HPS4

Summary

HPS4 (HPS4 biogenesis of lysosomal organelles complex 3 subunit 2, HGNC:15844) is a protein-coding gene on chromosome 22q12.1, encoding BLOC-3 complex member HPS4 (Q9NQG7). 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 component of biogenesis of lysosome-related organelles complexes (BLOC). BLOC complexes are important for the formation of endosomal-lysosomal organelles such as melanosomes and platelet dense granules. Mutations in this gene result in subtype 4 of Hermansky-Pudlak syndrome, a form of albinism. Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 89781 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Hermansky-Pudlak syndrome 4 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 946 total — 37 pathogenic, 47 likely-pathogenic
• Phenotypes (HPO): 13
• MANE Select transcript: NM_022081

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:15844
Approved symbol	HPS4
Name	HPS4 biogenesis of lysosomal organelles complex 3 subunit 2
Location	22q12.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA1667, LE, BLOC3S2
Ensembl gene	ENSG00000100099
Ensembl biotype	protein_coding
OMIM	606682
Entrez	89781

Gene structure

Transcript identifiers

Ensembl transcripts: 58 — 21 protein_coding, 18 retained_intron, 14 nonsense_mediated_decay, 5 protein_coding_CDS_not_defined

ENST00000336873, ENST00000398145, ENST00000402105, ENST00000422379, ENST00000429411, ENST00000439453, ENST00000459918, ENST00000464362, ENST00000466781, ENST00000473782, ENST00000479064, ENST00000481910, ENST00000483631, ENST00000485842, ENST00000491142, ENST00000496385, ENST00000519774, ENST00000699226, ENST00000699227, ENST00000699228, ENST00000699229, ENST00000699230, ENST00000699231, ENST00000699232, ENST00000699233, ENST00000699234, ENST00000699235, ENST00000699236, ENST00000699237, ENST00000699238, ENST00000699239, ENST00000699240, ENST00000699241, ENST00000699242, ENST00000699243, ENST00000699244, ENST00000699245, ENST00000699246, ENST00000699247, ENST00000699248, ENST00000699249, ENST00000699250, ENST00000699251, ENST00000699252, ENST00000699253, ENST00000699254, ENST00000699255, ENST00000699256, ENST00000699257, ENST00000885018, ENST00000885019, ENST00000885020, ENST00000885021, ENST00000885022, ENST00000940090, ENST00000940091, ENST00000940092, ENST00000960275

RefSeq mRNA: 12 — MANE Select: NM_022081 NM_001349896, NM_001349898, NM_001349899, NM_001349900, NM_001349901, NM_001349902, NM_001349903, NM_001349904, NM_001349905, NM_001410832, NM_022081, NM_152841

CCDS: CCDS13835, CCDS46677, CCDS93138, CCDS93139, CCDS93140

Canonical transcript exons

ENST00000398145 — 14 exons

Exon	Start	End
ENSE00001350699	26450882	26453404
ENSE00001822683	26483674	26483783
ENSE00003495536	26476993	26477136
ENSE00003542101	26457859	26457967
ENSE00003575833	26463917	26464826
ENSE00003581679	26468551	26468623
ENSE00003582763	26481722	26482240
ENSE00003582813	26472302	26472418
ENSE00003635101	26479265	26479355
ENSE00003651175	26458445	26458577
ENSE00003658319	26472832	26472939
ENSE00003685053	26470719	26470813
ENSE00003976023	26465455	26465551
ENSE00003976061	26466226	26466262

Expression profiles

Bgee: expression breadth ubiquitous, 261 present calls, max score 94.09.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 14.5571 / max 1468.3034, expressed in 1804 samples.

