Hermansky-Pudlak syndrome

Summary

Hermansky-Pudlak syndrome (MONDO:0019312) is a disease (an umbrella term covering 9 Mondo subtypes) with 11 cohort genes and 6 clinical trials. The dominant Reactome pathway is Golgi Associated Vesicle Biogenesis (4 cohort genes). Top therapeutic interventions include erythromycin, pirfenidone, and pravastatin.

At a glance

• Prevalence: 1-5 / 10 000 (Puerto rico) [Orphanet-validated]
• Umbrella term: 9 Mondo subtypes
• Cohort genes: 11
• ClinVar variants: 433
• Phenotypes (HPO): 39
• Clinical trials: 6

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	55	Puerto rico	Validated
Point prevalence	1-9 / 1 000 000	0.15	Worldwide	Not yet validated

Signs & symptoms

Clinical features (HPO)

39 HPO clinical features (Orphanet curated; top 39 by frequency):

HPO ID	Term	Frequency
HP:0000639	Nystagmus	Very frequent (80-99%)
HP:0001010	Hypopigmentation of the skin	Very frequent (80-99%)
HP:0001875	Decreased total neutrophil count	Very frequent (80-99%)
HP:0001892	Abnormal bleeding	Very frequent (80-99%)
HP:0002721	Immunodeficiency	Very frequent (80-99%)
HP:0007443	Partial albinism	Very frequent (80-99%)
HP:0007730	Iris hypopigmentation	Very frequent (80-99%)
HP:0000083	Renal insufficiency	Frequent (30-79%)
HP:0000421	Epistaxis	Frequent (30-79%)
HP:0000483	Astigmatism	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0000518	Cataract	Frequent (30-79%)
HP:0000545	Myopia	Frequent (30-79%)
HP:0000587	Abnormal optic nerve morphology	Frequent (30-79%)
HP:0000613	Photophobia	Frequent (30-79%)
HP:0000646	Amblyopia	Frequent (30-79%)
HP:0000649	Abnormality of visual evoked potentials	Frequent (30-79%)
HP:0000978	Bruising susceptibility	Frequent (30-79%)
HP:0001107	Ocular albinism	Frequent (30-79%)
HP:0002206	Pulmonary fibrosis	Frequent (30-79%)
HP:0005599	Hypopigmentation of hair	Frequent (30-79%)
HP:0400008	Menometrorrhagia	Frequent (30-79%)
HP:0000505	Visual impairment	Occasional (5-29%)
HP:0000527	Long eyelashes	Occasional (5-29%)
HP:0000682	Abnormality of dental enamel	Occasional (5-29%)
HP:0000962	Hyperkeratosis	Occasional (5-29%)
HP:0000995	Melanocytic nevus	Occasional (5-29%)
HP:0001072	Thickened skin	Occasional (5-29%)
HP:0001638	Cardiomyopathy	Occasional (5-29%)
HP:0001824	Weight loss	Occasional (5-29%)
HP:0001872	Abnormality of thrombocytes	Occasional (5-29%)
HP:0002024	Malabsorption	Occasional (5-29%)
HP:0002027	Abdominal pain	Occasional (5-29%)
HP:0002039	Anorexia	Occasional (5-29%)
HP:0002094	Dyspnea	Occasional (5-29%)
HP:0002239	Gastrointestinal hemorrhage	Occasional (5-29%)
HP:0002671	Basal cell carcinoma	Occasional (5-29%)
HP:0006739	Squamous cell carcinoma of the skin	Occasional (5-29%)
HP:0012378	Fatigue	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Hermansky-Pudlak syndrome
Mondo ID	MONDO:0019312
MeSH	D022861
OMIM	203300
Orphanet	79430
DOID	DOID:3753
ICD-10-CM	E70.331
ICD-11	2089801290
NCIT	C37261
SNOMED CT	9311003
UMLS	C0079504
MedGen	36313
GARD	0006643
MedDRA	10071775
NORD	1918
Is cancer (heuristic)	no

Also known as: Hermansky Pudlak syndrome · HPS

Data availability: 433 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 9 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic oculocutaneous albinism › Hermansky-Pudlak syndrome

