHLH_TARGETS_UP, GOBP_PROTEIN_TARGETING, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, GOBP_MYELOID_LEUKOCYTE_DIFFERENTIATION, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOBP_REGULATION_OF_CELLULAR_COMPONENT_BIOGENESIS, GOBP_REGULATION_OF_ACTIN_FILAMENT_BASED_PROCESS, GOBP_REGULATION_OF_LEUKOCYTE_DIFFERENTIATION, GOBP_REGULATION_OF_ANATOMICAL_STRUCTURE_SIZE

GO Biological Process (11): regulation of actin filament polymerization (GO:0030833), positive regulation of granulocyte differentiation (GO:0030854), granulocyte colony-stimulating factor signaling pathway (GO:0038158), regulation of apoptotic process (GO:0042981), negative regulation of apoptotic process (GO:0043066), positive regulation of transcription by RNA polymerase II (GO:0045944), positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction (GO:0051897), cellular response to cytokine stimulus (GO:0071345), regulation of actin filament organization (GO:0110053), regulation of autophagy of mitochondrion (GO:1903146), obsolete regulation of protein targeting to mitochondrion (GO:1903214)

GO Molecular Function (4): protein domain specific binding (GO:0019904), interleukin-1 binding (GO:0019966), signaling adaptor activity (GO:0035591), protein binding (GO:0005515)

GO Cellular Component (20): P-body (GO:0000932), nuclear envelope (GO:0005635), transcription regulator complex (GO:0005667), mitochondrion (GO:0005739), mitochondrial outer membrane (GO:0005741), mitochondrial intermembrane space (GO:0005758), mitochondrial matrix (GO:0005759), endoplasmic reticulum (GO:0005783), cell cortex (GO:0005938), actin cytoskeleton (GO:0015629), apical plasma membrane (GO:0016324), sarcoplasmic reticulum (GO:0016529), lamellipodium (GO:0030027), clathrin-coated vesicle (GO:0030136), nuclear membrane (GO:0031965), nucleus (GO:0005634), cytoplasm (GO:0005737), plasma membrane (GO:0005886), membrane (GO:0016020), cytoplasmic vesicle (GO:0031410)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	4
intracellular membrane-bounded organelle	3
apoptotic process	2
nucleus	2
endomembrane system	2
cell periphery	2
cellular anatomical structure	2
regulation of actin polymerization or depolymerization	1
actin filament polymerization	1
regulation of protein polymerization	1
positive regulation of myeloid leukocyte differentiation	1
granulocyte differentiation	1
regulation of granulocyte differentiation	1
cytokine-mediated signaling pathway	1
regulation of programmed cell death	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
positive regulation of DNA-templated transcription	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
response to cytokine	1
actin filament organization	1
regulation of actin cytoskeleton organization	1
regulation of supramolecular fiber organization	1
autophagy of mitochondrion	1
regulation of autophagy	1
protein binding	1
growth factor binding	1
cytokine binding	1
protein-macromolecule adaptor activity	1
binding	1
cytoplasmic ribonucleoprotein granule	1
organelle envelope	1
protein-containing complex	1
mitochondrial membrane	1
organelle outer membrane	1
mitochondrial envelope	1

Protein interactions and networks

STRING

1351 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HAX1	HCLS1	P14317	958
HAX1	CTTN	Q14247	900
HAX1	HTRA2	O43464	864
HAX1	ELANE	P08246	857
HAX1	PARL	Q9H300	822
HAX1	A0A1W2PP11	A0A1W2PP11	813
HAX1	CSF3R	Q99062	772
HAX1	G6PC3	Q9BUM1	762
HAX1	KIAA0513	O60268	754
HAX1	GNA13	Q14344	750
HAX1	GFI1	Q99684	727
HAX1	BCL2	P10415	695
HAX1	INTS4	Q96HW7	679
HAX1	JAGN1	Q8N5M9	658
HAX1	AKAP8L	Q9ULX6	605

IntAct

296 interactions, top by confidence:

A	B	Type	Score
HAX1	SAV1	psi-mi:“MI:0915”(physical association)	0.740
SAV1	HAX1	psi-mi:“MI:0403”(colocalization)	0.740
IFT27	IFT56	psi-mi:“MI:0914”(association)	0.690
PKN3	ARHGAP10	psi-mi:“MI:0914”(association)	0.680
HAX1	HTT	psi-mi:“MI:0915”(physical association)	0.670
PELO	HAX1	psi-mi:“MI:0915”(physical association)	0.660
HAX1	PELO	psi-mi:“MI:0403”(colocalization)	0.660
HAX1	IL1A	psi-mi:“MI:0915”(physical association)	0.620
IL1A	HAX1	psi-mi:“MI:0915”(physical association)	0.620

BioGRID (596): HAX1 (Affinity Capture-Western), BIRC3 (Affinity Capture-Western), BIRC3 (Reconstituted Complex), HAX1 (Reconstituted Complex), HAX1 (Affinity Capture-MS), HAX1 (Affinity Capture-MS), HAX1 (Affinity Capture-MS), HAX1 (Affinity Capture-MS), DPYSL5 (Affinity Capture-MS), STXBP1 (Affinity Capture-MS), ATP4A (Affinity Capture-MS), HPCAL1 (Affinity Capture-MS), NCALD (Affinity Capture-MS), HPCA (Affinity Capture-MS), CAMK2B (Affinity Capture-MS)

ESM2 similar proteins: A0A804C8T0, A4ZNR4, A4ZNR5, B2RX88, F7C1E2, O00165, O08623, O35387, O70367, O75829, O77770, P17404, P25686, P58340, Q03157, Q08E24, Q13501, Q15773, Q16626, Q29407, Q2KIE2, Q32KY3, Q3UIL6, Q4R992, Q5R491, Q5R4T3, Q5RBA5, Q5XIA0, Q64337, Q6AYN2, Q6BEG7, Q6IQ23, Q6PAQ9, Q7TNY7, Q7TSE9, Q7Z5B4, Q8BK03, Q8BPM6, Q8K3I4, Q8NFW9

Diamond homologs: O00165, O35387, Q2KIE2, Q7TSE9

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
HAX1	“down-regulates quantity by repression”	ATP2A2	“transcriptional regulation”
HAX1	“down-regulates quantity by destabilization”	ATP2A2	binding
PRKCD	“down-regulates quantity by destabilization”	HAX1	phosphorylation
FBXO25	“down-regulates quantity by destabilization”	HAX1	ubiquitination

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 129 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.

GO biological processes:

GO term	Partners	Fold	FDR
cell surface receptor protein tyrosine kinase signaling pathway	6	11.2×	3e-03
protein autophosphorylation	7	10.9×	1e-03
protein phosphorylation	10	7.3×	1e-03
positive regulation of MAPK cascade	8	6.9×	3e-03
positive regulation of canonical NF-kappaB signal transduction	8	6.2×	4e-03
positive regulation of apoptotic process	9	5.5×	4e-03
intracellular signal transduction	10	4.1×	1e-02

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	33
Likely pathogenic	25
Uncertain significance	329
Likely benign	266
Benign	6

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068848	NM_006118.4(HAX1):c.235_236del (p.Phe79fs)	Pathogenic
1071627	NM_006118.4(HAX1):c.146del (p.Pro49fs)	Pathogenic
1072845	NM_006118.4(HAX1):c.349G>T (p.Glu117Ter)	Pathogenic
1339545	NM_006118.4(HAX1):c.372_373insGATA (p.Leu125fs)	Pathogenic
1366366	NM_006118.4(HAX1):c.480G>A (p.Trp160Ter)	Pathogenic
1374231	NM_006118.4(HAX1):c.214_217dup (p.Ile73fs)	Pathogenic
1395898	NM_006118.4(HAX1):c.487C>T (p.Gln163Ter)	Pathogenic
1410664	NM_006118.4(HAX1):c.166del (p.His56fs)	Pathogenic
1438742	NM_006118.4(HAX1):c.368_381del (p.Gln123fs)	Pathogenic
1453309	NM_006118.4(HAX1):c.556+1del	Pathogenic
1453573	NM_006118.4(HAX1):c.58dup (p.Arg20fs)	Pathogenic
2033309	NM_006118.4(HAX1):c.518G>A (p.Trp173Ter)	Pathogenic
2098070	NM_006118.4(HAX1):c.216_217insC (p.Ile73fs)	Pathogenic
2116504	NM_006118.4(HAX1):c.154_155dup (p.Ser53fs)	Pathogenic
2415426	NM_006118.4(HAX1):c.163C>T (p.Gln55Ter)	Pathogenic
2692108	NM_006118.4(HAX1):c.212dup (p.Gly72fs)	Pathogenic
2715418	NM_006118.4(HAX1):c.43G>T (p.Gly15Ter)	Pathogenic
2806834	NM_006118.4(HAX1):c.432del (p.Leu145fs)	Pathogenic
2821680	NM_006118.4(HAX1):c.314dup (p.Pro105_Glu106insTer)	Pathogenic
2858293	NM_006118.4(HAX1):c.16del (p.Leu6fs)	Pathogenic
2858843	NM_006118.4(HAX1):c.103_106del (p.Glu35fs)	Pathogenic
2907291	NM_006118.4(HAX1):c.505-1G>C	Pathogenic
2911290	NM_006118.4(HAX1):c.173del (p.Pro58fs)	Pathogenic
3002493	NM_006118.4(HAX1):c.11_12del (p.Leu3_Phe4insTer)	Pathogenic
3713886	NM_006118.4(HAX1):c.339_340del (p.Glu113fs)	Pathogenic
4650	NM_006118.4(HAX1):c.568C>T (p.Gln190Ter)	Pathogenic
4651	NM_006118.4(HAX1):c.130_131insA (p.Trp44Ter)	Pathogenic
4653	NM_006118.4(HAX1):c.173dup (p.Pro58_Glu59insTer)	Pathogenic
4655	NM_006118.4(HAX1):c.376_434del (p.Arg126fs)	Pathogenic
4656	NM_006118.4(HAX1):c.125dup (p.Ser43fs)	Pathogenic

