VPS45

Summary

VPS45 (vacuolar protein sorting 45 homolog, HGNC:14579) is a protein-coding gene on chromosome 1q21.2, encoding Vacuolar protein sorting-associated protein 45 (Q9NRW7). May play a role in vesicle-mediated protein trafficking from the Golgi stack through the trans-Golgi network. It is a selective cancer dependency (DepMap: 33.4% of cell lines).

Vesicle mediated protein sorting plays an important role in segregation of intracellular molecules into distinct organelles. Genetic studies in yeast have identified more than 40 vacuolar protein sorting (VPS) genes involved in vesicle transport to vacuoles. This gene is a member of the Sec1 domain family, and shows a high degree of sequence similarity to mouse, rat and yeast Vps45. The exact function of this gene is not known, but its high expression in peripheral blood mononuclear cells suggests a role in trafficking proteins, including inflammatory mediators. Multiple alternatively spliced transcript variants have been found for this gene.

Source: NCBI Gene 11311 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital neutropenia-myelofibrosis-nephromegaly syndrome (Strong, GenCC)
• GWAS associations: 11
• Clinical variants (ClinVar): 694 total — 2 pathogenic, 15 likely-pathogenic
• Phenotypes (HPO): 16
• Cancer dependency (DepMap): dependent in 33.4% of screened cell lines
• MANE Select transcript: NM_007259

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14579
Approved symbol	VPS45
Name	vacuolar protein sorting 45 homolog
Location	1q21.2
Locus type	gene with protein product
Status	Approved
Aliases	h-vps45, H1
Ensembl gene	ENSG00000136631
Ensembl biotype	protein_coding
OMIM	610035
Entrez	11311

Gene structure

Transcript identifiers

Ensembl transcripts: 52 — 28 protein_coding, 12 nonsense_mediated_decay, 6 retained_intron, 6 protein_coding_CDS_not_defined

ENST00000369128, ENST00000419023, ENST00000460366, ENST00000462852, ENST00000472756, ENST00000477558, ENST00000478999, ENST00000491789, ENST00000497638, ENST00000618148, ENST00000642919, ENST00000643611, ENST00000643970, ENST00000644510, ENST00000644526, ENST00000644704, ENST00000647278, ENST00000698523, ENST00000698527, ENST00000698528, ENST00000698529, ENST00000698530, ENST00000698531, ENST00000698532, ENST00000698533, ENST00000698534, ENST00000698578, ENST00000698579, ENST00000698580, ENST00000698581, ENST00000698582, ENST00000698583, ENST00000698584, ENST00000698585, ENST00000698586, ENST00000698587, ENST00000698588, ENST00000698589, ENST00000698590, ENST00000698591, ENST00000698592, ENST00000698593, ENST00000698594, ENST00000698595, ENST00000698596, ENST00000698597, ENST00000698598, ENST00000900000, ENST00000900003, ENST00000900005, ENST00000963397, ENST00000963398

RefSeq mRNA: 3 — MANE Select: NM_007259 NM_001279353, NM_001279354, NM_007259

CCDS: CCDS60244, CCDS86017, CCDS944

Canonical transcript exons

ENST00000644510 — 15 exons

Exon	Start	End
ENSE00001071807	150082716	150082883
ENSE00001623089	150092302	150092409
ENSE00001782010	150093527	150093648
ENSE00002303636	150091937	150092095
ENSE00003459046	150072166	150072226
ENSE00003490160	150081884	150081997
ENSE00003659227	150076916	150076984
ENSE00003672418	150081342	150081476
ENSE00003679462	150110496	150110627
ENSE00003683343	150076233	150076312
ENSE00003724155	150077669	150077779
ENSE00003743423	150077094	150077231
ENSE00003973884	150068630	150068764
ENSE00003974074	150067776	150067950
ENSE00003974080	150144709	150145329

Expression profiles

Bgee: expression breadth ubiquitous, 291 present calls, max score 95.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 20.2250 / max 502.3765, expressed in 1780 samples.

FANTOM5 promoters (5 alternative TSS)

Promoter ID	TPM avg	Samples expressed
5049	11.3815	1757
5050	8.4468	1622
5051	0.2124	86
5047	0.1288	48
5048	0.0555	16

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar cortex	UBERON:0002129	95.76	gold quality
cerebellar hemisphere	UBERON:0002245	95.76	gold quality
right hemisphere of cerebellum	UBERON:0014890	95.52	gold quality
cerebellum	UBERON:0002037	95.25	gold quality
right adrenal gland cortex	UBERON:0035827	94.21	gold quality
right adrenal gland	UBERON:0001233	94.10	gold quality
adrenal tissue	UBERON:0018303	94.05	gold quality
ganglionic eminence	UBERON:0004023	93.99	gold quality
cerebellar vermis	UBERON:0004720	93.80	gold quality
left adrenal gland	UBERON:0001234	93.57	gold quality
monocyte	CL:0000576	93.51	gold quality
left adrenal gland cortex	UBERON:0035825	93.48	gold quality
calcaneal tendon	UBERON:0003701	93.28	gold quality
tibial artery	UBERON:0007610	93.22	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.22	gold quality
adrenal cortex	UBERON:0001235	93.21	gold quality
popliteal artery	UBERON:0002250	93.21	gold quality
lower esophagus	UBERON:0013473	93.21	gold quality
mononuclear cell	CL:0000842	93.20	gold quality
ventricular zone	UBERON:0003053	93.18	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.12	gold quality
adrenal gland	UBERON:0002369	92.97	gold quality
heart left ventricle	UBERON:0002084	92.90	gold quality
leukocyte	CL:0000738	92.88	gold quality
mucosa of stomach	UBERON:0001199	92.86	gold quality
right atrium auricular region	UBERON:0006631	92.83	gold quality
cardiac ventricle	UBERON:0002082	92.82	gold quality
cortical plate	UBERON:0005343	92.78	gold quality
apex of heart	UBERON:0002098	92.74	gold quality
adenohypophysis	UBERON:0002196	92.74	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.76

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

37 targeting VPS45, 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-432-3P	100.00	67.86	705
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-1296-3P	99.72	64.04	636
HSA-MIR-7161-5P	99.68	68.92	1592
HSA-MIR-548U	99.65	67.78	1463
HSA-MIR-1290	99.59	69.90	2079
HSA-MIR-3942-3P	99.57	69.03	2854
HSA-MIR-671-5P	99.52	67.11	1277
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-4507	99.14	65.27	515
HSA-MIR-3940-5P	99.14	65.26	493
HSA-MIR-491-5P	99.13	65.98	1468
HSA-MIR-4254	99.11	65.15	1315
HSA-MIR-6889-3P	98.84	67.35	1198
HSA-MIR-760	98.81	66.65	1392
HSA-MIR-330-5P	98.73	67.63	1788
HSA-MIR-6529-3P	98.68	66.76	1020
HSA-MIR-9500	98.62	66.54	1845
HSA-MIR-1246	98.54	66.21	959
HSA-MIR-302F	98.44	69.02	1776
HSA-MIR-135A-2-3P	98.40	66.74	442
HSA-MIR-135B-3P	98.40	67.35	426
HSA-MIR-619-3P	98.38	65.58	693
HSA-MIR-499B-5P	98.35	68.39	988
HSA-MIR-5681A	97.99	67.17	1658

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 33.4% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 7)

• Data implicate hVps45 and Rabenosyn-5 in post early endosome transport, and suggest that their interaction serves as a nexus to promote bidirectional transport along the endosome-to-recycling compartment and endosome-to-Golgi axes. (PMID:19931244)
• we identified a Thr224Asn mutation in the VPS45 gene in infants from consanguineous families who suffered from life-threatening neutropenia. (PMID:23599270)
• Defective endosomal intracellular protein trafficking due to biallelic mutations in VPS45 underlies a new immunodeficiency syndrome involving impaired neutrophil function. (PMID:23738510)
• A homozygous VPS45 p.E238K mutation is associated with severe congenital neutropenia with neurological impairment. (PMID:26358756)
• The Rab-binding module of FERARI (factors for endosome recycling and Rab interactions) consists of Rab11FIP5 and rabenosyn-5, while the SNARE-interacting module comprises VPS45 and VIPAS39. (PMID:31988382)
• SPI1-induced upregulation of lncRNA SNHG6 promotes non-small cell lung cancer via miR-485-3p/VPS45 axis. (PMID:32590190)
• Mammalian VPS45 orchestrates trafficking through the endosomal system. (PMID:33512427)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	vps45	ENSDARG00000061180
mus_musculus	Vps45	ENSMUSG00000015747
rattus_norvegicus	Vps45	ENSRNOG00000021173
drosophila_melanogaster	Vps45	FBGN0261049
caenorhabditis_elegans		WBGENE00016643

Paralogs (7): STXBP2 (ENSG00000076944), SCFD1 (ENSG00000092108), STXBP3 (ENSG00000116266), STXBP1 (ENSG00000136854), VPS33A (ENSG00000139719), VPS33B (ENSG00000184056), SCFD2 (ENSG00000184178)

Protein

Protein identifiers

Vacuolar protein sorting-associated protein 45 — Q9NRW7 (reviewed: Q9NRW7)

All UniProt accessions (31): A0A1B0GXI6, A0A2R8Y7W9, A0A2R8YD95, A0A2R8YDP1, A0A2R8YE10, A0A2R8YEX8, Q9NRW7, A0A2R8YF01, A0A8V8TLU0, A0A8V8TLW3, A0A8V8TLX3, A0A8V8TLX8, A0A8V8TLZ5, A0A8V8TM00, A0A8V8TM05, A0A8V8TM10, A0A8V8TMC6, A0A8V8TMD1, A0A8V8TMF8, A0A8V8TMG3, A0A8V8TMG7, A0A8V8TMH2, A0A8V8TNB6, A0A8V8TNE7, A0A8V8TNF0, A0A8V8TNF5, A0A8V8TNG0, A0A8V8TNM6, A0A8V8TNQ5, A0A8V8TNR0, B7Z7G7

UniProt curated annotations — full annotation on UniProt →

Function. May play a role in vesicle-mediated protein trafficking from the Golgi stack through the trans-Golgi network.

Subunit / interactions. Interacts with STX6. Interacts with ZFYVE20.

Subcellular location. Golgi apparatus membrane. Endosome membrane.

Tissue specificity. Ubiquitous. Expression was highest in testis, heart and brain, intermediate in kidney, spleen, prostate, ovary, small intestine and thymus and low in lung, skeletal muscle, placenta, colon, pancreas, peripheral blood leukocytes and liver.

Disease relevance. Neutropenia, severe congenital 5, autosomal recessive (SCN5) [MIM:615285] An autosomal recessive primary immunodeficiency disorder characterized primarily by neutropenia and neutrophil dysfunction, a lack of response to G-CSF, life-threatening infections, bone marrow fibrosis, and renal extramedullary hematopoiesis. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the STXBP/unc-18/SEC1 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NRW7-1	1	yes
Q9NRW7-2	2

RefSeq proteins (3): NP_001266282, NP_001266283, NP_009190* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001619	Sec1-like	Family
IPR027482	Sec1-like_dom2	Homologous_superfamily
IPR036045	Sec1-like_sf	Homologous_superfamily
IPR043127	Sec-1-like_dom3a	Homologous_superfamily
IPR043154	Sec-1-like_dom1	Homologous_superfamily

Pfam: PF00995

UniProt features (26 total): sequence conflict 18, splice variant 3, modified residue 2, sequence variant 2, chain 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NRW7-F1	90.65	0.78

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 (2): 307, 441

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6811438	Intra-Golgi traffic
R-HSA-9754560	SARS-CoV-2 modulates autophagy
R-HSA-983231	Factors involved in megakaryocyte development and platelet production

MSigDB gene sets: 182 (showing top): GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, AP4_Q6, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, CAGCTG_AP4_Q5, AACWWCAANK_UNKNOWN, FREAC3_01, OCT1_03, HEN1_01, WTGAAAT_UNKNOWN, TCF11_01, CAIRO_HEPATOBLASTOMA_UP, KEGG_ENDOCYTOSIS, MODULE_48, ACEVEDO_LIVER_CANCER_UP

GO Biological Process (3): intracellular protein transport (GO:0006886), vesicle-mediated transport (GO:0016192), protein transport (GO:0015031)

GO Molecular Function (1): protein binding (GO:0005515)