Related subtypes (3): Chediak-Higashi syndrome, oculocerebral hypopigmentation syndrome, Cross type, Griscelli syndrome

Subtypes (9): Hermansky-Pudlak syndrome 2, Hermansky-Pudlak syndrome 7, Hermansky-Pudlak syndrome 8, Hermansky-Pudlak syndrome 9, Hermansky-Pudlak syndrome 10, Hermansky-Pudlak syndrome with pulmonary fibrosis, Hermansky-Pudlak syndrome without pulmonary fibrosis, Kotzot-Richter syndrome, Hermansky-Pudlak syndrome 11

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

433 retrieved; paginated sample, class counts are floors:

137 uncertain significance, 73 pathogenic/likely pathogenic, 53 likely pathogenic, 47 likely benign, 46 conflicting classifications of pathogenicity, 40 pathogenic, 21 benign, 16 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1878314	NM_003664.5(AP3B1):c.1789dup (p.Ile597fs)	AP3B1	Pathogenic	criteria provided, single submitter
813287	GRCh37/hg19 6p24.3(chr6:8023117-8042179)x0	BLOC1S5	Pathogenic	no assertion criteria provided
870631	NM_201280.3(BLOC1S5):c.345del (p.Val116fs)	BLOC1S5	Pathogenic	no assertion criteria provided
30412	NM_012388.4(BLOC1S6):c.232C>T (p.Gln78Ter)	BLOC1S6	Pathogenic	criteria provided, single submitter
996272	NM_012388.4(BLOC1S6):c.335dup (p.His112fs)	BLOC1S6	Pathogenic	criteria provided, multiple submitters, no conflicts
1067518	NM_032383.5(HPS3):c.2589+2T>C	CP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067748	NM_032383.5(HPS3):c.2796+2T>C	CP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069806	NM_032383.5(HPS3):c.2587C>T (p.Gln863Ter)	CP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1356541	NM_032383.5(HPS3):c.2796+1del	CP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1359726	NM_032383.5(HPS3):c.2318del (p.Thr773fs)	CP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1395878	NM_032383.5(HPS3):c.2733del (p.Leu911_Leu912insTer)	CP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2676082	NM_032383.5(HPS3):c.2507T>G (p.Leu836Ter)	CP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4081445	NM_032383.5(HPS3):c.2398_2399del (p.Phe800fs)	CP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4611	NM_032383.5(HPS3):c.2482-2A>G	CP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4612	NM_032383.5(HPS3):c.2589+1G>C	CP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
548481	NM_032383.5(HPS3):c.2739_2742del (p.Glu913fs)	CP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
627049	NM_032383.5(HPS3):c.2814dup (p.Leu939fs)	CP	Pathogenic	criteria provided, multiple submitters, no conflicts
627283	NM_032383.5(HPS3):c.2463dup (p.Arg822fs)	CP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
930923	NM_032383.5(HPS3):c.2464C>T (p.Arg822Ter)	CP	Pathogenic	criteria provided, multiple submitters, no conflicts
962603	NM_032383.5(HPS3):c.2589+1G>T	CP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1704604	NM_032122.5(DTNBP1):c.448_449del (p.Met150fs)	DTNBP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074133	NM_000195.5(HPS1):c.988-1G>T	HPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1341377	NM_000195.5(HPS1):c.1507C>T (p.Gln503Ter)	HPS1	Pathogenic	criteria provided, single submitter
1341378	NM_000195.5(HPS1):c.1375del (p.Ser459fs)	HPS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1341379	NM_000195.5(HPS1):c.1315C>T (p.Arg439Ter)	HPS1	Pathogenic	criteria provided, multiple submitters, no conflicts
1341380	NM_000195.5(HPS1):c.962del (p.Gly321fs)	HPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1341381	NM_000195.5(HPS1):c.928C>T (p.Gln310Ter)	HPS1	Pathogenic	criteria provided, single submitter
1341386	NM_000195.5(HPS1):c.1858-1G>A	HPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1341397	NM_000195.5(HPS1):c.1513C>T (p.Gln505Ter)	HPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1355628	NM_000195.5(HPS1):c.1940+2T>C	HPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 11 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
BLOC1S5	Strong	Autosomal recessive	Hermansky-Pudlak syndrome 11	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
BLOC1S5	Orphanet:231531	Hermansky-Pudlak syndrome due to BLOC-1 deficiency
HPS3	Orphanet:231512	Hermansky-Pudlak syndrome due to BLOC-2 deficiency
HPS4	Orphanet:231500	Hermansky-Pudlak syndrome due to BLOC-3 deficiency
HPS5	Orphanet:231512	Hermansky-Pudlak syndrome due to BLOC-2 deficiency
DTNBP1	Orphanet:231531	Hermansky-Pudlak syndrome due to BLOC-1 deficiency
HPS6	Orphanet:231512	Hermansky-Pudlak syndrome due to BLOC-2 deficiency
BLOC1S3	Orphanet:231531	Hermansky-Pudlak syndrome due to BLOC-1 deficiency
CP	Orphanet:48818	Aceruloplasminemia
HPS1	Orphanet:231500	Hermansky-Pudlak syndrome due to BLOC-3 deficiency
AP3B1	Orphanet:664500	Hermansky-Pudlak syndrome due to AP3B1 deficiency
BLOC1S6	Orphanet:231531	Hermansky-Pudlak syndrome due to BLOC-1 deficiency