SpliceAI

1152 predictions. Top by Δscore:

Variant	Effect	Δscore
1:154270177:A:AG	acceptor_gain	1.0000
1:154270177:AT:A	acceptor_gain	1.0000
1:154270178:T:G	acceptor_gain	1.0000
1:154270178:T:TA	acceptor_gain	1.0000
1:154272781:GA:G	donor_gain	1.0000
1:154272783:G:GG	donor_gain	1.0000
1:154273497:GGA:G	donor_gain	1.0000
1:154273535:G:GG	donor_gain	1.0000
1:154273846:T:G	donor_gain	1.0000
1:154274945:TGCAG:T	acceptor_loss	1.0000
1:154274947:CA:C	acceptor_loss	1.0000
1:154274948:A:AG	acceptor_gain	1.0000
1:154274948:A:AT	acceptor_loss	1.0000
1:154274948:AGTTT:A	acceptor_gain	1.0000
1:154274949:G:GT	acceptor_gain	1.0000
1:154274949:GT:G	acceptor_gain	1.0000
1:154274949:GTT:G	acceptor_gain	1.0000
1:154274949:GTTT:G	acceptor_gain	1.0000
1:154274949:GTTTG:G	acceptor_gain	1.0000
1:154275001:GGT:G	donor_loss	1.0000
1:154275002:G:GG	donor_gain	1.0000
1:154275002:G:T	donor_loss	1.0000
1:154275003:T:G	donor_loss	1.0000
1:154275149:TCCA:T	acceptor_loss	1.0000
1:154275150:CCAG:C	acceptor_loss	1.0000
1:154275151:CAGA:C	acceptor_loss	1.0000
1:154275152:A:AC	acceptor_loss	1.0000
1:154275258:GGG:G	donor_gain	1.0000
1:154275259:GGG:G	donor_gain	1.0000
1:154275388:TGTA:T	acceptor_loss	1.0000

AlphaMissense

1858 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:154275219:T:C	F208L	0.972
1:154275221:C:A	F208L	0.972
1:154275221:C:G	F208L	0.972
1:154275225:A:C	S210R	0.971
1:154275227:C:A	S210R	0.971
1:154275227:C:G	S210R	0.971
1:154275231:T:C	S212P	0.970
1:154273545:T:C	F88S	0.969
1:154273850:G:C	K131N	0.969
1:154273850:G:T	K131N	0.969
1:154273352:T:C	F24L	0.967
1:154273354:T:A	F24L	0.967
1:154273354:T:G	F24L	0.967
1:154273846:T:A	L130H	0.964
1:154275420:G:C	D231H	0.960
1:154275422:C:A	D231E	0.960
1:154275422:C:G	D231E	0.960
1:154275409:G:C	R227P	0.959
1:154273846:T:C	L130P	0.956
1:154275421:A:T	D231V	0.956
1:154273843:T:C	M129T	0.951
1:154272727:A:C	S2R	0.948
1:154272729:C:A	S2R	0.948
1:154272729:C:G	S2R	0.948
1:154274995:G:C	D184H	0.945
1:154273844:G:A	M129I	0.944
1:154273844:G:C	M129I	0.944
1:154273844:G:T	M129I	0.944
1:154273523:T:C	F81L	0.943
1:154273525:T:A	F81L	0.943

dbSNP variants (sampled 300 via entrez): RS1000023555 (1:154275093 T>G), RS1000173291 (1:154270775 T>TG), RS1000402034 (1:154275502 G>A,C), RS1001540570 (1:154275603 C>T), RS1001600867 (1:154273407 G>A,C,T), RS1001841649 (1:154272576 C>A,G,T), RS1001874105 (1:154273884 G>A), RS1003614124 (1:154271168 G>A), RS1003673560 (1:154270875 G>A), RS1003920111 (1:154271102 T>A), RS1005926694 (1:154273089 A>C,G), RS1006265217 (1:154272503 G>A,C,T), RS1006314044 (1:154272884 C>A,T), RS1007601587 (1:154272012 T>G), RS1007653291 (1:154273209 G>T)

Disease associations

OMIM: gene MIM:605998 | disease phenotypes: MIM:610738, MIM:202700, MIM:256800

GenCC curated gene-disease

Disease	Classification	Inheritance
Kostmann syndrome	Definitive	Autosomal recessive

Mondo (5): Kostmann syndrome (MONDO:0012548), severe congenital neutropenia (MONDO:0018542), hereditary sensory and autonomic neuropathy type 4 (MONDO:0009746), congenital portosystemic shunt (MONDO:0018811), neutropenia (MONDO:0001475)

Orphanet (4): Kostmann syndrome (Orphanet:99749), Severe congenital neutropenia (Orphanet:42738), Hereditary sensory and autonomic neuropathy type 4 (Orphanet:642), Congenital portosystemic shunt (Orphanet:480531)

HPO phenotypes

14 total (14 of 14 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000405	Conductive hearing impairment
HP:0000407	Sensorineural hearing impairment
HP:0001249	Intellectual disability
HP:0001250	Seizure
HP:0001263	Global developmental delay
HP:0001875	Decreased total neutrophil count
HP:0002312	Clumsiness
HP:0002495	Impaired vibratory sensation
HP:0002718	Recurrent bacterial infections
HP:0002863	Myelodysplasia
HP:0003593	Infantile onset
HP:0006721	Acute lymphoblastic leukemia
HP:0011463	Childhood onset

GWAS associations

16 associations (top):

Study	Trait	p-value
GCST004294_8	Nicotine dependence	4.000000e-06
GCST005989_3	Serum total protein levels	5.000000e-09
GCST005990_38	Non-albumin protein levels	1.000000e-12
GCST008103_125	Bipolar disorder	2.000000e-06
GCST010142_92	Fish- and plant-related diet	6.000000e-14
GCST010244_260	Triglyceride levels	1.000000e-20
GCST010696_22	Cortical thickness (min-P)	4.000000e-10
GCST010697_50	Cortical surface area (min-P)	1.000000e-12
GCST010698_81	Subcortical volume (min-P)	1.000000e-23
GCST010699_7	Brain morphology (min-P)	1.000000e-10
GCST010700_11	Cortical thickness (MOSTest)	4.000000e-13
GCST010701_73	Cortical surface area (MOSTest)	4.000000e-09
GCST010702_45	Subcortical volume (MOSTest)	4.000000e-10
GCST010703_276	Brain morphology (MOSTest)	2.000000e-15
GCST90002397_773	Mean spheric corpuscular volume	1.000000e-18
GCST90002405_82	Reticulocyte count	1.000000e-11

EFO canonical traits (5, from GWAS)

EFO ID	Trait name
EFO:0008111	diet measurement
EFO:0004530	triglyceride measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0007986	reticulocyte count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D009503	Neutropenia	C15.378.243.750.184.564; C15.378.553.546.184.564
C537592	Neutropenia, Severe Congenital, Autosomal Recessive 3 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295644 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	affects response to substance, affects expression, affects localization, increases expression	2
Tunicamycin	increases expression	2
Cyclosporine	increases expression	2
methylmercuric chloride	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects expression	1
beta-lapachone	increases expression	1
arsenite	increases reaction, affects binding	1
perfluorooctanoic acid	increases expression	1
manganese chloride	decreases expression, increases abundance	1
leptomycin B	affects localization	1
N,N,N’,N’-tetrakis(2-pyridylmethyl)ethylenediamine	increases expression	1
beta-methylcholine	affects expression	1
di-n-butylphosphoric acid	affects expression	1
benzyloxycarbonylleucyl-leucyl-leucine aldehyde	affects expression	1
perfluorooctane sulfonic acid	increases expression	1
AM 251	increases expression	1
3-(4-methylphenylsulfonyl)-2-propenenitrile	decreases expression	1
ICG 001	increases expression	1
UCF 101	decreases degradation	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	increases expression	1
Acetylcysteine	decreases expression, decreases reaction	1
Ethanol	affects cotreatment, increases abundance, increases expression	1
Carbamazepine	affects expression	1
Diethylstilbestrol	decreases expression	1
Doxorubicin	increases expression	1
Gasoline	increases abundance, increases expression, affects cotreatment	1
Gentamicins	increases reaction, increases expression	1
Ivermectin	decreases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118562	Binding	Binding affinity to HAX1 in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

5 cell lines: 3 induced pluripotent stem cell, 2 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_A4HL	HAX1W44X-iPSC	Induced pluripotent stem cell
CVCL_A4HM	HAX1corrected-iPSC#1	Induced pluripotent stem cell
CVCL_A4HN	HAX1corrected-iPSC#2	Induced pluripotent stem cell
CVCL_SQ92	HAP1 HAX1 (-) 1	Cancer cell line	Male
CVCL_SQ93	HAP1 HAX1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01859637	PHASE4	TERMINATED	Immunogenicity, Safety, and Efficacy of Zarzio®/Filgrastim HEXAL® in Patients With Severe Chronic Neutropenia
NCT00030758	PHASE4	UNKNOWN	Filgrastim or Pegfilgrastim in Preventing Neutropenia in Women Receiving Chemotherapy Following Surgery for Breast Cancer
NCT00125723	PHASE4	COMPLETED	FIRST - Study of Pegfilgrastim Administered in the First and Subsequent Cycles of Myelosuppressive Chemotherapy
NCT00194857	PHASE4	TERMINATED	Treatment of Anemia and Neutropenia in HIV/HCV Coinfected Patients Treated With Pegylated Interferon and Ribavirin
NCT00257790	PHASE4	COMPLETED	The Tobramycin Study
NCT00277160	PHASE4	COMPLETED	A Study of Primary Prophylaxis With Neulasta (Pegfilgrastim) Versus Secondary Prophylaxis After Chemotherapy in Elderly Subjects (>/= 65 Years Old) With Cancer
NCT00686543	PHASE4	COMPLETED	Oral Posaconazole in High Risk Patients With Gastrointestinal Dysfunction (Study P05115)
NCT01086878	PHASE4	COMPLETED	Safety of Cotrimoxazole in HIV- and HAART-exposed Infants
NCT01114165	PHASE4	COMPLETED	Value of the LightCycler® SeptiFast Test MGRADE for the Pathogen Detection in Neutropenic Hematological Patients
NCT01135589	PHASE4	UNKNOWN	Micafungin Prevention Study for Fungal Disease in Child Receiving Allogenic Hematopoietic Stem Cell Transplantation
NCT01571518	PHASE4	UNKNOWN	Prevention of Neutropenia After Using G-CSF With TAC Chemotherapy
NCT02621905	PHASE4	COMPLETED	Steady-State Comparative Bioavailability Study in Prophylaxis Patients of Lozanoc® 50 mg With Sporanox® 100 mg
NCT02967341	PHASE4	UNKNOWN	Blood Draw Validation for Ciprofloxacin Pharmacokinetic Research in Pediatric Cancer Patients
NCT04009941	PHASE4	COMPLETED	Efficacy and Safety of 4.5mg PEG-rhG-CSF Per Cycle in Preventing Neutropenia After Intensive Chemotherapy for Breast Cancer
NCT04904614	PHASE4	COMPLETED	Letermovir Use in Heart Transplant Recipients
NCT05626530	PHASE4	RECRUITING	Letermovir for Secondary Prophylaxis in Solid Organ Transplant Recipients
NCT06145321	PHASE4	ACTIVE_NOT_RECRUITING	Continuous Versus Bolus Administration of G-CSF in Children With Cancer
NCT00001338	PHASE3	COMPLETED	A Prospective, Randomized, Phase III Trial of FLAC (5-Fluorouracil, Leucovorin, Adriamycin, Cytoxan) Chemotherapy With GM-CSF (Granulocyte-Macrophage Colony-Stimulating Factor) Versus PIXY 321 in Advanced Breast Cancer
NCT00001646	PHASE3	COMPLETED	Voriconazole vs. Amphotericin B in the Treatment of Invasive Aspergillosis
NCT00002658	PHASE3	UNKNOWN	Combination Chemotherapy, Biological Therapy, and Bone Marrow Transplantation in Treating Patients With Acute Myeloid Leukemia
NCT00002719	PHASE3	COMPLETED	Combination Chemotherapy With or Without G-CSF in Treating Older Patients With Acute Myeloid Leukemia
NCT00003739	PHASE3	COMPLETED	Antibiotic Therapy With or Without G-CSF in Treating Children With Neutropenia and Fever Caused by Chemotherapy
NCT00020865	PHASE3	UNKNOWN	Levofloxacin Compared With Cefepime in Treating Cancer Patients With Fever and Neutropenia
NCT00035594	PHASE3	COMPLETED	Pegfilgrastim as Support to Advanced Breast Cancer Patients Receiving Chemotherapy
NCT00044486	PHASE3	COMPLETED	Prophylaxis Trial of Posaconazole Versus Standard Azole Therapy for Neutropenic Patients (Study P01899)
NCT00107081	PHASE3	TERMINATED	Low-risk Fever and Neutropenia in Children With Cancer: Safety and Efficacy of Oral Antibiotics in an Outpatient Setting
NCT00445497	PHASE3	UNKNOWN	Early Hospital Discharge or Standard Inpatient Care in Cancer Patients Receiving Antibiotics for Febrile Neutropenia
NCT00529282	PHASE3	TERMINATED	A Study of Ceftobiprole in Patients With Fever and Neutropenia.
NCT00627393	PHASE3	COMPLETED	Safety and Effectiveness of Granulocyte Transfusions in Resolving Infection in People With Neutropenia (The RING Study)
NCT00770172	PHASE3	COMPLETED	G-CSF in Preventing Neutropenia in Patients With Solid Tumors Who Are Receiving Chemotherapy
NCT00784368	PHASE3	COMPLETED	A Pharmacokinetic Study of JK1211(Itraconazole [Itrizole]) Oral Solution in Participants With Deep Mycosis and Those With Febrile Neutropenia Suspected of Fungal Infection
NCT00806351	PHASE3	TERMINATED	An Evaluation Of The Effectiveness And Safety Of Anidulafungin Compared To Caspofungin For The Treatment Of Serious Fungal Infection Due To Candida In Patients With A Dysfunctional Immune System
NCT00911170	PHASE3	COMPLETED	PAVES: Pegfilgrastim Anti-vascular Endothelial Growth Factor (VEGF) Evaluation Study
NCT01307579	PHASE3	COMPLETED	Caspofungin Versus Fluconazole in Preventing Invasive Fungal Infections (IFI) in Patients Undergoing Chemotherapy for Acute Myeloid Leukemia
NCT01371656	PHASE3	COMPLETED	Levofloxacin in Preventing Infection in Young Patients With Acute Leukemia Receiving Chemotherapy or Undergoing Stem Cell Transplantation
NCT01560195	PHASE3	UNKNOWN	A Study of Pegylated rhG-CSF as Support to Advanced Non-Small-Cell Lung Cancer (NSCLC) Patients Receiving Chemotherapy Receiving Chemotherapy
NCT01611051	PHASE3	COMPLETED	A Study Comparing Pegylated rhG-CSF and rhG-CSF as Support to Breast Cancer Patients Receiving Chemotherapy
NCT02238873	PHASE3	UNKNOWN	Pegfilgrastim on Day +3 Compared to Day +1 After Salvage Chemotherapy for Patients With Refractory or Relapsed Aggressive Lymphoma
NCT02414581	PHASE3	COMPLETED	Mouthwash With Chlorhexidine 0.12%/Ethyl Alcohol 7% Compared to Ethyl Alcohol 7%
NCT02643420	PHASE3	COMPLETED	SPI-2012 vs Pegfilgrastim in the Management of Neutropenia in Participants With Breast Cancer With Docetaxel and Cyclophosphamide (ADVANCE)