HPS1

Summary

HPS1 (HPS1 biogenesis of lysosomal organelles complex 3 subunit 1, HGNC:5163) is a protein-coding gene on chromosome 10q24.2, encoding BLOC-3 complex member HPS1 (Q92902). Component of the BLOC-3 complex, a complex that acts as a guanine exchange factor (GEF) for RAB32 and RAB38, promotes the exchange of GDP to GTP, converting them from an inactive GDP-bound form into an active GTP-bound form.

This gene encodes a protein that may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. The encoded protein is a component of three different protein complexes termed biogenesis of lysosome-related organelles complex (BLOC)-3, BLOC4, and BLOC5. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 1. Alternative splicing results in multiple transcript variants. A pseudogene related to this gene is located on chromosome 22.

Source: NCBI Gene 3257 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Hermansky-Pudlak syndrome 1 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 1,327 total — 78 pathogenic, 85 likely-pathogenic
• Phenotypes (HPO): 25
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_000195

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:5163
Approved symbol	HPS1
Name	HPS1 biogenesis of lysosomal organelles complex 3 subunit 1
Location	10q24.2
Locus type	gene with protein product
Status	Approved
Aliases	BLOC3S1
Ensembl gene	ENSG00000107521
Ensembl biotype	protein_coding
OMIM	604982
Entrez	3257

Gene structure

Transcript identifiers

Ensembl transcripts: 80 — 39 protein_coding, 19 retained_intron, 18 nonsense_mediated_decay, 4 protein_coding_CDS_not_defined

ENST00000325103, ENST00000338546, ENST00000361490, ENST00000414009, ENST00000462743, ENST00000465957, ENST00000467246, ENST00000474873, ENST00000478087, ENST00000498219, ENST00000699112, ENST00000699113, ENST00000699114, ENST00000699115, ENST00000699116, ENST00000699117, ENST00000699118, ENST00000699119, ENST00000699120, ENST00000699121, ENST00000699122, ENST00000699123, ENST00000699124, ENST00000699125, ENST00000699126, ENST00000699127, ENST00000699128, ENST00000699129, ENST00000699130, ENST00000699131, ENST00000699132, ENST00000699133, ENST00000699134, ENST00000699135, ENST00000699136, ENST00000699137, ENST00000699138, ENST00000699139, ENST00000699140, ENST00000699141, ENST00000699142, ENST00000699143, ENST00000699144, ENST00000699145, ENST00000699146, ENST00000699147, ENST00000699148, ENST00000699149, ENST00000699150, ENST00000699151, ENST00000699152, ENST00000699153, ENST00000699154, ENST00000699155, ENST00000699156, ENST00000699157, ENST00000699158, ENST00000884306, ENST00000884307, ENST00000884308, ENST00000884309, ENST00000884310, ENST00000884311, ENST00000884312, ENST00000884313, ENST00000884314, ENST00000884315, ENST00000884316, ENST00000884317, ENST00000884318, ENST00000914266, ENST00000914267, ENST00000914268, ENST00000914269, ENST00000963957, ENST00000963958, ENST00000963959, ENST00000963960, ENST00000963961, ENST00000963962

RefSeq mRNA: 18 — MANE Select: NM_000195 NM_000195, NM_001311345, NM_001322476, NM_001322477, NM_001322478, NM_001322479, NM_001322480, NM_001322481, NM_001322482, NM_001322483, NM_001322484, NM_001322485, NM_001322487, NM_001322489, NM_001322490, NM_001322491, NM_001322492, NM_182639

CCDS: CCDS7475, CCDS7476, CCDS91313, CCDS91314, CCDS91315, CCDS91316

Canonical transcript exons

ENST00000361490 — 20 exons

Exon	Start	End
ENSE00000719207	98429791	98429889
ENSE00000811219	98416198	98417726
ENSE00003536136	98435635	98435772
ENSE00003756513	98443124	98443240
ENSE00003975673	98424313	98424374
ENSE00003975674	98425818	98425985
ENSE00003975686	98422369	98422513
ENSE00003975687	98427215	98427264
ENSE00003975695	98423753	98423887
ENSE00003975700	98429573	98429642
ENSE00003975713	98433983	98434091
ENSE00003975718	98445300	98445404
ENSE00003975726	98425541	98425720
ENSE00003975736	98446807	98446935
ENSE00003975740	98431131	98431291
ENSE00003975742	98418175	98418257
ENSE00003975744	98435272	98435414
ENSE00003975751	98423603	98423668
ENSE00003975755	98430571	98430670
ENSE00003975762	98420045	98420158

Expression profiles

Bgee: expression breadth ubiquitous, 231 present calls, max score 96.22.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 30.6992 / max 236.7775, expressed in 1820 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
110971	30.2308	1820
110970	0.3273	174
110969	0.1411	44

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	96.22	gold quality
stromal cell of endometrium	CL:0002255	96.05	gold quality
small intestine Peyer’s patch	UBERON:0003454	95.72	gold quality
monocyte	CL:0000576	95.29	gold quality
transverse colon	UBERON:0001157	95.22	gold quality
endocervix	UBERON:0000458	95.18	gold quality
minor salivary gland	UBERON:0001830	95.00	gold quality
metanephros cortex	UBERON:0010533	94.81	gold quality
right adrenal gland cortex	UBERON:0035827	94.80	gold quality
right coronary artery	UBERON:0001625	94.78	gold quality
mucosa of transverse colon	UBERON:0004991	94.72	gold quality
right uterine tube	UBERON:0001302	94.71	gold quality
mucosa of stomach	UBERON:0001199	94.66	gold quality
lower esophagus muscularis layer	UBERON:0035833	94.66	gold quality
right adrenal gland	UBERON:0001233	94.65	gold quality
lower esophagus	UBERON:0013473	94.65	gold quality
mononuclear cell	CL:0000842	94.61	gold quality
left adrenal gland	UBERON:0001234	94.61	gold quality
leukocyte	CL:0000738	94.57	gold quality
left adrenal gland cortex	UBERON:0035825	94.57	gold quality
body of uterus	UBERON:0009853	94.56	gold quality
body of stomach	UBERON:0001161	94.52	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	94.43	gold quality
right lobe of thyroid gland	UBERON:0001119	94.35	gold quality
thoracic aorta	UBERON:0001515	94.30	gold quality
spleen	UBERON:0002106	94.28	gold quality
ascending aorta	UBERON:0001496	94.27	gold quality
right ovary	UBERON:0002118	94.25	gold quality
popliteal artery	UBERON:0002250	94.24	gold quality
tibial artery	UBERON:0007610	94.24	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.51
E-HCAD-10	no	2.03

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

69 targeting HPS1, 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-4673	100.00	66.64	1490
HSA-MIR-3689D	100.00	66.14	1181
HSA-MIR-6851-5P	100.00	65.63	1294
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4531	99.99	69.70	3181
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-6780B-5P	99.96	69.60	2562
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-5680	99.91	69.83	3421
HSA-LET-7A-2-3P	99.87	70.53	1921
HSA-LET-7G-3P	99.85	70.43	1929
HSA-MIR-3663-3P	99.84	70.39	798
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-4666B	99.64	68.69	1282
HSA-MIR-4276	99.56	67.66	2514
HSA-MIR-7844-5P	99.55	68.56	1428
HSA-MIR-4437	99.52	65.29	1266
HSA-MIR-3147	99.52	66.34	388
HSA-MIR-5584-5P	99.49	68.22	2814
HSA-MIR-1207-5P	99.49	69.11	2983

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 17)