Cohort genes → proteins

11 cohort genes, 11 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	11

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
BLOC1S5	HGNC:18561	ENSG00000188428	Q8TDH9	Biogenesis of lysosome-related organelles complex 1 subunit 5	gencc,clinvar
HPS3	HGNC:15597	ENSG00000163755	Q969F9	BLOC-2 complex member HPS3	clinvar
HPS4	HGNC:15844	ENSG00000100099	Q9NQG7	BLOC-3 complex member HPS4	clinvar
HPS5	HGNC:17022	ENSG00000110756	Q9UPZ3	BLOC-2 complex member HPS5	clinvar
DTNBP1	HGNC:17328	ENSG00000047579	Q96EV8	Dysbindin	clinvar
HPS6	HGNC:18817	ENSG00000166189	Q86YV9	BLOC-2 complex member HPS6	clinvar
BLOC1S3	HGNC:20914	ENSG00000189114	Q6QNY0	Biogenesis of lysosome-related organelles complex 1 subunit 3	clinvar
CP	HGNC:2295	ENSG00000047457	P00450	Ceruloplasmin	clinvar
HPS1	HGNC:5163	ENSG00000107521	Q92902	BLOC-3 complex member HPS1	clinvar
AP3B1	HGNC:566	ENSG00000132842	O00203	AP-3 complex subunit beta-1	clinvar
BLOC1S6	HGNC:8549	ENSG00000104164	Q9UL45	Biogenesis of lysosome-related organelles complex 1 subunit 6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
BLOC1S5	Biogenesis of lysosome-related organelles complex 1 subunit 5	Component of the BLOC-1 complex, a complex that is required for normal biogenesis of lysosome-related organelles (LRO), such as platelet dense granules and melanosomes.
HPS3	BLOC-2 complex member HPS3	Involved in early stages of melanosome biogenesis and maturation.
HPS4	BLOC-3 complex member HPS4	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.
HPS5	BLOC-2 complex member HPS5	May regulate the synthesis and function of lysosomes and of highly specialized organelles, such as melanosomes and platelet dense granules.
DTNBP1	Dysbindin	Component of the BLOC-1 complex, a complex that is required for normal biogenesis of lysosome-related organelles (LRO), such as platelet dense granules and melanosomes.
HPS6	BLOC-2 complex member HPS6	May regulate the synthesis and function of lysosomes and of highly specialized organelles, such as melanosomes and platelet dense granules.
BLOC1S3	Biogenesis of lysosome-related organelles complex 1 subunit 3	Component of the BLOC-1 complex, a complex that is required for normal biogenesis of lysosome-related organelles (LRO), such as platelet dense granules and melanosomes.
CP	Ceruloplasmin	Multifunctional blue, copper-binding (6-7 atoms per molecule) glycoprotein.
HPS1	BLOC-3 complex member HPS1	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.
AP3B1	AP-3 complex subunit beta-1	Subunit of non-clathrin- and clathrin-associated adaptor protein complex 3 (AP-3) that plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes.
BLOC1S6	Biogenesis of lysosome-related organelles complex 1 subunit 6	Component of the BLOC-1 complex, a complex that is required for normal biogenesis of lysosome-related organelles (LRO), such as platelet dense granules and melanosomes.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 9 · Druggable fraction: 0.09

