Hermansky-Pudlak syndrome 2

Summary

Hermansky-Pudlak syndrome 2 (MONDO:0011997) is a disease caused by AP3B1 (GenCC Definitive), with 4 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: AP3B1 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 841

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		40	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Hermansky-Pudlak syndrome 2
Mondo ID	MONDO:0011997
MeSH	C537709
OMIM	608233
Orphanet	183678, 664500
DOID	DOID:0060540
NCIT	C150368
UMLS	C1842362
MedGen	374912
GARD	0015026
Is cancer (heuristic)	no

Also known as: AP3B1 Hermansky-Pudlak syndrome · Hermansky Pudlak syndrome 2 · Hermansky-Pudlak syndrome 2 · Hermansky-Pudlak syndrome caused by mutation in AP3B1 · Hermansky-Pudlak syndrome type 2 · HPS-2 · HPS2 · Platelet defects and oculocutaneous albinism

Data availability: 841 ClinVar variants · 4 GenCC gene-disease records · 3 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › leukocyte disorder › leukopenia › agranulocytosis › neutropenia › constitutional neutropenia › Hermansky-Pudlak syndrome 2

Related subtypes (12): cyclic hematopoiesis, Chediak-Higashi syndrome, Cohen syndrome, glycogen storage disease Ib, Lichtenstein syndrome, Barth syndrome, poikiloderma with neutropenia, Griscelli syndrome type 2, primary immunodeficiency syndrome due to p14 deficiency, neutropenia-monocytopenia-deafness syndrome, severe congenital neutropenia, WHIM syndrome 1

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

600 retrieved; paginated sample, class counts are floors:

253 uncertain significance, 237 likely benign, 28 pathogenic, 24 likely pathogenic, 20 conflicting classifications of pathogenicity, 19 benign/likely benign, 15 benign, 4 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2424719	NC_000005.9:g.(?76115008)(78281071_?)del	AGGF1	Pathogenic	criteria provided, single submitter
1071422	NM_003664.5(AP3B1):c.1619dup (p.Ala541fs)	AP3B1	Pathogenic	criteria provided, single submitter
1072382	NM_003664.5(AP3B1):c.2694_2712del (p.Met899fs)	AP3B1	Pathogenic	criteria provided, single submitter
1370969	NM_003664.5(AP3B1):c.2738del (p.Lys913fs)	AP3B1	Pathogenic	criteria provided, single submitter
1416408	NM_003664.5(AP3B1):c.237_238del (p.Phe80fs)	AP3B1	Pathogenic	criteria provided, single submitter
1451475	NM_003664.5(AP3B1):c.2757del (p.Ile919fs)	AP3B1	Pathogenic	criteria provided, single submitter
1455598	NM_003664.5(AP3B1):c.2801del (p.Asn934fs)	AP3B1	Pathogenic	criteria provided, single submitter
1456202	NM_003664.5(AP3B1):c.1101dup (p.Phe368fs)	AP3B1	Pathogenic	criteria provided, single submitter
1684305	NM_003664.5(AP3B1):c.310C>T (p.Arg104Ter)	AP3B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1878314	NM_003664.5(AP3B1):c.1789dup (p.Ile597fs)	AP3B1	Pathogenic	criteria provided, single submitter
2019152	NM_003664.5(AP3B1):c.778del (p.Trp260fs)	AP3B1	Pathogenic	criteria provided, single submitter
2030913	NM_003664.5(AP3B1):c.1255C>T (p.Gln419Ter)	AP3B1	Pathogenic	criteria provided, single submitter
2088339	NM_003664.5(AP3B1):c.1945C>T (p.Arg649Ter)	AP3B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224760	NM_003664.5(AP3B1):c.2702C>G (p.Ser901Cys)	AP3B1	Pathogenic	no assertion criteria provided
224761	NM_003664.5(AP3B1):c.1754del (p.Val585fs)	AP3B1	Pathogenic	no assertion criteria provided
224762	NM_003664.5(AP3B1):c.716G>A (p.Trp239Ter)	AP3B1	Pathogenic	no assertion criteria provided
224763	NM_003664.5(AP3B1):c.177del (p.Lys59fs)	AP3B1	Pathogenic	criteria provided, multiple submitters, no conflicts
224764	NM_003664.4(AP3B1):c.1839_1842delTAGA	AP3B1	Pathogenic	criteria provided, single submitter
2503438	NM_003664.5(AP3B1):c.364C>T (p.Arg122Ter)	AP3B1	Pathogenic	criteria provided, single submitter
2676731	NM_003664.5(AP3B1):c.1363+1G>A	AP3B1	Pathogenic	criteria provided, single submitter
2676750	NM_003664.5(AP3B1):c.2640del (p.Gly881fs)	AP3B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2698780	NM_003664.5(AP3B1):c.1973_1983dup (p.Pro662fs)	AP3B1	Pathogenic	criteria provided, single submitter
2705668	NM_003664.5(AP3B1):c.753T>G (p.Tyr251Ter)	AP3B1	Pathogenic	criteria provided, single submitter
2717774	NM_003664.5(AP3B1):c.2675_2679del (p.Pro892fs)	AP3B1	Pathogenic	criteria provided, single submitter
2739632	NM_003664.5(AP3B1):c.2734C>T (p.Arg912Ter)	AP3B1	Pathogenic	criteria provided, single submitter
2748816	NM_003664.5(AP3B1):c.1408del (p.Gln470fs)	AP3B1	Pathogenic	criteria provided, single submitter
2749771	NM_003664.5(AP3B1):c.1930_1937del (p.Pro644fs)	AP3B1	Pathogenic	criteria provided, single submitter
2812558	NM_003664.5(AP3B1):c.1907T>G (p.Leu636Ter)	AP3B1	Pathogenic	criteria provided, single submitter
2837529	NM_003664.5(AP3B1):c.1286del (p.Gly429fs)	AP3B1	Pathogenic	criteria provided, single submitter
3239765	NM_003664.5(AP3B1):c.3015_3016dup (p.Thr1006fs)	AP3B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 6 · 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
AP3B1	Definitive	Autosomal recessive	Hermansky-Pudlak syndrome 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
AP3B1	Orphanet:664500	Hermansky-Pudlak syndrome due to AP3B1 deficiency
HPS3	Orphanet:231512	Hermansky-Pudlak syndrome due to BLOC-2 deficiency
AGGF1	Orphanet:90308	Capillary-lymphatic-venous malformation with segmental distribution
AP3D1	Orphanet:1000	Ocular albinism with late-onset sensorineural deafness
AP3D1	Orphanet:54	X-linked recessive ocular albinism
AP3D1	Orphanet:664511	Early-onset severe Hermansky-Pudlak syndrome with hearing loss, due to AP3D1 deficiency

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
AP3B1	HGNC:566	ENSG00000132842	O00203	AP-3 complex subunit beta-1	gencc,clinvar
HPS3	HGNC:15597	ENSG00000163755	Q969F9	BLOC-2 complex member HPS3	clinvar
AGGF1	HGNC:24684	ENSG00000164252	Q8N302	Angiogenic factor with G patch and FHA domains 1	clinvar
AP3D1	HGNC:568	ENSG00000065000	O14617	AP-3 complex subunit delta-1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
HPS3	BLOC-2 complex member HPS3	Involved in early stages of melanosome biogenesis and maturation.
AGGF1	Angiogenic factor with G patch and FHA domains 1	Promotes angiogenesis and the proliferation of endothelial cells.
AP3D1	AP-3 complex subunit delta-1	Part of the AP-3 complex, an adaptor-related complex which is not clathrin-associated.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 4 · 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	4	1.8×	0.097

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
AP3B1	Other/Unknown	no		Clathrin/coatomer_adapt-like_N, ARM-like, B-adaptin_app_sub_C
HPS3	Other/Unknown	no		HPS3, HPS3_N, HPS3_C
AGGF1	Other/Unknown	no		FHA_dom, G_patch_dom, SMAD_FHA_dom_sf
AP3D1	Other/Unknown	no		Clathrin/coatomer_adapt-like_N, AP3D_dom_metazoa, ARM-like

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
tendon of biceps brachii	2
calcaneal tendon	1
tendon	1
ileal mucosa	1
jejunal mucosa	1
secondary oocyte	1
choroid plexus epithelium	1
epithelium of nasopharynx	1
palpebral conjunctiva	1
adenohypophysis	1
pituitary gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
AP3B1	289	ubiquitous	marker	tendon of biceps brachii, calcaneal tendon, tendon
HPS3	245	ubiquitous	marker	ileal mucosa, secondary oocyte, jejunal mucosa
AGGF1	284	ubiquitous	marker	choroid plexus epithelium, epithelium of nasopharynx, palpebral conjunctiva
AP3D1	295	ubiquitous	marker	tendon of biceps brachii, adenohypophysis, pituitary gland

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AP3B1	2,527
AP3D1	2,108
AGGF1	1,205
HPS3	768

Intra-cohort edges

A	B	Sources
AP3B1	AP3D1	biogrid_interaction, string_interaction
AP3B1	HPS3	string_interaction
AP3D1	HPS3	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AP3D1	O14617	6
AP3B1	O00203	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
HPS3	Q969F9	82.67
AGGF1	Q8N302	66.24

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 4 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
Oncogenic MAPK signaling	2	248.3×	1e-04	AP3B1, AGGF1
Signaling by BRAF and RAF1 fusions	2	170.4×	1e-04	AP3B1, AGGF1
Diseases of signal transduction by growth factor receptors and second messengers	2	56.8×	8e-04	AP3B1, AGGF1
Disease	2	13.1×	0.012	AP3B1, AGGF1
trans-Golgi Network Vesicle Budding	1	126.9×	0.013	AP3B1
Golgi Associated Vesicle Biogenesis	1	100.2×	0.013	AP3B1
Membrane Trafficking	1	18.5×	0.057	AP3B1
Vesicle-mediated transport	1	17.4×	0.057	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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
melanosome assembly	3	665.2×	2e-07	AP3B1, HPS3, AP3D1
platelet dense granule organization	3	505.6×	3e-07	AP3B1, HPS3, AP3D1
positive regulation of NK T cell differentiation	2	2106.5×	4e-06	AP3B1, AP3D1
clathrin-coated vesicle cargo loading, AP-3-mediated	2	1203.7×	8e-06	AP3B1, AP3D1
antigen processing and presentation, exogenous lipid antigen via MHC class Ib	2	1203.7×	8e-06	AP3B1, AP3D1
anterograde synaptic vesicle transport	2	495.6×	4e-05	AP3B1, AP3D1
melanosome organization	2	324.1×	9e-05	AP3B1, AP3D1
anterograde axonal transport	2	290.6×	1e-04	AP3B1, AP3D1
obsolete establishment of protein localization to mitochondrial membrane involved in mitochondrial fission	1	2106.5×	0.002	AP3B1
neurotransmitter receptor transport, postsynaptic endosome to lysosome	1	2106.5×	0.002	AP3D1
vesicle-mediated transport	2	48.1×	0.003	AP3B1, AP3D1
synaptic vesicle budding from endosome	1	1404.3×	0.003	AP3D1
skin epidermis development	1	1053.2×	0.003	AP3B1
zinc ion import into lysosome	1	1053.2×	0.003	AP3D1
synaptic vesicle coating	1	842.6×	0.003	AP3D1
synaptic vesicle membrane organization	1	842.6×	0.003	AP3D1
intracellular protein transport	2	32.4×	0.004	AP3B1, AP3D1
Golgi to vacuole transport	1	468.1×	0.005	AP3D1
endosome to melanosome transport	1	421.3×	0.006	AP3D1
protein targeting to vacuole	1	324.1×	0.007	AP3D1
granulocyte differentiation	1	300.9×	0.007	AP3B1
synaptic vesicle recycling	1	300.9×	0.007	AP3D1
lung morphogenesis	1	263.3×	0.007	AP3B1
respiratory system process	1	234.1×	0.008	AP3B1
pigmentation	1	175.5×	0.010	HPS3
homeostasis of number of cells	1	168.5×	0.010	AP3B1
protein targeting to lysosome	1	156.0×	0.010	AP3B1
toll-like receptor signaling pathway	1	150.5×	0.010	AP3B1
protein localization to membrane	1	150.5×	0.010	AP3D1
protein localization to cell surface	1	123.9×	0.012	AP3B1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) 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
HPS3	0	0
AGGF1	0	0
AP3D1	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): 0.

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

Symbol	Assays	Type breakdown
AP3B1	8	Binding:8
AP3D1	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	HPS3, AGGF1, AP3D1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
AP3D1	1	AP3B1
HPS3	0	—
AGGF1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.