Hermansky-Pudlak syndrome 3

Summary

Hermansky-Pudlak syndrome 3 (MONDO:0013555) is a disease caused by HPS3 (GenCC Definitive), with 2 cohort genes.

At a glance

• Causal gene: HPS3 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 276

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Hermansky-Pudlak syndrome 3
Mondo ID	MONDO:0013555
OMIM	614072
DOID	DOID:0060541
UMLS	C3888001
MedGen	854708
GARD	0018333
Is cancer (heuristic)	no

Also known as: Hermansky-Pudlak syndrome 3 · Hermansky-Pudlak syndrome caused by mutation in HPS3 · Hermansky-Pudlak syndrome type 3 · HPS3 · HPS3 Hermansky-Pudlak syndrome

Data availability: 276 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic oculocutaneous albinism › Hermansky-Pudlak syndrome › Hermansky-Pudlak syndrome without pulmonary fibrosis › Hermansky-Pudlak syndrome 3

Related subtypes (2): Hermansky-Pudlak syndrome 5, Hermansky-Pudlak syndrome 6

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

276 retrieved; paginated sample, class counts are floors:

99 likely pathogenic, 57 uncertain significance, 47 pathogenic/likely pathogenic, 21 pathogenic, 18 benign, 16 conflicting classifications of pathogenicity, 12 benign/likely benign, 6 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
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
1449318	NM_032383.5(HPS3):c.2343_2344del (p.Phe781fs)	CP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453955	NM_032383.5(HPS3):c.2589+1G>A	CP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1964579	NM_032383.5(HPS3):c.2424del (p.Ile807_Trp808insTer)	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
3241753	NM_032383.5(HPS3):c.2766T>G (p.Tyr922Ter)	CP	Pathogenic	criteria provided, single submitter
3377064	NM_032383.5(HPS3):c.2424G>A (p.Trp808Ter)	CP	Pathogenic	criteria provided, single submitter
3588688	NM_032383.5(HPS3):c.2805G>A (p.Trp935Ter)	CP	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
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
971795	NM_032383.5(HPS3):c.2471C>A (p.Ser824Ter)	CP	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070715	NM_032383.5(HPS3):c.1686C>A (p.Tyr562Ter)	HPS3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072050	NM_032383.5(HPS3):c.2090_2094del (p.Met697fs)	HPS3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072164	NM_032383.5(HPS3):c.1842_1843del (p.Leu614_Tyr615insTer)	HPS3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323065	NM_032383.5(HPS3):c.995_996dup (p.Leu333fs)	HPS3	Pathogenic	criteria provided, multiple submitters, no conflicts
1324543	NM_032383.5(HPS3):c.1778G>A (p.Trp593Ter)	HPS3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1355617	NM_032383.5(HPS3):c.1561del (p.Leu521fs)	HPS3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1424991	NM_032383.5(HPS3):c.35C>A (p.Ser12Ter)	HPS3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1427081	NM_032383.5(HPS3):c.1868_1872del (p.Asn623fs)	HPS3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1427312	NM_032383.5(HPS3):c.436G>T (p.Gly146Ter)	HPS3	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 2 · 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
HPS3	Definitive	Autosomal recessive	Hermansky-Pudlak syndrome 3	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HPS3	Orphanet:231512	Hermansky-Pudlak syndrome due to BLOC-2 deficiency
CP	Orphanet:48818	Aceruloplasminemia

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
HPS3	HGNC:15597	ENSG00000163755	Q969F9	BLOC-2 complex member HPS3	gencc,clinvar
CP	HGNC:2295	ENSG00000047457	P00450	Ceruloplasmin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
HPS3	BLOC-2 complex member HPS3	Involved in early stages of melanosome biogenesis and maturation.
CP	Ceruloplasmin	Multifunctional blue, copper-binding (6-7 atoms per molecule) glycoprotein.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Enzyme (other)	1	6.0×	0.320
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HPS3	Other/Unknown	no		HPS3, HPS3_N, HPS3_C
CP	Enzyme (other)	yes	1.16.3.1	Cu-oxidase_2nd, Cu_oxidase_Cu_BS, Cupredoxin

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
ileal mucosa	1
jejunal mucosa	1
secondary oocyte	1
liver	1
palpebral conjunctiva	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HPS3	245	ubiquitous	marker	ileal mucosa, secondary oocyte, jejunal mucosa
CP	234	broad	marker	right lobe of liver, liver, palpebral conjunctiva

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CP	2,661
HPS3	768

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CP	P00450	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HPS3	Q969F9	82.67

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SLC40A1 causes hemochromatosis 4 (HFE4) (macrophages)	1	5710.0×	5e-04	CP
Defective CP causes aceruloplasminemia (ACERULOP)	1	5710.0×	5e-04	CP
Metal ion SLC transporters	1	601.0×	0.003	CP
Iron uptake and transport	1	346.1×	0.004	CP
Post-translational protein phosphorylation	1	100.2×	0.012	CP
Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs)	1	86.5×	0.012	CP

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
intracellular copper ion homeostasis	1	468.1×	0.004	CP
melanosome assembly	1	443.5×	0.004	HPS3
pigmentation	1	351.1×	0.004	HPS3
platelet dense granule organization	1	337.0×	0.004	HPS3
intracellular iron ion homeostasis	1	122.1×	0.008	CP

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HPS3	0	0
CP	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CP	1.16.3.1	ferroxidase

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

0 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.

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	0
C	Druggable family + PDB, no drug	1	CP
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	HPS3

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
HPS3	0	—
CP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.