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	9	1.5×	0.217
Scaffold/PPI	1	1.6×	0.616
Enzyme (other)	1	1.1×	0.616

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
BLOC1S5	Other/Unknown	no		Bloc1s5
HPS3	Other/Unknown	no		HPS3, HPS3_N, HPS3_C
HPS4	Other/Unknown	no		HPS4, CCZ1/INTU/HSP4_longin_1, CCZ1/INTU/HSP4_longin_3
HPS5	Scaffold/PPI	no		WD40/YVTN_repeat-like_dom_sf, HPS5, WD40_repeat_dom_sf
DTNBP1	Other/Unknown	no		Dysbindin
HPS6	Other/Unknown	no		BLOC-2_complex_Hps6_subunit, HPS6_C, HPS6_N
BLOC1S3	Other/Unknown	no		BLOC-1_complex_su-3
CP	Enzyme (other)	yes	1.16.3.1	Cu-oxidase_2nd, Cu_oxidase_Cu_BS, Cupredoxin
HPS1	Other/Unknown	no		HPS1, FUZ/MON1/HPS1_longin_3, FUZ/MON1/HPS1_longin_2
AP3B1	Other/Unknown	no		Clathrin/coatomer_adapt-like_N, ARM-like, B-adaptin_app_sub_C
BLOC1S6	Other/Unknown	no		BLOC-1_pallidin, Snapin/Pallidin/Snn1

Expression context

Cohort genes with no expression data: 0.

10 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	11
unknown	0

Top tissues across cohort

Tissue	Cohort genes
pancreatic ductal cell	2
secondary oocyte	2
liver	2
tendon of biceps brachii	2
granulocyte	2
stromal cell of endometrium	2
kidney epithelium	1
visceral pleura	1
ileal mucosa	1
jejunal mucosa	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
male germ line stem cell (sensu Vertebrata) in testis	1
sural nerve	1
nucleus accumbens	1
putamen	1
gingival epithelium	1
oocyte	1
upper arm skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
BLOC1S5	257	ubiquitous	marker	pancreatic ductal cell, visceral pleura, kidney epithelium
HPS3	245	ubiquitous	marker	ileal mucosa, secondary oocyte, jejunal mucosa
HPS4	261	ubiquitous	marker	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex
HPS5	134	ubiquitous	marker	sural nerve, male germ line stem cell (sensu Vertebrata) in testis, liver
DTNBP1	249	ubiquitous	marker	tendon of biceps brachii, nucleus accumbens, putamen
HPS6	216	ubiquitous	yes	granulocyte, gingival epithelium, stromal cell of endometrium
BLOC1S3	225	ubiquitous	marker	oocyte, secondary oocyte, upper arm skin
CP	234	broad	marker	right lobe of liver, liver, palpebral conjunctiva
HPS1	231	ubiquitous	marker	granulocyte, stromal cell of endometrium, small intestine Peyer’s patch
AP3B1	289	ubiquitous	marker	tendon of biceps brachii, calcaneal tendon, tendon
BLOC1S6	262	ubiquitous	marker	epithelial cell of pancreas, colonic epithelium, pancreatic ductal cell

Protein interactions among cohort

Intra-cohort edges: 41.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CP	2,661
AP3B1	2,527
DTNBP1	1,501
BLOC1S6	1,227
HPS6	965
BLOC1S5	768
HPS3	768
HPS5	664
HPS4	623
BLOC1S3	604

Intra-cohort edges

A	B	Sources
AP3B1	BLOC1S3	string_interaction
AP3B1	BLOC1S6	string_interaction
AP3B1	DTNBP1	string_interaction
AP3B1	HPS3	string_interaction
AP3B1	HPS4	string_interaction
AP3B1	HPS5	string_interaction
AP3B1	HPS6	string_interaction
BLOC1S3	BLOC1S5	biogrid_interaction, intact, string_interaction
BLOC1S3	BLOC1S6	biogrid_interaction, intact, string_interaction
BLOC1S3	DTNBP1	intact, string_interaction
BLOC1S3	HPS1	string_interaction
BLOC1S3	HPS3	string_interaction
BLOC1S3	HPS4	string_interaction
BLOC1S3	HPS5	string_interaction
BLOC1S3	HPS6	string_interaction
BLOC1S5	BLOC1S6	intact, string_interaction
BLOC1S5	DTNBP1	biogrid_interaction, intact, string_interaction
BLOC1S5	HPS3	string_interaction
BLOC1S5	HPS5	string_interaction
BLOC1S5	HPS6	string_interaction
BLOC1S6	DTNBP1	intact, string_interaction
BLOC1S6	HPS1	string_interaction
BLOC1S6	HPS3	string_interaction
BLOC1S6	HPS4	string_interaction
BLOC1S6	HPS5	string_interaction
BLOC1S6	HPS6	string_interaction
DTNBP1	HPS1	string_interaction
DTNBP1	HPS3	string_interaction
DTNBP1	HPS4	string_interaction
DTNBP1	HPS5	string_interaction
DTNBP1	HPS6	string_interaction
HPS1	HPS3	string_interaction
HPS1	HPS4	intact, string_interaction
HPS1	HPS5	string_interaction
HPS1	HPS6	string_interaction
HPS3	HPS4	string_interaction
HPS3	HPS5	intact, string_interaction
HPS3	HPS6	biogrid_interaction, intact, string_interaction
HPS4	HPS5	string_interaction
HPS4	HPS6	string_interaction
HPS5	HPS6	biogrid_interaction, intact, string_interaction

Structural data

PDB: 4 · AlphaFold-only: 7 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AP3B1	O00203	5
CP	P00450	4
HPS4	Q9NQG7	1
HPS1	Q92902	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
BLOC1S5	Q8TDH9	87.86
BLOC1S6	Q9UL45	84.10
HPS3	Q969F9	82.67
HPS6	Q86YV9	77.54
DTNBP1	Q96EV8	75.92
HPS5	Q9UPZ3	73.21
BLOC1S3	Q6QNY0	71.38

