Hermansky-Pudlak syndrome 1

Summary

Hermansky-Pudlak syndrome 1 (MONDO:0008748) is a disease caused by HPS1 (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Causal gene: HPS1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 383
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Hermansky-Pudlak syndrome 1
Mondo ID	MONDO:0008748
MeSH	C538539
OMIM	203300
DOID	DOID:0060539
NCIT	C150367
UMLS	C2931875
MedGen	419514
GARD	0018331
Is cancer (heuristic)	no

Also known as: Hermansky-Pudlak syndrome 1 · Hermansky-Pudlak syndrome caused by mutation in HPS1 · Hermansky-Pudlak syndrome type 1 · HPS1 · HPS1 Hermansky-Pudlak syndrome

Data availability: 383 ClinVar variants · 3 GenCC gene-disease records · 8 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › respiratory system disorder › lower respiratory tract disorder › lung disorder › interstitial lung disease › interstitial lung disease specific to childhood › Hermansky-Pudlak syndrome with pulmonary fibrosis › Hermansky-Pudlak syndrome 1

Related subtypes (1): Hermansky-Pudlak syndrome 4

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

383 retrieved; paginated sample, class counts are floors:

158 uncertain significance, 56 likely pathogenic, 44 conflicting classifications of pathogenicity, 37 pathogenic/likely pathogenic, 32 benign, 27 likely benign, 18 pathogenic, 11 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068714	NM_000195.5(HPS1):c.1925del (p.Gly642fs)	HPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070980	NM_000195.5(HPS1):c.814C>T (p.Gln272Ter)	HPS1	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
1179029	NM_000195.5(HPS1):c.780dup (p.Arg261fs)	HPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1324541	NM_000195.5(HPS1):c.9C>A (p.Cys3Ter)	HPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1338329	NM_000195.5(HPS1):c.1440_1459del (p.Ile481fs)	HPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
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
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
1384691	NM_000195.5(HPS1):c.97_100del (p.Ser33fs)	HPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1416237	NM_000195.5(HPS1):c.937G>A (p.Gly313Ser)	HPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1445812	NM_000195.5(HPS1):c.1473dup (p.Ser492fs)	HPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452567	NM_000195.5(HPS1):c.716T>C (p.Leu239Pro)	HPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1499624	NM_000195.5(HPS1):c.2003T>C (p.Leu668Pro)	HPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1684357	NM_000195.5(HPS1):c.610G>T (p.Glu204Ter)	HPS1	Pathogenic	no assertion criteria provided
191013	NM_000195.5(HPS1):c.1395G>A (p.Trp465Ter)	HPS1	Pathogenic	criteria provided, single submitter
1958073	NM_000195.5(HPS1):c.484C>T (p.Gln162Ter)	HPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21091	NM_000195.5(HPS1):c.1189del (p.Gln397fs)	HPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21097	NM_000195.5(HPS1):c.1744-2A>C	HPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21103	NM_000195.5(HPS1):c.355del (p.His119fs)	HPS1	Pathogenic	criteria provided, multiple submitters, no conflicts
21104	NM_000195.5(HPS1):c.391C>T (p.Arg131Ter)	HPS1	Pathogenic	criteria provided, multiple submitters, no conflicts
2113923	NM_000195.5(HPS1):c.310dup (p.Asp104fs)	HPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2154613	NM_000195.5(HPS1):c.1777del (p.Leu593fs)	HPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2164818	NM_000195.5(HPS1):c.987+1G>A	HPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2676039	NM_000195.5(HPS1):c.533del (p.Gln178fs)	HPS1	Pathogenic	criteria provided, single submitter
2676040	NM_000195.5(HPS1):c.1198del (p.Asp400fs)	HPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2676055	NM_000195.5(HPS1):c.1771A>T (p.Arg591Ter)	HPS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 8 · 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
HPS1	Definitive	Autosomal recessive	Hermansky-Pudlak syndrome 1	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HPS1	Orphanet:231500	Hermansky-Pudlak syndrome due to BLOC-3 deficiency
ETV6	Orphanet:146	Differentiated thyroid carcinoma
ETV6	Orphanet:168629	Autosomal thrombocytopenia with normal platelets
ETV6	Orphanet:2030	Fibrosarcoma
ETV6	Orphanet:2665	Congenital mesoblastic nephroma
ETV6	Orphanet:314950	Primary hypereosinophilic syndrome
ETV6	Orphanet:585929	B-lymphoblastic leukemia/lymphoma with t(12;21)(p13.2;q22.1)
ETV6	Orphanet:98823	Chronic myelomonocytic leukemia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HPS1	HGNC:5163	ENSG00000107521	Q92902	BLOC-3 complex member HPS1	gencc,clinvar
ETV6	HGNC:3495	ENSG00000139083	P41212	Transcription factor ETV6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
ETV6	Transcription factor ETV6	Transcriptional repressor; binds to the DNA sequence 5’-CCGGAAGT-3'.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.0

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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HPS1	Other/Unknown	no		HPS1, FUZ/MON1/HPS1_longin_3, FUZ/MON1/HPS1_longin_2
ETV6	Other/Unknown	no		Ets_dom, Pointed_dom, SAM/pointed_sf

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	1
small intestine Peyer’s patch	1
stromal cell of endometrium	1
mammary duct	1
mucosa of paranasal sinus	1
parotid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HPS1	231	ubiquitous	marker	granulocyte, stromal cell of endometrium, small intestine Peyer’s patch
ETV6	252	ubiquitous	marker	mucosa of paranasal sinus, parotid gland, mammary duct

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ETV6	2,225
HPS1	409

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ETV6	P41212	44
HPS1	Q92902	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Signaling by membrane-tethered fusions of PDGFRA or PDGFRB	1	1142.0×	0.003	ETV6
Signaling by FLT3 fusion proteins	1	285.5×	0.005	ETV6
RAB GEFs exchange GTP for GDP on RABs	1	62.1×	0.016	HPS1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
vitellogenesis	1	1685.2×	0.007	ETV6
mesenchymal cell apoptotic process	1	766.0×	0.007	ETV6
melanosome assembly	1	443.5×	0.007	HPS1
platelet dense granule organization	1	337.0×	0.007	HPS1
hematopoietic stem cell proliferation	1	324.1×	0.007	ETV6
lysosome organization	1	153.2×	0.013	HPS1
neurogenesis	1	104.0×	0.016	ETV6
vesicle-mediated transport	1	48.1×	0.031	HPS1
visual perception	1	39.8×	0.033	HPS1
cell differentiation	1	14.6×	0.081	ETV6
negative regulation of transcription by RNA polymerase II	1	8.9×	0.120	ETV6
regulation of transcription by RNA polymerase II	1	5.8×	0.164	ETV6

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ETV6	CERITINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ETV6	4	4
HPS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CERITINIB	4	ETV6
GILTERITINIB	4	ETV6
ERDAFITINIB	4	ETV6
LY-2874455	1	ETV6

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ETV6	11	Binding:11

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

4 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)
CERITINIB	4	ETV6
GILTERITINIB	4	ETV6
ERDAFITINIB	4	ETV6
LY-2874455	1	ETV6

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ETV6
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	HPS1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HPS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns