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GeneE
10 sources retrieved Β· Most recent: April 2026 Β· Index updated 15 days ago
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HPS4
HPS4 biogenesis of lysosomal organelles complex 3 subunit 2
Chromosome 22 Β· 22q12.1
NCBI Gene: 89781Ensembl: ENSG00000100099.22HGNC: HGNC:15844UniProt: A0A8V8TMY3
33PubMed Papers
21Diseases
0Drugs
91Pathogenic Variants
RESEARCH IMPACT
Variant-Rich
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
guanyl-nucleotide exchange factor activityprotein bindingsmall GTPase bindingprotein homodimerization activityHermansky-Pudlak syndrome with pulmonary fibrosisHermansky-Pudlak syndromelung diseasegenetic disorder
✦AI Summary

HPS4 is a component of the BLOC-3 (biogenesis of lysosomal organelles complex 3) protein complex, which functions as a guanine exchange factor for the small GTPases RAB32 and RAB38 1. The BLOC-3 complex, composed of one copy each of HPS1 and HPS4 that tightly associate via their longin domains, facilitates the conversion of RAB32/38 from inactive GDP-bound to active GTP-bound states, promoting their membrane localization 1. This complex is essential for biogenesis of lysosome-related organelles, particularly melanosomes, and controls melanin production 2. HPS4 mutations cause Hermansky-Pudlak syndrome type 4 (HPS-4), an autosomal recessive disorder characterized by oculocutaneous albinism, platelet storage pool defects with bleeding diathesis, and notably, progressive fibrosing interstitial lung disease (ILD) 34. HPS-4-related pulmonary fibrosis is a leading cause of mortality in affected patients, developing at younger ages than idiopathic pulmonary fibrosis and currently manageable only by lung transplantation, though nintedanib may provide temporary stabilization 35. Additionally, HPS4 variants show associations with cognitive function, particularly working memory in healthy individuals and executive function in schizophrenia 6.

Sources cited
1
BLOC-3 structure: HPS1-HPS4 complex with longin domains; GEF activity for RAB32/38 and RAB9A; essential for melanosome biogenesis
PMID: 40140412
2
HPS1 and HPS4 form BLOC-3 complex (~175 kDa); involved in lysosomal-related organelle biogenesis; distinct from AP-3 mechanism
PMID: 12756248
3
HPS-4 causes oculocutaneous albinism, platelet disorder, bleeding, and progressive fibrosing ILD as leading cause of mortality
PMID: 41110930
4
HPS-4 associated with pulmonary fibrosis at younger age than idiopathic pulmonary fibrosis; lung transplant currently the only definitive treatment
PMID: 27514596
5
HPS-4 mutations cause Hermansky-Pudlak syndrome; nintedanib may stabilize pulmonary function; 51 reported patients with 37 unique mutations identified
PMID: 41277635
6
HPS4 variants associated with working memory in healthy subjects and executive function in schizophrenia patients
PMID: 24168225
Disease Associationsβ“˜21
Hermansky-Pudlak syndrome with pulmonary fibrosisOpen Targets
0.80Strong
Hermansky-Pudlak syndromeOpen Targets
0.74Strong
lung diseaseOpen Targets
0.37Weak
genetic disorderOpen Targets
0.34Weak
oculocutaneous albinismOpen Targets
0.12Weak
idiopathic pulmonary fibrosisOpen Targets
0.11Weak
Griscelli diseaseOpen Targets
0.08Suggestive
Griscelli disease type 3Open Targets
0.07Suggestive
Griscelli syndrome type 3Open Targets
0.07Suggestive
Tietz syndromeOpen Targets
0.07Suggestive
Dowling-Degos diseaseOpen Targets
0.06Suggestive
Griscelli disease type 1Open Targets
0.06Suggestive
Griscelli syndrome type 1Open Targets
0.06Suggestive
oculocutaneous albinism type 3Open Targets
0.06Suggestive
Neurofibromatosis type 6Open Targets
0.06Suggestive
schizophreniaOpen Targets
0.06Suggestive
familial generalized lentiginosisOpen Targets
0.05Suggestive
Waardenburg syndrome type 2Open Targets
0.05Suggestive
Tietze syndromeOpen Targets
0.05Suggestive
Waardenburg syndrome, IIa 2FOpen Targets
0.05Suggestive
Hermansky-Pudlak syndrome 4UniProt
Pathogenic Variants91
NM_022081.6(HPS4):c.1132C>T (p.Gln378Ter)Pathogenic
Hermansky-Pudlak syndrome|not provided|Hermansky-Pudlak syndrome 4
β˜…β˜…β˜†β˜†2026β†’ Residue 378
NM_022081.6(HPS4):c.706+1G>APathogenic
not provided|Hermansky-Pudlak syndrome 4
β˜…β˜…β˜†β˜†2026
NM_022081.6(HPS4):c.649C>T (p.Arg217Ter)Pathogenic
Hermansky-Pudlak syndrome 4|not provided|See cases|Hermansky-Pudlak syndrome
β˜…β˜…β˜†β˜†2025β†’ Residue 217
NM_022081.6(HPS4):c.1546C>T (p.Gln516Ter)Pathogenic
Hermansky-Pudlak syndrome 4|not provided
β˜…β˜…β˜†β˜†2025β†’ Residue 516
NM_022081.6(HPS4):c.1184del (p.Pro395fs)Pathogenic
not provided|Hermansky-Pudlak syndrome 4
β˜…β˜…β˜†β˜†2025β†’ Residue 395
NM_022081.6(HPS4):c.47del (p.Asn16fs)Pathogenic
Hermansky-Pudlak syndrome 4|not provided
β˜…β˜…β˜†β˜†2024β†’ Residue 16
NM_022081.6(HPS4):c.673_686delPathogenic
Hermansky-Pudlak syndrome 4|not provided
β˜…β˜…β˜†β˜†2024
NM_022081.6(HPS4):c.1535C>G (p.Ser512Ter)Likely pathogenic
Hermansky-Pudlak syndrome|Hermansky-Pudlak syndrome 4
β˜…β˜…β˜†β˜†2024β†’ Residue 512
NM_022081.6(HPS4):c.1767_1768del (p.Leu590fs)Pathogenic
Hermansky-Pudlak syndrome 4|not provided
β˜…β˜…β˜†β˜†2023β†’ Residue 590
NM_022081.6(HPS4):c.1088_1101del (p.Leu363fs)Pathogenic
not provided|Hermansky-Pudlak syndrome 4
β˜…β˜…β˜†β˜†2023β†’ Residue 363
NM_022081.6(HPS4):c.133-2A>GLikely pathogenic
Hermansky-Pudlak syndrome 4|not provided
β˜…β˜…β˜†β˜†2023
NM_022081.6(HPS4):c.2054del (p.Pro685fs)Pathogenic
Hermansky-Pudlak syndrome 4
β˜…β˜…β˜†β˜†2023β†’ Residue 685
NM_022081.6(HPS4):c.1330G>T (p.Glu444Ter)Pathogenic
Hermansky-Pudlak syndrome 4|not provided
β˜…β˜…β˜†β˜†2023β†’ Residue 444
NM_022081.6(HPS4):c.148C>T (p.Gln50Ter)Pathogenic
not provided|Hermansky-Pudlak syndrome 4
β˜…β˜…β˜†β˜†2023β†’ Residue 50
NM_022081.6(HPS4):c.667C>T (p.Gln223Ter)Pathogenic
not provided
β˜…β˜†β˜†β˜†2026β†’ Residue 223
NM_022081.6(HPS4):c.417G>A (p.Trp139Ter)Pathogenic
not provided
β˜…β˜†β˜†β˜†2025β†’ Residue 139
NM_022081.6(HPS4):c.1714-5_1732delLikely pathogenic
not provided
β˜…β˜†β˜†β˜†2025
NM_022081.6(HPS4):c.1462C>T (p.Gln488Ter)Pathogenic
not provided
β˜…β˜†β˜†β˜†2025β†’ Residue 488
NM_022081.6(HPS4):c.1739del (p.Asn580fs)Pathogenic
Hermansky-Pudlak syndrome 4
β˜…β˜†β˜†β˜†2025β†’ Residue 580
NM_022081.6(HPS4):c.133-570_502-34delPathogenic
Hermansky-Pudlak syndrome 4
β˜…β˜†β˜†β˜†2025
View on ClinVar β†—
Related Genes
BLOC1S1Protein interaction99%SNAPINProtein interaction99%BLOC1S4Protein interaction99%BLOC1S5Protein interaction99%AP3B1Protein interaction94%BLOC1S6Protein interaction94%
Tissue Expression6 tissues
Bone Marrow
100%
Ovary
38%
Liver
27%
Lung
23%
Brain
19%
Heart
13%
Gene Interaction Network
Click a node to explore
HPS4BLOC1S1SNAPINBLOC1S4BLOC1S5AP3B1BLOC1S6
PROTEIN STRUCTURE
Preparing viewer…
AlphaFoldAI-predicted Β· UniProt Q6P1K3
View on AlphaFold β†—
Constraintβ“˜
LOEUFβ“˜
0.79LoF Tolerant
pLIβ“˜
0.00Tolerant
Observed/Expected LoF0.61 [0.47–0.79]
RankingsWhere HPS4 stands among ~20K protein-coding genes
  • #11,350of 20,598
    Most Researched33
  • #844of 5,498
    Most Pathogenic Variants91 Β· top quartile
  • #6,572of 17,882
    Most Constrained (LOEUF)0.79
Genes detectedHPS4
Sources retrieved10 papers
Response timeβ€”
πŸ“„ Sources
10β–Ό
1
PMID: 20301464
1.00
2
Hermansky-Pudlak Syndrome.
PMID: 41110930
Clin Chest Med Β· 2025
0.90
3
Hermansky-Pudlak Syndrome.
PMID: 27514596
Clin Chest Med Β· 2016
0.80
4
BLOC-3, a protein complex containing the Hermansky-Pudlak syndrome gene products HPS1 and HPS4.
PMID: 12756248
J Biol Chem Β· 2003
0.70
5
Association of the Hermansky-Pudlak syndrome type 4 (HPS4) gene variants with cognitive function in patients with schizophrenia and healthy subjects.
PMID: 24168225
BMC Psychiatry Β· 2013
0.60