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 15. Enrichment computed across 11 evidence-associated genes (7 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Golgi Associated Vesicle Biogenesis	4	114.5×	3e-07	DTNBP1, BLOC1S3, AP3B1, BLOC1S6
trans-Golgi Network Vesicle Budding	3	108.8×	1e-05	BLOC1S3, AP3B1, BLOC1S6
Defective SLC40A1 causes hemochromatosis 4 (HFE4) (macrophages)	1	815.7×	0.003	CP
Defective CP causes aceruloplasminemia (ACERULOP)	1	815.7×	0.003	CP
RAB GEFs exchange GTP for GDP on RABs	2	35.5×	0.003	HPS4, HPS1
Membrane Trafficking	3	15.9×	0.003	BLOC1S3, AP3B1, BLOC1S6
Vesicle-mediated transport	3	14.9×	0.003	BLOC1S3, AP3B1, BLOC1S6
Metal ion SLC transporters	1	85.9×	0.022	CP
Iron uptake and transport	1	49.4×	0.033	CP
Oncogenic MAPK signaling	1	35.5×	0.042	AP3B1
Signaling by BRAF and RAF1 fusions	1	24.4×	0.055	AP3B1
Post-translational protein phosphorylation	1	14.3×	0.085	CP
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	12.4×	0.090	CP
Diseases of signal transduction by growth factor receptors and second messengers	1	8.1×	0.125	AP3B1
Disease	1	1.9×	0.427	AP3B1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 11 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
platelet dense granule organization	8	490.2×	1e-19	HPS3, HPS4, HPS5, DTNBP1, HPS6, BLOC1S3, HPS1, AP3B1
melanosome assembly	6	483.8×	2e-14	HPS3, HPS4, HPS5, HPS6, HPS1, AP3B1
anterograde synaptic vesicle transport	5	450.6×	8e-12	BLOC1S5, DTNBP1, BLOC1S3, AP3B1, BLOC1S6
melanosome organization	5	294.6×	6e-11	BLOC1S5, DTNBP1, BLOC1S3, AP3B1, BLOC1S6
anterograde axonal transport	5	264.1×	9e-11	BLOC1S5, DTNBP1, BLOC1S3, AP3B1, BLOC1S6
blood coagulation	6	94.8×	2e-10	HPS4, HPS5, DTNBP1, HPS6, AP3B1, BLOC1S6
endosome to melanosome transport	3	459.6×	3e-07	BLOC1S5, BLOC1S3, BLOC1S6
melanosome transport	3	208.9×	4e-06	BLOC1S5, BLOC1S3, BLOC1S6
positive regulation of pigment cell differentiation	2	1532.0×	4e-06	BLOC1S5, BLOC1S6
neuron projection development	4	44.4×	1e-05	BLOC1S5, DTNBP1, BLOC1S3, BLOC1S6
vesicle-mediated transport	4	35.0×	3e-05	BLOC1S5, HPS4, HPS1, AP3B1
secretion of lysosomal enzymes	2	612.8×	3e-05	BLOC1S3, BLOC1S6
lysosome organization	3	83.6×	4e-05	HPS4, HPS1, AP3B1
positive regulation of natural killer cell activation	2	383.0×	7e-05	BLOC1S3, BLOC1S6
protein transmembrane transport	2	235.7×	2e-04	DTNBP1, BLOC1S6
respiratory system process	2	170.2×	3e-04	AP3B1, BLOC1S6
melanocyte differentiation	2	145.9×	4e-04	HPS4, BLOC1S6
pigmentation	2	127.7×	5e-04	HPS3, BLOC1S3
homeostasis of number of cells	2	122.6×	6e-04	AP3B1, BLOC1S6
protein targeting	2	66.6×	0.002	HPS4, BLOC1S6
lipid homeostasis	2	61.3×	0.002	HPS6, BLOC1S6
bradykinin biosynthetic process	1	1532.0×	0.003	BLOC1S6
circadian sleep/wake cycle	1	1532.0×	0.003	BLOC1S6
positive regulation of eye pigmentation	1	1532.0×	0.003	HPS4
positive regulation of glutamate neurotransmitter secretion in response to membrane depolarization	1	766.0×	0.005	DTNBP1
obsolete establishment of protein localization to mitochondrial membrane involved in mitochondrial fission	1	766.0×	0.005	AP3B1
memory	2	33.3×	0.005	DTNBP1, BLOC1S6
intracellular nitric oxide homeostasis	1	510.7×	0.007	BLOC1S6
positive regulation of NK T cell differentiation	1	383.0×	0.008	AP3B1
regulation of dopamine receptor signaling pathway	1	383.0×	0.008	DTNBP1

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Bosentan, Letrozole, Norfloxacin, Sorafenib.

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 10

Druggability breadth: 3 of 11 evidence-associated genes (27%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
AP3B1	1	2
BLOC1S5	0	0
HPS3	0	0
HPS4	0	0
HPS5	0	0
DTNBP1	0	0
HPS6	0	0
BLOC1S3	0	0
CP	0	0
HPS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	AP3B1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
AP3B1	8	Binding:8
BLOC1S5	6	Binding:6
HPS6	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CP	1.16.3.1	ferroxidase

Pharmacogenomics

Cohort genes with a PharmGKB record: 11; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

1 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	AP3B1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	1	AP3B1
C	Druggable family + PDB, no drug	1	CP
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	9	BLOC1S5, HPS3, HPS4, HPS5, DTNBP1, HPS6, BLOC1S3, HPS1, BLOC1S6

Undrugged target profiles

10 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
HPS4	0	AP3B1
BLOC1S5	6	—
HPS3	0	—
HPS5	0	—
DTNBP1	0	—
HPS6	1	—
BLOC1S3	0	—
CP	0	—
HPS1	0	—
BLOC1S6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	4
PHASE1/PHASE2	1
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00467831	PHASE1/PHASE2	TERMINATED	Pilot Study of a Multi-Drug Regimen for Severe Pulmonary Fibrosis in Hermansky-Pudlak Syndrome
NCT04193592	PHASE2	UNKNOWN	Efficacy and Safety of Pirfenidone Treatment in HPS-ILD
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

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ERYTHROMYCIN	4	1
PIRFENIDONE	4	1
PRAVASTATIN	4	1
ZILEUTON	4	1
CHEMBL5435500	0	1