• Description of mutations in HPS genes that cause Hermansky-Pudlak syndrome (review) (PMID:12125811)
• Four novel mutations were discovered and the diagnosis of HPS-1, available only on molecular grounds, has important prognostic and treatment implications. (PMID:12442288)
• identification as a component of two complexes, BLOC-3 and BLOC-4, involved in the biogenesis of lysosome-related organelles (PMID:12663659)
• observations demonstrate that the Hermansky-Pudlak syndrome 1(HPS1) and HPS4 proteins are components of a cytosolic complex that is involved in the biogenesis of lysosomal-related organelles (PMID:12756248)
• Biogenesis of lysosome-related organelles complex 3 (BLOC-3): a complex containing the Hermansky-Pudlak syndrome (HPS) proteins HPS1 and HPS4. (PMID:12847290)
• Mutations in this gene are associated with Hermansky-Pudlak syndrome type 1. (PMID:16020891)
• The first case report of a Chinese Hermansky-Pudlak syndrome patient with a novel mutation on HPS1 gene. (PMID:19665357)
• Data show that recombinant HPS1-HPS4 produced in insect cells can be efficiently isolated as a 1:1 heterodimer, and might function as a Rab9 effector in the biogenesis of lysosome-related organelles. (PMID:20048159)
• Three different mutations in the HPS1 gene were found in the two families. (PMID:20514622)
• a previously unreported missense mutation (G313S) at the 3’ splice junction of exon 10 of Hermansky-Pudlak syndrome 1 protein resulted in activation of a cryptic intronic splice site causing an aberrantly spliced HPS1 mRNA (PMID:20662851)
• Seven mutations (six previously unreported) were described in the HPS1, HPS4, and HPS5 genes among Hermansky-Pudlak Syndrome patients of Mexican, Uruguayan, Honduran, Cuban, Venezuelan, and Salvadoran ancestries. (PMID:21833017)
• BLOC-3 is a Rab32 and Rab38 guanine nucleotide exchange factor, with a specific function in the biogenesis of lysosome-related organelles. Silencing of the BLOC-3 subunits Hps1 and Hps4 results in the mislocalization of Rab32 and Rab38. (PMID:23084991)
• HPS1 mutation is associated with high hypopigmentation in Hermansky-Pudlak syndrome. (PMID:27593200)
• HPS1 Regulates the Maturation of Large Dense Core Vesicles and Lysozyme Secretion in Paneth Cells. (PMID:33224134)
• Hermansky-Pudlak syndrome: Five Chinese patients with novel variants in HPS1 and HPS6. (PMID:33878481)
• Modeling of lung phenotype of Hermansky-Pudlak syndrome type I using patient-specific iPSCs. (PMID:34736469)
• Delineating Novel and Known Pathogenic Variants in TYR, OCA2 and HPS-1 Genes in Eight Oculocutaneous Albinism (OCA) Pakistani Families. (PMID:35328057)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	hps1	ENSDARG00000026170
mus_musculus	Hps1	ENSMUSG00000025188
rattus_norvegicus	Hps1	ENSRNOG00000045838
drosophila_melanogaster	HPS1	FBGN0033973

Protein

Protein identifiers

BLOC-3 complex member HPS1 — Q92902 (reviewed: Q92902)

Alternative names: Hermansky-Pudlak syndrome 1 protein

All UniProt accessions (19): Q92902, A0A0S2Z3U9, A0A0S2Z4H4, A0A8V8TMQ9, A0A8V8TMR7, A0A8V8TMR9, A0A8V8TMS4, A0A8V8TN79, A0A8V8TN86, A0A8V8TN90, A0A8V8TN94, A0A8V8TN99, A0A8V8TP54, A0A8V8TP59, A0A8V8TP64, A0A8V8TP71, A0A8V8TPI6, A0A8V8TPJ1, H0Y4K4

UniProt curated annotations — full annotation on UniProt →

Function. Component of the BLOC-3 complex, a complex that acts as a guanine exchange factor (GEF) for RAB32 and RAB38, promotes the exchange of GDP to GTP, converting them from an inactive GDP-bound form into an active GTP-bound form. The BLOC-3 complex plays an important role in the control of melanin production and melanosome biogenesis and promotes the membrane localization of RAB32 and RAB38.

Subunit / interactions. Component of the biogenesis of lysosome-related organelles complex-3 (or BLOC-3), a heterodimer of HPS1 and HPS4. HPS1 cannot but BLOC-3 complex (heterodimer of HPS1 and HPS4) can interact with the GTP-bound form of RAB9A and RAB9B. HPS1 and BLOC-3 complex do not interact with the GDP-bound form of RAB9A and RAB9B.

Tissue specificity. Ubiquitous.

Disease relevance. Hermansky-Pudlak syndrome 1 (HPS1) [MIM:203300] A form of Hermansky-Pudlak syndrome, a genetically heterogeneous autosomal recessive disorder characterized by oculocutaneous albinism, bleeding due to platelet storage pool deficiency, and lysosomal storage defects. This syndrome results from defects of diverse cytoplasmic organelles including melanosomes, platelet dense granules and lysosomes. Ceroid storage in the lungs is associated with pulmonary fibrosis, a common cause of premature death in individuals with HPS. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (4)

UniProt ID	Names	Canonical?
Q92902-1	I	yes
Q92902-2	II
Q92902-3	III
Q92902-4	IV

RefSeq proteins (18): NP_000186, NP_001298274, NP_001309405, NP_001309406, NP_001309407, NP_001309408, NP_001309409, NP_001309410, NP_001309411, NP_001309412, NP_001309413, NP_001309414, NP_001309416, NP_001309418, NP_001309419, NP_001309420, NP_001309421, NP_872577 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026053	HPS1	Family
IPR043970	FUZ/MON1/HPS1_longin_3	Domain
IPR043971	FUZ/MON1/HPS1_longin_2	Domain
IPR043972	FUZ/MON1/HPS1_longin_1	Domain

Pfam: PF19036, PF19037, PF19038

UniProt features (23 total): sequence variant 8, repeat 4, splice variant 4, sequence conflict 2, compositionally biased region 2, chain 1, region of interest 1, short sequence motif 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
8ZWC	ELECTRON MICROSCOPY	3.19

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92902-F1	81.44	0.56

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-8876198	RAB GEFs exchange GTP for GDP on RABs

MSigDB gene sets: 229 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, TGGTGCT_MIR29A_MIR29B_MIR29C, WANG_CLIM2_TARGETS_UP, GOBP_VACUOLE_ORGANIZATION, GOBP_VESICLE_ORGANIZATION, XU_HGF_TARGETS_REPRESSED_BY_AKT1_DN, MODULE_45, MODULE_64, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GRAESSMANN_RESPONSE_TO_MC_AND_DOXORUBICIN_DN, GOBP_CELLULAR_PIGMENTATION, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, HEIDENBLAD_AMPLICON_8Q24_DN, CHANDRAN_METASTASIS_DN

GO Biological Process (5): lysosome organization (GO:0007040), visual perception (GO:0007601), vesicle-mediated transport (GO:0016192), platelet dense granule organization (GO:0060155), melanosome assembly (GO:1903232)

GO Molecular Function (3): guanyl-nucleotide exchange factor activity (GO:0005085), protein dimerization activity (GO:0046983), protein binding (GO:0005515)

GO Cellular Component (5): cytoplasm (GO:0005737), lysosome (GO:0005764), cytosol (GO:0005829), BLOC-3 complex (GO:0031085), cytoplasmic vesicle (GO:0031410)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Rab regulation of trafficking	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	2
cytoplasm	2
lytic vacuole organization	1
sensory perception of light stimulus	1
transport	1
cellular process	1
secretory granule organization	1
melanosome organization	1
organelle assembly	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
protein binding	1
binding	1
intracellular anatomical structure	1
lytic vacuole	1
BLOC complex	1
intracellular vesicle	1

Protein interactions and networks

STRING

356 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HPS1	HPS4	Q9NQG7	727
HPS1	HPS3	Q969F9	666
HPS1	HPS6	Q86YV9	561
HPS1	BLOC1S6	Q9UL45	544
HPS1	RAB38	P57729	521
HPS1	RAB32	Q13637	499
HPS1	HPD	P32754	453
HPS1	HPS5	Q9UPZ3	446
HPS1	BLOC1S3	Q6QNY0	376
HPS1	LRMDA	Q9H2I8	372
HPS1	GTF2H1	P32780	352
HPS1	ANKRD27	Q96NW4	351
HPS1	TYRP1	P17643	336
HPS1	OCA2	Q04671	324
HPS1	DTNBP1	Q96EV8	319

IntAct

30 interactions, top by confidence:

A	B	Type	Score
HPS1	HPS4	psi-mi:“MI:0407”(direct interaction)	0.810
HPS4	HPS1	psi-mi:“MI:0915”(physical association)	0.810
HPS1	HPS4	psi-mi:“MI:0915”(physical association)	0.810
RAB9A	HPS1	psi-mi:“MI:0914”(association)	0.350
P		psi-mi:“MI:0914”(association)	0.350
FUZ	UBB	psi-mi:“MI:0914”(association)	0.350
HPS1	ZBTB10	psi-mi:“MI:0914”(association)	0.350
HPS1	SLC27A2	psi-mi:“MI:0914”(association)	0.350
ARHGEF35	RFPL4A	psi-mi:“MI:0914”(association)	0.350
FUZ	PRORP	psi-mi:“MI:0914”(association)	0.350
HPS1	PLPBP	psi-mi:“MI:0914”(association)	0.350
HPS1	nhaA	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (23): SALL1 (Affinity Capture-MS), SALL2 (Affinity Capture-MS), FAM208A (Affinity Capture-MS), SLC27A2 (Affinity Capture-MS), AMBRA1 (Affinity Capture-MS), ZBTB10 (Affinity Capture-MS), SALL1 (Affinity Capture-MS), HPS1 (Affinity Capture-MS), SALL2 (Affinity Capture-MS), AMBRA1 (Affinity Capture-MS), ZBTB10 (Affinity Capture-MS), ZBTB10 (Affinity Capture-MS), HPS1 (Affinity Capture-MS), AMBRA1 (Affinity Capture-MS), SALL1 (Affinity Capture-MS)

ESM2 similar proteins: A2RT67, A2RUS2, A4IHY1, B0CM32, B0KW86, E1B8U2, E7F240, F1MDL2, O08983, O94955, O95456, P48553, Q05AX3, Q0P5F2, Q1JQA1, Q1RMZ1, Q2HJ90, Q3T0J1, Q3TLI0, Q3ZBK8, Q4KM95, Q5FVM6, Q5R4T7, Q5R989, Q5RAQ5, Q5RFG8, Q60GF7, Q6DG91, Q6VNB8, Q7Z7H3, Q80TA6, Q8BXK4, Q8CHQ0, Q8IZQ1, Q8K2I9, Q8NFZ0, Q91W96, Q92902, Q96QE5, Q99LV7

Diamond homologs: O08983, Q60HF3, Q92902

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
HPS1	“form complex”	BLOC-3	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

1327 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	78
Likely pathogenic	85
Uncertain significance	374
Likely benign	589
Benign	73

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1068594	NC_000010.10:g.(?100193687)(100203007_?)del	Pathogenic
1069099	NM_000195.5(HPS1):c.724C>T (p.Gln242Ter)	Pathogenic
1072016	NM_000195.5(HPS1):c.1090dup (p.Leu364fs)	Pathogenic
1075194	NM_000195.5(HPS1):c.619del (p.Leu207fs)	Pathogenic
1076439	NM_000195.5(HPS1):c.1887dup (p.Val630fs)	Pathogenic
1341377	NM_000195.5(HPS1):c.1507C>T (p.Gln503Ter)	Pathogenic
1341378	NM_000195.5(HPS1):c.1375del (p.Ser459fs)	Pathogenic
1341379	NM_000195.5(HPS1):c.1315C>T (p.Arg439Ter)	Pathogenic
1341381	NM_000195.5(HPS1):c.928C>T (p.Gln310Ter)	Pathogenic
1351968	NM_000195.5(HPS1):c.1666dup (p.Ala556fs)	Pathogenic
1354870	NM_000195.5(HPS1):c.846dup (p.Gly283fs)	Pathogenic
1379049	NM_000195.5(HPS1):c.921del (p.Gly308fs)	Pathogenic
1410590	NM_000195.5(HPS1):c.214_217del (p.Phe72fs)	Pathogenic
1448353	NM_000195.5(HPS1):c.1870C>T (p.Gln624Ter)	Pathogenic
1456679	NM_000195.5(HPS1):c.1209del (p.Met404fs)	Pathogenic
1457207	NC_000010.10:g.(?100202871)(100203007_?)del	Pathogenic
1460353	NC_000010.10:g.(?100177321)(100185762_?)del	Pathogenic
1684357	NM_000195.5(HPS1):c.610G>T (p.Glu204Ter)	Pathogenic
191013	NM_000195.5(HPS1):c.1395G>A (p.Trp465Ter)	Pathogenic
1917905	NM_000195.5(HPS1):c.898_925del (p.Tyr300fs)	Pathogenic
1976830	NM_000195.5(HPS1):c.1324C>T (p.Gln442Ter)	Pathogenic
2028842	NM_000195.5(HPS1):c.871del (p.Thr291fs)	Pathogenic
2045009	NM_000195.5(HPS1):c.462G>A (p.Trp154Ter)	Pathogenic
2059821	NM_000195.5(HPS1):c.1277dup (p.Asp427fs)	Pathogenic
2094297	NM_000195.5(HPS1):c.25G>T (p.Glu9Ter)	Pathogenic
2100467	NM_000195.5(HPS1):c.1842G>A (p.Trp614Ter)	Pathogenic
21103	NM_000195.5(HPS1):c.355del (p.His119fs)	Pathogenic
21104	NM_000195.5(HPS1):c.391C>T (p.Arg131Ter)	Pathogenic
2123792	NM_000195.5(HPS1):c.175_179dup (p.Thr60_Met61insTer)	Pathogenic
2134957	NM_000195.5(HPS1):c.828_829insGGGAGGCAGAAGGGGTGGAGGGAGCCAGGTCAGATAGGAGCTAACCAGC (p.His277fs)	Pathogenic

SpliceAI

3603 predictions. Top by Δscore:

Variant	Effect	Δscore
10:98417723:CTTC:C	acceptor_gain	1.0000
10:98417727:C:CC	acceptor_gain	1.0000
10:98418125:ATCAC:A	donor_gain	1.0000
10:98418255:CCC:C	acceptor_gain	1.0000
10:98418256:CCC:C	acceptor_gain	1.0000
10:98420042:TA:T	donor_loss	1.0000
10:98420043:A:AC	donor_gain	1.0000
10:98420044:C:CC	donor_gain	1.0000
10:98420154:CAGAC:C	acceptor_gain	1.0000
10:98420155:AGAC:A	acceptor_gain	1.0000
10:98420156:GAC:G	acceptor_gain	1.0000
10:98420159:C:CC	acceptor_gain	1.0000
10:98420159:CTGG:C	acceptor_loss	1.0000
10:98420160:T:C	acceptor_loss	1.0000
10:98423511:C:A	donor_gain	1.0000
10:98423527:C:A	donor_gain	1.0000
10:98423530:T:TA	donor_gain	1.0000
10:98423749:TTACC:T	donor_loss	1.0000
10:98423750:TACCG:T	donor_loss	1.0000
10:98423751:A:AC	donor_gain	1.0000
10:98423751:AC:A	donor_gain	1.0000
10:98423751:ACCG:A	donor_gain	1.0000
10:98423752:C:CC	donor_gain	1.0000
10:98423752:CC:C	donor_gain	1.0000
10:98423752:CCG:C	donor_gain	1.0000
10:98423752:CCGC:C	donor_gain	1.0000
10:98423752:CCGCA:C	donor_gain	1.0000
10:98423883:GCAGC:G	acceptor_gain	1.0000
10:98423884:CAGC:C	acceptor_gain	1.0000
10:98423884:CAGCC:C	acceptor_gain	1.0000

AlphaMissense

4543 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
10:98424368:A:G	W448R	0.995
10:98424368:A:T	W448R	0.995
10:98417667:A:G	L667P	0.994
10:98423629:C:A	K524N	0.994
10:98423629:C:G	K524N	0.994
10:98422467:G:T	R549S	0.993
10:98423641:G:C	F520L	0.992
10:98423641:G:T	F520L	0.992
10:98423643:A:G	F520L	0.992
10:98422466:C:G	R549P	0.991
10:98424354:C:A	K452N	0.991
10:98424354:C:G	K452N	0.991
10:98424358:A:G	F451S	0.990
10:98435308:C:T	G121E	0.989
10:98431239:A:G	L187P	0.988
10:98420064:A:G	L613P	0.987
10:98425683:A:G	L398P	0.986
10:98425917:G:C	F352L	0.986
10:98425917:G:T	F352L	0.986
10:98425919:A:G	F352L	0.986
10:98435309:C:A	G121W	0.986
10:98423852:A:G	L478P	0.985
10:98417721:A:G	L649P	0.984
10:98420124:A:G	L593P	0.984
10:98423660:A:G	L514P	0.983
10:98431173:G:T	A209D	0.983
10:98425918:A:G	F352S	0.982
10:98431143:G:T	A219E	0.982
10:98431174:C:G	A209P	0.982
10:98430638:A:G	L234P	0.981

dbSNP variants (sampled 300 via entrez): RS1000131177 (10:98414165 C>T), RS1000162143 (10:98413985 G>A), RS1000198878 (10:98442689 G>A,T), RS1000244712 (10:98419075 C>T), RS1000249334 (10:98448163 A>T), RS1000279586 (10:98441927 T>C), RS1000353848 (10:98447642 C>G), RS1000636425 (10:98430413 C>T), RS1000681206 (10:98437738 A>G,T), RS1000879954 (10:98443274 C>G,T), RS1001067154 (10:98422043 G>A,T), RS1001097787 (10:98418887 G>A), RS1001164471 (10:98435904 G>A,T), RS1001306395 (10:98447008 G>A,C), RS1001318610 (10:98427708 C>G)

Disease associations

OMIM: gene MIM:604982 | disease phenotypes: MIM:203300

GenCC curated gene-disease

Disease	Classification	Inheritance
Hermansky-Pudlak syndrome 1	Definitive	Autosomal recessive
Hermansky-Pudlak syndrome with pulmonary fibrosis	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Hermansky-Pudlak syndrome 1	Definitive	AR

Mondo (3): Hermansky-Pudlak syndrome 1 (MONDO:0008748), Hermansky-Pudlak syndrome (MONDO:0019312), Hermansky-Pudlak syndrome with pulmonary fibrosis (MONDO:0016501)

Orphanet (2): Hermansky-Pudlak syndrome due to BLOC-3 deficiency (Orphanet:231500), Hermansky-Pudlak syndrome (Orphanet:79430)

HPO phenotypes

25 total (25 of 25 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000083	Renal insufficiency
HP:0000225	Gingival bleeding
HP:0000421	Epistaxis
HP:0000613	Photophobia
HP:0000618	Blindness
HP:0000639	Nystagmus
HP:0000978	Bruising susceptibility
HP:0000995	Melanocytic nevus
HP:0001010	Hypopigmentation of the skin
HP:0001022	Albinism
HP:0001107	Ocular albinism
HP:0001141	Severely reduced visual acuity
HP:0001480	Freckling
HP:0001638	Cardiomyopathy
HP:0002027	Abdominal pain
HP:0002037	Inflammation of the large intestine
HP:0002091	Restrictive ventilatory defect
HP:0002206	Pulmonary fibrosis
HP:0002573	Hematochezia
HP:0002583	Colitis
HP:0003010	Prolonged bleeding time
HP:0005599	Hypopigmentation of hair
HP:0007603	Freckles in sun-exposed areas
HP:0031364	Ecchymosis

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001762_344	Obesity-related traits	4.000000e-07
GCST008524_16	Bitter non-alcoholic beverage consumption	2.000000e-06
GCST009391_1902	Metabolite levels	4.000000e-33

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0005116	urinary metabolite measurement
EFO:0010093	bitter non-alcoholic beverage consumption measurement
EFO:0010463	asymmetric dimethylarginine measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D022861	Hermanski-Pudlak Syndrome	C11.270.040.545.400; C15.378.100.100.515; C15.378.100.685.400; C15.378.140.735.400; C15.378.463.735.400; C16.320.099.515; C16.320.290.040.100.400; C16.320.565.100.102.100.400; C16.320.850.080.100.400; C17.800.621.440.102.100.400; C17.800.827.080.100.400; C18.452.648.100.102.100.400
C538539	Albinism with hemorrhagic diathesis and pigmented reticuloendothelial cells (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1061115	HPS1	3	0.00	1	methylphenidate

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, increases methylation	4
entinostat	increases expression, affects cotreatment	2
Panobinostat	affects cotreatment, increases expression	2
Benzo(a)pyrene	affects methylation, increases methylation	2
Nickel	increases expression	2
Phenylmercuric Acetate	affects cotreatment, increases expression	2
aristolochic acid I	increases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
bisphenol A	affects cotreatment, decreases expression	1
beta-lapachone	decreases expression	1
sodium arsenite	increases expression	1
aflatoxin B2	decreases methylation	1
perfluorooctane sulfonic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
jinfukang	increases expression	1
Decitabine	affects expression	1
Air Pollutants	affects expression, increases abundance	1
Dexamethasone	affects cotreatment, decreases expression	1
Diethylstilbestrol	decreases expression	1
Diuron	decreases expression	1
Doxorubicin	decreases expression	1
Indomethacin	decreases expression, affects cotreatment	1
Methyl Methanesulfonate	increases expression	1
Ozone	affects expression, increases abundance	1
Smoke	decreases expression	1
1-Methyl-3-isobutylxanthine	affects cotreatment, decreases expression	1

Cellosaurus cell lines

11 cell lines: 3 transformed cell line, 3 spontaneously immortalized cell line, 3 cancer cell line, 1 finite cell line, 1 induced pluripotent stem cell

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

Cellosaurus	Name	Category	Sex
CVCL_0R43	GM13958	Transformed cell line	Female
CVCL_0R44	GM14606	Transformed cell line	Female
CVCL_0R45	GM14609	Finite cell line	Female
CVCL_DQ88	CHOPHPS1	Induced pluripotent stem cell	Female
CVCL_E7FW	HPM clone #3	Spontaneously immortalized cell line	Male
CVCL_E7FX	HPM clone #4	Spontaneously immortalized cell line	Male
CVCL_E7FY	HPM clone #4-HPS1	Spontaneously immortalized cell line	Male
CVCL_N198	GM12928	Transformed cell line	Female
CVCL_SR64	HAP1 HPS1 (-) 1	Cancer cell line	Male
CVCL_XP60	HAP1 HPS1 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04193592	PHASE2	UNKNOWN	Efficacy and Safety of Pirfenidone Treatment in HPS-ILD
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT00467831	PHASE1/PHASE2	TERMINATED	Pilot Study of a Multi-Drug Regimen for Severe Pulmonary Fibrosis in Hermansky-Pudlak Syndrome
NCT00001456	Not specified	RECRUITING	Clinical and Basic Investigations Into Hermansky-Pudlak Syndrome
NCT00084305	Not specified	ACTIVE_NOT_RECRUITING	Analysis of Specimens From Individuals With Pulmonary Fibrosis
NCT01417520	Not specified	COMPLETED	Clinical and Pathophysiological Investigations Into Erdheim Chester Disease
NCT02368340	Not specified	COMPLETED	A Longitudinal Study of Hermansky-Pudlak Syndrome Pulmonary Fibrosis