FANTOM5 promoters (23 alternative TSS)

Promoter ID	TPM avg	Samples expressed
193422	8.8371	1776
193421	1.5455	737
193423	1.4664	933
193404	0.5579	50
193418	0.4540	156
193406	0.2538	38
193420	0.2242	94
193419	0.1992	90
193403	0.1287	13
193408	0.1252	51

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar hemisphere	UBERON:0002245	94.09	gold quality
right hemisphere of cerebellum	UBERON:0014890	94.03	gold quality
cerebellar cortex	UBERON:0002129	93.94	gold quality
cerebellum	UBERON:0002037	92.57	gold quality
skin of leg	UBERON:0001511	92.22	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	92.18	gold quality
sural nerve	UBERON:0015488	92.18	gold quality
skin of abdomen	UBERON:0001416	91.42	gold quality
right testis	UBERON:0004534	90.70	gold quality
left testis	UBERON:0004533	90.58	gold quality
right uterine tube	UBERON:0001302	90.28	gold quality
adenohypophysis	UBERON:0002196	89.83	gold quality
testis	UBERON:0000473	89.75	gold quality
body of pancreas	UBERON:0001150	89.34	gold quality
zone of skin	UBERON:0000014	89.26	gold quality
pituitary gland	UBERON:0000007	89.01	gold quality
left ovary	UBERON:0002119	88.25	gold quality
mucosa of stomach	UBERON:0001199	88.12	gold quality
metanephros cortex	UBERON:0010533	87.98	gold quality
ganglionic eminence	UBERON:0004023	87.75	gold quality
tibia	UBERON:0000979	87.70	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	87.60	gold quality
pancreas	UBERON:0001264	87.55	gold quality
right frontal lobe	UBERON:0002810	87.49	gold quality
right ovary	UBERON:0002118	87.41	gold quality
left lobe of thyroid gland	UBERON:0001120	87.30	gold quality
cortical plate	UBERON:0005343	87.22	gold quality
right lobe of thyroid gland	UBERON:0001119	87.17	gold quality
lower esophagus mucosa	UBERON:0035834	87.13	gold quality
ovary	UBERON:0000992	86.99	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-HCAD-4	yes	45.85
E-HCAD-6	yes	42.12
E-ANND-3	yes	7.73

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ELF1, ERF, GTF2I

miRNA regulators (miRDB)

54 targeting HPS4, 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-8485	100.00	77.57	4731
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-12118	100.00	65.88	1270
HSA-MIR-4713-3P	100.00	65.92	505
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4283	100.00	66.42	2097
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-3173-3P	99.98	66.49	1217
HSA-MIR-6891-5P	99.98	66.53	1372
HSA-MIR-6508-5P	99.92	70.67	2465
HSA-MIR-329-3P	99.91	66.56	1234
HSA-MIR-362-3P	99.91	66.38	1267
HSA-MIR-8067	99.86	69.59	2260
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-6079	99.84	68.54	1170
HSA-MIR-4420	99.82	70.08	1624
HSA-MIR-181B-2-3P	99.81	70.06	1646
HSA-MIR-181B-3P	99.81	70.06	1646
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-378G	99.71	64.90	1106
HSA-MIR-9851-3P	99.63	69.68	1110
HSA-MIR-5003-5P	99.61	69.13	1624
HSA-MIR-18A-3P	99.56	65.68	1092
HSA-MIR-671-5P	99.52	67.11	1277
HSA-MIR-582-5P	99.47	70.79	2635
HSA-MIR-593-5P	99.34	69.50	965

Literature-anchored findings (GeneRIF, showing 10)

• identification of mutations which establish HPS4 as important in Herman-Pudlak syndrome, and identification of mouse homolog light-ear gene (PMID:11836498)
• identification as a component of two complexes, BLOC-3 and BLOC-4, involved in the biogenesis of lysosome-related organelles (PMID:12663659)
• Hermansky-Pudlak syndrome type 4 (HPS-4) patients exhibited iris transillumination, variable hair and skin pigmentation, absent platelet dense bodies, and occasional pulmonary fibrosis and granulomatous colitis. (PMID:12664304)
• 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)
• HPS4 but not HPS3 associates with HPS1 in a complex, which we term biogenesis of lysosome-related organelles complex 3 (BLOC-3) (PMID:12847290)
• 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)
• 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)
• These results suggest that the HPS4 gene confers a susceptibility to schizophrenia. (PMID:23563589)
• These findings suggested the involvement of HPS4 in the working memory of healthy subjects and in the executive function deficits in schizophrenia. (PMID:24168225)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	hps4	ENSDARG00000013795
mus_musculus	Hps4	ENSMUSG00000042328
rattus_norvegicus	Hps4	ENSRNOG00000000661
drosophila_melanogaster	HPS4	FBGN0034261

Protein

Protein identifiers

BLOC-3 complex member HPS4 — Q9NQG7 (reviewed: Q9NQG7)

Alternative names: Hermansky-Pudlak syndrome 4 protein, Light-ear protein homolog

All UniProt accessions (16): Q9NQG7, A0A8V8TMW9, A0A8V8TMY3, A0A8V8TMZ0, A0A8V8TN01, A0A8V8TN06, A0A8V8TNE4, A0A8V8TNF3, A0A8V8TPB3, A0A8V8TPB5, A0A8V8TPP5, A0A8V8TPP9, E5RG08, F1LLU8, F8VYA9, F8WC53

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. HPS4 and the BLOC-3 complex interact with the GTP-bound form of RAB9A and RAB9B but not with the GDP-bound form of RAB9A and RAB9B. The BLOC-3 complex does not interact with RAB5A, RAB7A and RAB27A.

Disease relevance. Hermansky-Pudlak syndrome 4 (HPS4) [MIM:614073] 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?
Q9NQG7-1	1	yes
Q9NQG7-2	2
Q9NQG7-3	3
Q9NQG7-4	4

RefSeq proteins (12): NP_001336825, NP_001336827, NP_001336828, NP_001336829, NP_001336830, NP_001336831, NP_001336832, NP_001336833, NP_001336834, NP_001397761, NP_071364, NP_690054 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR026091	HPS4	Family
IPR043987	CCZ1/INTU/HSP4_longin_1	Domain
IPR043989	CCZ1/INTU/HSP4_longin_3	Domain

Pfam: PF19031, PF19033

UniProt features (16 total): sequence variant 5, splice variant 4, region of interest 2, sequence conflict 2, chain 1, compositionally biased region 1, modified residue 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-Q9NQG7-F1	62.83	0.31

Functional residue map

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

Post-translational modifications (1): 355

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: 215 (showing top): WANG_CLIM2_TARGETS_UP, GOBP_VACUOLE_ORGANIZATION, GOCC_VACUOLAR_MEMBRANE, GOCC_SECRETORY_GRANULE, GOBP_VESICLE_ORGANIZATION, GOBP_PROTEIN_TARGETING, GOBP_CELLULAR_PIGMENTATION, GOBP_VESICLE_MEDIATED_TRANSPORT, REACTOME_MEMBRANE_TRAFFICKING, GOBP_ESTABLISHMENT_OF_PROTEIN_LOCALIZATION_TO_ORGANELLE, GOMF_GTPASE_BINDING, PATIL_LIVER_CANCER, GOBP_PIGMENTATION, GOBP_WOUND_HEALING, GOBP_SECRETORY_GRANULE_ORGANIZATION

GO Biological Process (11): protein targeting (GO:0006605), lysosome organization (GO:0007040), blood coagulation (GO:0007596), hemostasis (GO:0007599), vesicle-mediated transport (GO:0016192), melanocyte differentiation (GO:0030318), positive regulation of eye pigmentation (GO:0048075), protein stabilization (GO:0050821), platelet dense granule organization (GO:0060155), melanosome assembly (GO:1903232), obsolete positive regulation of protein targeting to mitochondrion (GO:1903955)

GO Molecular Function (5): guanyl-nucleotide exchange factor activity (GO:0005085), small GTPase binding (GO:0031267), protein homodimerization activity (GO:0042803), protein dimerization activity (GO:0046983), protein binding (GO:0005515)

GO Cellular Component (9): cytoplasm (GO:0005737), lysosome (GO:0005764), lysosomal membrane (GO:0005765), cytosol (GO:0005829), membrane (GO:0016020), BLOC-3 complex (GO:0031085), cytoplasmic vesicle (GO:0031410), melanosome (GO:0042470), platelet dense granule (GO:0042827)

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	3
cytoplasm	2
establishment of protein localization	1
lytic vacuole organization	1
hemostasis	1
wound healing	1
coagulation	1
regulation of body fluid levels	1
transport	1
cellular process	1
pigment cell differentiation	1
eye pigmentation	1
regulation of eye pigmentation	1
positive regulation of developmental pigmentation	1
regulation of protein stability	1
secretory granule organization	1
melanosome organization	1
organelle assembly	1
GTP binding	1
GDP binding	1
GTPase regulator activity	1
GTPase binding	1
identical protein binding	1
protein dimerization activity	1
protein binding	1
binding	1
intracellular anatomical structure	1
lytic vacuole	1
lysosome	1
lytic vacuole membrane	1
BLOC complex	1
intracellular vesicle	1
pigment granule	1
secretory granule	1

Protein interactions and networks

STRING

588 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HPS4	HPS3	Q969F9	989
HPS4	HPS6	Q86YV9	985
HPS4	HPS5	Q9UPZ3	974
HPS4	AP3B1	O00203	934
HPS4	BLOC1S3	Q6QNY0	921
HPS4	DTNBP1	Q96EV8	903
HPS4	BLOC1S6	Q9UL45	877
HPS4	SP4	Q02446	763
HPS4	HPS1	Q92902	727
HPS4	TYRP1	P17643	662
HPS4	RAB38	P57729	629
HPS4	RAB32	Q13637	627
HPS4	CCZ1B	P86790	609
HPS4	LRMDA	Q9H2I8	581
HPS4	LYST	Q99698	570

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
HPS4	RAB9A	psi-mi:“MI:0915”(physical association)	0.480
HPS4	HPS4	psi-mi:“MI:0407”(direct interaction)	0.440
HPS4	RAB9B	psi-mi:“MI:0915”(physical association)	0.370
RAB9A	HPS1	psi-mi:“MI:0914”(association)	0.350
ARHGEF35	RFPL4A	psi-mi:“MI:0914”(association)	0.350
RAB32	HPS4	psi-mi:“MI:0403”(colocalization)	0.270
DISC1	HPS4	psi-mi:“MI:0915”(physical association)	0.000
RAC1	HPS4	psi-mi:“MI:0915”(physical association)	0.000
DSCR9	HPS4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (5): HPS4 (Affinity Capture-MS), HPS4 (Proximity Label-MS), HPS4 (Two-hybrid), HPS4 (Affinity Capture-RNA), HPS4 (Two-hybrid)

ESM2 similar proteins: A0JPH4, A2AGX3, A2RRU4, A3KFU9, A6QM06, A7YWH3, B9U3F2, G5E8P0, O15040, O75129, P97260, Q12770, Q17RG1, Q2M3C6, Q2R2B1, Q32KQ7, Q4R5A4, Q562E2, Q5M9F0, Q5MNU5, Q5RA50, Q5SYB0, Q6GQT6, Q6L8S8, Q6L9W6, Q6PCP7, Q80TL0, Q80Z10, Q80Z30, Q86V42, Q8BHR8, Q8BZB3, Q8C0R7, Q8CIV2, Q8JZL1, Q8K0Z9, Q8K451, Q8NFM7, Q8NFN8, Q8VZJ0

Diamond homologs: Q99KG7, Q9NQG7

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
HPS4	“form complex”	BLOC-3	binding
TFEB	“up-regulates quantity by expression”	HPS4	“transcriptional regulation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	37
Likely pathogenic	47
Uncertain significance	312
Likely benign	426
Benign	47

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1323066	NM_022081.6(HPS4):c.1152del (p.Gly385fs)	Pathogenic
1436016	NM_022081.6(HPS4):c.1387del (p.Arg463fs)	Pathogenic
1451621	NM_022081.6(HPS4):c.1818_1819insC (p.Tyr607fs)	Pathogenic
2072993	NM_022081.6(HPS4):c.451del (p.Ser151fs)	Pathogenic
2088207	NM_022081.6(HPS4):c.793C>T (p.Gln265Ter)	Pathogenic
2426711	NC_000022.10:g.(?26859863)(26864609_?)del	Pathogenic
2699462	NM_022081.6(HPS4):c.117C>G (p.Tyr39Ter)	Pathogenic
2708500	NM_022081.6(HPS4):c.1818_1825dup (p.Arg609fs)	Pathogenic
2725299	NM_022081.6(HPS4):c.839C>G (p.Ser280Ter)	Pathogenic
2746365	NM_022081.6(HPS4):c.1187del (p.Asp396fs)	Pathogenic
2759359	NM_022081.6(HPS4):c.1529C>G (p.Ser510Ter)	Pathogenic
2799506	NM_022081.6(HPS4):c.1217_1218del (p.Leu406fs)	Pathogenic
2826538	NM_022081.6(HPS4):c.145C>T (p.Gln49Ter)	Pathogenic
2839862	NM_022081.6(HPS4):c.829C>T (p.Gln277Ter)	Pathogenic
2861392	NM_022081.6(HPS4):c.49del (p.Tyr17fs)	Pathogenic
2867045	NM_022081.6(HPS4):c.1903dup (p.Leu635fs)	Pathogenic
3241757	NM_022081.6(HPS4):c.45G>A (p.Trp15Ter)	Pathogenic
3248136	NC_000022.10:g.(?26853805)(26854563_?)del	Pathogenic
3248137	NC_000022.10:g.(?26864497)(26873122_?)del	Pathogenic
3613725	NM_022081.6(HPS4):c.667C>T (p.Gln223Ter)	Pathogenic
3615051	NM_022081.6(HPS4):c.417G>A (p.Trp139Ter)	Pathogenic
3640336	NM_022081.6(HPS4):c.1368del (p.Arg457fs)	Pathogenic
3645167	NM_022081.6(HPS4):c.1184del (p.Pro395fs)	Pathogenic
3649593	NM_022081.6(HPS4):c.2016del (p.Gln672fs)	Pathogenic
4073703	NM_022081.6(HPS4):c.1739del (p.Asn580fs)	Pathogenic
4073704	NM_022081.6(HPS4):c.133-570_502-34del	Pathogenic
4077105	NM_022081.6(HPS4):c.1693_1694del (p.Ser565fs)	Pathogenic
4125	NM_022081.6(HPS4):c.1891C>T (p.Gln631Ter)	Pathogenic
4126	NM_022081.6(HPS4):c.2089_2093dup (p.Lys699fs)	Pathogenic
4127	NM_022081.6(HPS4):c.57del (p.Leu20fs)	Pathogenic

SpliceAI

2477 predictions. Top by Δscore:

Variant	Effect	Δscore
22:26453220:T:TA	donor_gain	1.0000
22:26457972:C:CT	acceptor_gain	1.0000
22:26457972:C:T	acceptor_gain	1.0000
22:26457973:A:T	acceptor_gain	1.0000
22:26457984:C:CT	acceptor_gain	1.0000
22:26458439:TCTTA:T	donor_loss	1.0000
22:26458440:CTTA:C	donor_loss	1.0000
22:26458441:TTA:T	donor_loss	1.0000
22:26458442:TA:T	donor_loss	1.0000
22:26458443:A:AC	donor_gain	1.0000
22:26458443:AC:A	donor_gain	1.0000
22:26458444:C:CC	donor_gain	1.0000
22:26458444:CC:C	donor_gain	1.0000
22:26458444:CCCAT:C	donor_gain	1.0000
22:26458573:TGGTA:T	acceptor_gain	1.0000
22:26458574:GGTA:G	acceptor_gain	1.0000
22:26458576:TA:T	acceptor_gain	1.0000
22:26458578:C:CC	acceptor_gain	1.0000
22:26463916:CCA:C	donor_gain	1.0000
22:26463921:T:TA	donor_gain	1.0000
22:26464827:C:CA	acceptor_loss	1.0000
22:26466261:CT:C	acceptor_gain	1.0000
22:26466263:C:CC	acceptor_gain	1.0000
22:26470717:A:AC	donor_gain	1.0000
22:26470717:ACAGT:A	donor_gain	1.0000
22:26470718:C:CC	donor_gain	1.0000
22:26470718:CAGT:C	donor_gain	1.0000
22:26470718:CAGTC:C	donor_gain	1.0000
22:26472300:A:AC	donor_gain	1.0000
22:26472301:C:CC	donor_gain	1.0000

AlphaMissense

4610 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:26458566:G:C	S575R	0.994
22:26458566:G:T	S575R	0.994
22:26458568:T:G	S575R	0.994
22:26468618:A:T	V201D	0.990
22:26472388:A:G	W139R	0.990
22:26472388:A:T	W139R	0.990
22:26477023:A:C	F82L	0.989
22:26477023:A:T	F82L	0.989
22:26477025:A:G	F82L	0.989
22:26477024:A:G	F82S	0.988
22:26479277:A:C	F40L	0.988
22:26479277:A:T	F40L	0.988
22:26479279:A:G	F40L	0.988
22:26458534:A:G	L586P	0.987
22:26453350:G:C	F670L	0.986
22:26453350:G:T	F670L	0.986
22:26453351:A:G	F670S	0.986
22:26453352:A:G	F670L	0.986
22:26453261:A:G	L700P	0.983
22:26453290:G:C	F690L	0.983
22:26453290:G:T	F690L	0.983
22:26453292:A:G	F690L	0.983
22:26453381:G:T	A660D	0.983
22:26458546:A:G	L582P	0.983
22:26465515:A:T	V248D	0.983
22:26463966:A:G	L555P	0.982
22:26476995:A:G	W92R	0.982
22:26476995:A:T	W92R	0.982
22:26477082:A:G	C63R	0.980
22:26479341:A:G	F19S	0.980

dbSNP variants (sampled 300 via entrez): RS1000071036 (22:26478608 T>C), RS1000110642 (22:26484302 G>C), RS1000179881 (22:26483517 G>A,T), RS1000232053 (22:26461477 G>A), RS1000318509 (22:26462003 G>A), RS1000403114 (22:26455818 A>G), RS1000471590 (22:26466972 T>C), RS1000620436 (22:26457165 T>C), RS1000734577 (22:26456956 A>G), RS1000969308 (22:26450990 G>A,C), RS1000991498 (22:26478552 CAG>C), RS1001008363 (22:26446503 CT>C,CTT), RS1001034697 (22:26457244 T>C), RS1001040890 (22:26446276 C>A,T), RS1001051785 (22:26484207 A>G)

Disease associations

OMIM: gene MIM:606682 | disease phenotypes: MIM:203300, MIM:614073, MIM:203100, MIM:178500

GenCC curated gene-disease

Disease	Classification	Inheritance
Hermansky-Pudlak syndrome 4	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 4	Definitive	AR

Mondo (5): Hermansky-Pudlak syndrome (MONDO:0019312), Hermansky-Pudlak syndrome 4 (MONDO:0013556), oculocutaneous albinism (MONDO:0018910), interstitial lung disease 2 (MONDO:0800497), Hermansky-Pudlak syndrome with pulmonary fibrosis (MONDO:0016501)

Orphanet (5): Hermansky-Pudlak syndrome (Orphanet:79430), Hermansky-Pudlak syndrome due to BLOC-3 deficiency (Orphanet:231500), Oculocutaneous albinism (Orphanet:55), Idiopathic pulmonary fibrosis (Orphanet:2032), Acute interstitial pneumonia (Orphanet:79126)

HPO phenotypes

13 total (13 of 13 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000132	Menorrhagia
HP:0000421	Epistaxis
HP:0000666	Horizontal nystagmus
HP:0000978	Bruising susceptibility
HP:0001022	Albinism
HP:0001107	Ocular albinism
HP:0001892	Abnormal bleeding
HP:0002091	Restrictive ventilatory defect
HP:0002206	Pulmonary fibrosis
HP:0007663	Reduced visual acuity
HP:0007750	Hypoplasia of the fovea
HP:0033263	Absent platelet dense granules

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002988_5	Ischemic stroke	9.000000e-07
GCST007672_1	3-month functional outcome in ischaemic stroke (modified Rankin score)	9.000000e-06

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009603	stroke outcome severity measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D016115	Albinism, Oculocutaneous	C11.270.040.545; C16.320.290.040.100; C16.320.565.100.102.100; C16.320.850.080.100; C17.800.621.440.102.100; C17.800.827.080.100; C18.452.648.100.102.100
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

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression	5
FR900359	decreases phosphorylation	1
triphenyl phosphate	affects expression	1
beta-lapachone	decreases expression, increases expression	1
methylparaben	increases expression	1
sodium arsenite	affects 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, decreases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
jinfukang	increases expression	1
(+)-JQ1 compound	decreases expression	1
Sunitinib	increases expression	1
Arsenic	increases methylation	1
Benzo(a)pyrene	increases methylation	1
Caffeine	affects phosphorylation	1
Doxorubicin	decreases expression	1
Smoke	decreases expression	1
Theophylline	decreases expression	1
Tretinoin	decreases expression	1
Aflatoxin B1	increases methylation	1
Cadmium Chloride	decreases expression	1
Okadaic Acid	decreases expression	1
Lactic Acid	decreases expression	1

Cellosaurus cell lines

1 cell lines: 1 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_E1ZI	HAP1 HPS4 (-)	Cancer cell line	Male

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04193592	PHASE2	UNKNOWN	Efficacy and Safety of Pirfenidone Treatment in HPS-ILD
NCT00001596	PHASE2	COMPLETED	Oral Pirfenidone for the Pulmonary Fibrosis of Hermansky-Pudlak Syndrome
NCT01663935	PHASE2	TERMINATED	Vision Response to Dopamine Replacement
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
NCT07313618	EARLY_PHASE1	RECRUITING	Safety and Efficacy of a Single Suprachoroidal Injection of JWK010 Gene Therapy in Subjects With Oculocutaneous Albinism Type 1 (OCA1)
NCT00001153	Not specified	COMPLETED	Visual Function and Ocular Pigmentation in Albinism
NCT00808106	Not specified	COMPLETED	Clinical, Cellular, and Molecular Investigation Into Oculocutaneous Albinism
NCT02200263	Not specified	COMPLETED	The Effects of Lutein and Zeaxanthin Supplementation on Vision in Patients With Albinism
NCT04068961	Not specified	COMPLETED	New Strategies of Genetic Study of Patients With Oculocutaneous Albinism
NCT06138509	Not specified	RECRUITING	Peripheral Serotonin and Albinism
NCT06372353	Not specified	COMPLETED	The Effect Of Baduanjin Exercises In Patients With Idiopathic Pulmonary Fibrosis
NCT06644144	Not specified	RECRUITING	P4O2 ILD Extension