GO Cellular Component (8): Golgi membrane (GO:0000139), Golgi apparatus (GO:0005794), synaptic vesicle (GO:0008021), endosome membrane (GO:0010008), membrane (GO:0016020), endosome (GO:0005768), endomembrane system (GO:0012505), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
Intra-Golgi and retrograde Golgi-to-ER traffic	1
SARS-CoV-2-host interactions	1
Hemostasis	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular protein localization	2
transport	2
bounding membrane of organelle	2
cytoplasm	2
endomembrane system	2
cellular anatomical structure	2
protein transport	1
intracellular transport	1
cellular process	1
establishment of protein localization	1
binding	1
Golgi apparatus	1
intracellular membrane-bounded organelle	1
exocytic vesicle	1
presynapse	1
endosome	1
cytoplasmic vesicle membrane	1
cytoplasmic vesicle	1
vacuole	1
plasma membrane	1
intracellular vesicle	1

Protein interactions and networks

STRING

1388 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
VPS45	RBSN	Q9H1K0	998
VPS45	STX16	O14662	937
VPS45	STX5	Q13190	908
VPS45	RAB5A	P20339	883
VPS45	EEA1	Q15075	857
VPS45	VPS16	Q9H269	853
VPS45	STX6	O43752	810
VPS45	VIPAS39	Q9H9C1	806
VPS45	VPS18	Q9P253	802
VPS45	TGFBRAP1	Q8WUH2	789
VPS45	VPS8	Q8N3P4	778
VPS45	VPS39	Q96JC1	777
VPS45	EHD1	Q9H4M9	746
VPS45	SCFD1	Q8WVM8	707
VPS45	VTI1B	Q9UEU0	688

IntAct

124 interactions, top by confidence:

A	B	Type	Score
RBSN	VPS45	psi-mi:“MI:0915”(physical association)	0.800
VPS45	RBSN	psi-mi:“MI:0915”(physical association)	0.800
NAPA	SNAP23	psi-mi:“MI:0914”(association)	0.780
RFX3	RFX1	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
STX6	GOSR2	psi-mi:“MI:0914”(association)	0.670
ANKRD46	ATRN	psi-mi:“MI:0914”(association)	0.640
ASPH	STXBP3	psi-mi:“MI:0914”(association)	0.640
STX12	SNAP23	psi-mi:“MI:0914”(association)	0.640
TRDN	TMEM223	psi-mi:“MI:0914”(association)	0.640
VPS45	STX16	psi-mi:“MI:0915”(physical association)	0.620
VPS45	STX16	psi-mi:“MI:0914”(association)	0.620
STX16	VPS45	psi-mi:“MI:0915”(physical association)	0.560
NIPAL3	VPS45	psi-mi:“MI:0915”(physical association)	0.560
NAPA	NBAS	psi-mi:“MI:0914”(association)	0.530
	XPO1	psi-mi:“MI:0914”(association)	0.530
VAMP5	NBAS	psi-mi:“MI:0914”(association)	0.530
SLC39A4	TMEM120B	psi-mi:“MI:0914”(association)	0.530
CHRNA4	FZD6	psi-mi:“MI:0914”(association)	0.530
ANKH	FAM234B	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
VPS45	STX16	psi-mi:“MI:0915”(physical association)	0.400
NIPAL3	VPS45	psi-mi:“MI:0915”(physical association)	0.400
HSCB	VPS45	psi-mi:“MI:0915”(physical association)	0.370
BCAR3	VPS45	psi-mi:“MI:0915”(physical association)	0.370
VPS45	CASP8	psi-mi:“MI:0915”(physical association)	0.370

BioGRID (252): RBSN (Two-hybrid), VPS45 (Affinity Capture-MS), VPS45 (Affinity Capture-MS), VPS45 (Affinity Capture-MS), VPS45 (Affinity Capture-MS), VPS45 (Affinity Capture-MS), VPS45 (Affinity Capture-MS), VPS45 (Affinity Capture-MS), DAG1 (Co-fractionation), RBSN (Co-fractionation), SCFD1 (Co-fractionation), VPS33A (Co-fractionation), VPS45 (Co-fractionation), VPS45 (Affinity Capture-MS), VPS45 (Two-hybrid)

ESM2 similar proteins: A0SXL6, A5PKR8, A7RG82, A7RR04, A8PB32, A8X9U4, A8XT37, B0VZR4, B0WXB8, B3MGZ0, B3NRK6, B4GGT6, B4HQJ2, B4JVN0, B4KML2, B4MCL6, B4MRZ9, B4P4H2, B4QEE3, B4S3A5, B6K6L6, B7PJS6, O08700, O96719, P05197, P13639, P34617, P52874, P58252, P97390, Q08BB1, Q10299, Q16WA6, Q28ZT4, Q3UJK4, Q5R8Z3, Q6NUA1, Q7K284, Q7QJW7, Q7ZXP8

Diamond homologs: O08700, O49048, P38932, P97390, Q09805, Q54GE3, Q9NRW7

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 118 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
Retrograde transport at the Trans-Golgi-Network	9	24.4×	4e-08
Intra-Golgi traffic	7	22.4×	5e-06
Intra-Golgi and retrograde Golgi-to-ER traffic	8	10.3×	5e-05
Clathrin-mediated endocytosis	8	8.4×	1e-04
Cargo recognition for clathrin-mediated endocytosis	6	7.8×	1e-03
Membrane Trafficking	13	6.0×	3e-05
Vesicle-mediated transport	13	5.6×	3e-05
RAF/MAP kinase cascade	7	5.3×	3e-03

GO biological processes:

GO term	Partners	Fold	FDR
vesicle fusion	8	44.6×	6e-09
obsolete vesicle docking	5	35.5×	5e-05
membrane fusion	6	34.7×	8e-06
intra-Golgi vesicle-mediated transport	5	24.4×	3e-04
endocytic recycling	6	14.9×	4e-04
retrograde transport, endosome to Golgi	6	11.4×	1e-03
cellular response to type II interferon	5	9.6×	9e-03
MAPK cascade	6	8.5×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	15
Uncertain significance	204
Likely benign	402
Benign	32

Top pathogenic / likely-pathogenic (17)

Variant ID	HGVS	Classification
4682508	GRCh37/hg19 1q21.1-44(chr1:143932350-249224684)x3	Pathogenic
55906	NM_007259.5(VPS45):c.671C>A (p.Thr224Asn)	Pathogenic
4063279	NM_007259.5(VPS45):c.30C>G (p.Tyr10Ter)	Likely pathogenic
4063281	NM_007259.5(VPS45):c.702del (p.Met235fs)	Likely pathogenic
4063282	NM_007259.5(VPS45):c.1420del (p.Leu474fs)	Likely pathogenic
430321	NM_007259.5(VPS45):c.1403C>T (p.Pro468Leu)	Likely pathogenic
4815523	NM_007259.5(VPS45):c.1173T>G (p.Tyr391Ter)	Likely pathogenic
4815524	NM_007259.5(VPS45):c.1257T>G (p.Tyr419Ter)	Likely pathogenic
4815525	NM_007259.5(VPS45):c.1258C>T (p.Arg420Ter)	Likely pathogenic
4815526	NM_007259.5(VPS45):c.1297C>T (p.Arg433Ter)	Likely pathogenic
4815527	NM_007259.5(VPS45):c.178C>T (p.Arg60Ter)	Likely pathogenic
4815528	NM_007259.5(VPS45):c.272del (p.Tyr91fs)	Likely pathogenic
4815529	NM_007259.5(VPS45):c.387C>G (p.Tyr129Ter)	Likely pathogenic
4815530	NM_007259.5(VPS45):c.390_403delinsG (p.Ile130fs)	Likely pathogenic
4815531	NM_007259.5(VPS45):c.769_770insTG (p.Lys257fs)	Likely pathogenic
4815533	NM_007259.5(VPS45):c.896del (p.Pro299fs)	Likely pathogenic
55907	NM_007259.5(VPS45):c.712G>A (p.Glu238Lys)	Likely pathogenic

SpliceAI

2200 predictions. Top by Δscore:

Variant	Effect	Δscore
1:150068625:TACA:T	acceptor_loss	1.0000
1:150068627:CA:C	acceptor_loss	1.0000
1:150068628:A:AG	acceptor_gain	1.0000
1:150068628:A:AT	acceptor_loss	1.0000
1:150068629:G:GC	acceptor_gain	1.0000
1:150068629:G:T	acceptor_loss	1.0000
1:150068629:GA:G	acceptor_gain	1.0000
1:150068629:GACT:G	acceptor_gain	1.0000
1:150068739:C:T	donor_gain	1.0000
1:150068761:AAAG:A	donor_loss	1.0000
1:150068766:T:G	donor_loss	1.0000
1:150072227:G:GG	donor_gain	1.0000
1:150076292:G:GT	donor_gain	1.0000
1:150076308:TTC:T	donor_gain	1.0000
1:150076309:TCA:T	donor_gain	1.0000
1:150076310:CAG:C	donor_gain	1.0000
1:150076311:AGG:A	donor_loss	1.0000
1:150076313:GT:G	donor_loss	1.0000
1:150077667:A:AG	acceptor_gain	1.0000
1:150077668:G:GC	acceptor_gain	1.0000
1:150077668:GC:G	acceptor_gain	1.0000
1:150077668:GCAA:G	acceptor_gain	1.0000
1:150077775:ACCAG:A	donor_loss	1.0000
1:150077776:CCAGG:C	donor_loss	1.0000
1:150077777:CAG:C	donor_loss	1.0000
1:150077778:AGGTA:A	donor_loss	1.0000
1:150077779:GG:G	donor_loss	1.0000
1:150077780:G:GC	donor_loss	1.0000
1:150077781:T:A	donor_loss	1.0000
1:150081340:A:AG	acceptor_gain	1.0000

AlphaMissense

3741 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:150076238:A:C	S99R	1.000
1:150076240:T:A	S99R	1.000
1:150076240:T:G	S99R	1.000
1:150076275:C:A	A111D	1.000
1:150081342:T:A	W230R	1.000
1:150081342:T:C	W230R	1.000
1:150067931:T:C	L25P	0.999
1:150067934:T:C	L26P	0.999
1:150067939:G:C	D28H	0.999
1:150067940:A:T	D28V	0.999
1:150068642:A:C	S36R	0.999
1:150068644:T:A	S36R	0.999
1:150068644:T:G	S36R	0.999
1:150068688:T:C	L51P	0.999
1:150068733:T:C	L66P	0.999
1:150072194:T:C	L86P	0.999
1:150076274:G:C	A111P	0.999
1:150076280:G:C	A113P	0.999
1:150076283:G:C	D114H	0.999
1:150076299:T:A	V119E	0.999
1:150077182:G:C	R176P	0.999
1:150077730:T:C	L213P	0.999
1:150081391:G:C	R246P	0.999
1:150081930:T:C	L290P	0.999
1:150082723:T:A	V315D	0.999
1:150082762:T:A	V328D	0.999
1:150082792:T:C	L338P	0.999
1:150110600:G:A	G533E	0.999
1:150067931:T:G	L25R	0.998
1:150068670:T:C	L45P	0.998

dbSNP variants (sampled 300 via entrez): RS1000008129 (1:150100520 G>A), RS1000165681 (1:150093034 G>T), RS1000280024 (1:150092725 T>A), RS1000389623 (1:150132452 G>A,C), RS1000532532 (1:150077908 G>A), RS1000599068 (1:150125932 C>T), RS1000711284 (1:150071250 T>C), RS1000716755 (1:150119912 C>T), RS1000747839 (1:150119643 A>G), RS1000812055 (1:150085356 T>C), RS1000837716 (1:150139526 G>T), RS1001061829 (1:150145247 A>G), RS1001164819 (1:150070802 C>T), RS1001264084 (1:150072020 C>T), RS1001341209 (1:150107222 C>T)

Disease associations

OMIM: gene MIM:610035 | disease phenotypes: MIM:615285, MIM:202700

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital neutropenia-myelofibrosis-nephromegaly syndrome	Strong	Autosomal recessive

Mondo (2): congenital neutropenia-myelofibrosis-nephromegaly syndrome (MONDO:0014118), severe congenital neutropenia (MONDO:0018542)

Orphanet (2): Congenital neutropenia-myelofibrosis-nephromegaly syndrome (Orphanet:369852), Severe congenital neutropenia (Orphanet:42738)

HPO phenotypes

16 total (16 of 16 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000105	Enlarged kidney
HP:0001263	Global developmental delay
HP:0001508	Failure to thrive
HP:0001744	Splenomegaly
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count
HP:0001882	Decreased total leukocyte count
HP:0001903	Anemia
HP:0001978	Extramedullary hematopoiesis
HP:0002028	Chronic diarrhea
HP:0002240	Hepatomegaly
HP:0002719	Recurrent infections
HP:0003593	Infantile onset
HP:0003623	Neonatal onset
HP:0010702	Increased circulating immunoglobulin concentration

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST000963_1	Uric acid levels	2.000000e-06
GCST000963_6	Uric acid levels	2.000000e-06
GCST002539_32	Schizophrenia	4.000000e-10
GCST002904_1	Obesity in adult survivors of childhood cancer not exposed to cranial radiation	5.000000e-06
GCST006803_67	Schizophrenia	7.000000e-10
GCST007257_3	Broad depression or schizophrenia	5.000000e-11
GCST008103_32	Bipolar disorder	5.000000e-08
GCST008595_14	Cognitive ability, years of educational attainment or schizophrenia (pleiotropy)	7.000000e-09
GCST009600_143	Anorexia nervosa, attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, or Tourette syndrome (pleiotropy)	2.000000e-12
GCST010002_366	Refractive error	3.000000e-15
GCST012227_1042	Hip circumference adjusted for BMI	3.000000e-10

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004761	uric acid measurement
EFO:0004337	intelligence
EFO:0004784	self reported educational attainment
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
dicrotophos	decreases expression	1
methylmercuric chloride	decreases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases methylation	1
tetrahydropalmatine	increases expression	1
sodium arsenite	increases expression	1
cobaltous chloride	decreases expression	1
benzo(e)pyrene	decreases methylation	1
beta-methylcholine	affects expression	1
CGP 52608	affects binding, increases reaction	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
pentabrominated diphenyl ether 100	decreases expression	1
hexabrominated diphenyl ether 153	decreases expression	1
Sunitinib	decreases expression	1
Leflunomide	decreases expression	1
Acetaminophen	increases expression	1
Air Pollutants	decreases expression, increases abundance	1
Air Pollutants, Occupational	decreases expression	1
Coal	decreases expression, increases abundance	1
Coumestrol	increases expression	1
Doxorubicin	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Ivermectin	decreases expression	1
Lead	decreases expression	1
Methapyrilene	decreases methylation	1
Methyl Methanesulfonate	increases expression	1
Nickel	decreases expression	1
Smoke	decreases expression, increases abundance	1
Valproic Acid	decreases methylation	1
Cyclosporine	decreases expression	1

Clinical trials (associated diseases)

15 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
NCT00301834	PHASE2	COMPLETED	Alemtuzumab, Fludarabine, and Busulfan Followed By Donor Stem Cell Transplant in Treating Young Patients With Hematologic Disorders
NCT00909584	PHASE2	TERMINATED	Study of Ezatiostat (Telintra Tablets) for Treatment of Severe Chronic Neutropenia
NCT01529827	PHASE2	COMPLETED	Fludarabine Phosphate, Melphalan, and Low-Dose Total-Body Irradiation Followed by Donor Peripheral Blood Stem Cell Transplant in Treating Patients With Hematologic Malignancies
NCT04844177	PHASE2	UNKNOWN	Total Lymphoid Irradiation Pre-HSCT in Severe Congenital Neutropenia
NCT00295971	PHASE1	COMPLETED	Donor Stem Cell Transplant in Treating Young Patients With Myelodysplastic Syndrome, Leukemia, Bone Marrow Failure Syndrome, or Severe Immunodeficiency Disease
NCT01917708	PHASE1	COMPLETED	Bone Marrow Transplant With Abatacept for Non-Malignant Diseases
NCT00176852	PHASE2/PHASE3	COMPLETED	Stem Cell Transplant for Hemoglobinopathy
NCT00305708	PHASE1/PHASE2	COMPLETED	Busulfan, Antithymocyte Globulin, and Fludarabine Followed By a Donor Stem Cell Transplant in Treating Young Patients With Blood Disorders, Bone Marrow Disorders, Chronic Myelogenous Leukemia in First Chronic Phase, or Acute Myeloid Leukemia in First Remission
NCT01852370	PHASE1/PHASE2	ENROLLING_BY_INVITATION	Sequential Cadaveric Lung and Bone Marrow Transplant for Immune Deficiency Diseases
NCT01966367	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	CD34+ (Non-Malignant) Stem Cell Selection for Patients Receiving Allogeneic Stem Cell Transplantation
NCT01319851	Not specified	TERMINATED	Alefacept and Allogeneic Hematopoietic Stem Cell Transplantation
NCT02179359	Not specified	TERMINATED	Hematopoietic Stem Cell Transplant for High Risk Hemoglobinopathies
NCT02720679	Not specified	RECRUITING	Investigation of the Genetics of Hematologic Diseases
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening