Hermansky-Pudlak syndrome 4

Summary

Hermansky-Pudlak syndrome 4 (MONDO:0013556) is a disease caused by HPS4 (GenCC Definitive), with 1 cohort gene and 1 clinical trial.

At a glance

• Causal gene: HPS4 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 192
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Hermansky-Pudlak syndrome 4
Mondo ID	MONDO:0013556
OMIM	614073
DOID	DOID:0060542
UMLS	C3484357
MedGen	483344
GARD	0018332
Is cancer (heuristic)	no

Also known as: Hermansky-Pudlak syndrome 4 · Hermansky-Pudlak syndrome caused by mutation in HPS4 · Hermansky-Pudlak syndrome type 4 · HPS4 · HPS4 Hermansky-Pudlak syndrome

Data availability: 192 ClinVar variants · 4 GenCC gene-disease records.

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 4

Related subtypes (1): Hermansky-Pudlak 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

192 retrieved; paginated sample, class counts are floors:

67 uncertain significance, 38 likely pathogenic, 37 conflicting classifications of pathogenicity, 16 benign, 12 pathogenic, 11 pathogenic/likely pathogenic, 7 likely benign, 4 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1204924	NM_022081.6(HPS4):c.706+1G>A	HPS4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1323066	NM_022081.6(HPS4):c.1152del (p.Gly385fs)	HPS4	Pathogenic	criteria provided, single submitter
1455295	NM_022081.6(HPS4):c.1088_1101del (p.Leu363fs)	HPS4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1684417	NM_022081.6(HPS4):c.2054del (p.Pro685fs)	HPS4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2138424	NM_022081.6(HPS4):c.47del (p.Asn16fs)	HPS4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
228266	NM_022081.6(HPS4):c.1132C>T (p.Gln378Ter)	HPS4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2412666	NM_022081.6(HPS4):c.1546C>T (p.Gln516Ter)	HPS4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2413185	NM_022081.6(HPS4):c.1767_1768del (p.Leu590fs)	HPS4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2676125	NM_022081.6(HPS4):c.1330G>T (p.Glu444Ter)	HPS4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2676132	NM_022081.6(HPS4):c.673_686del	HPS4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3241757	NM_022081.6(HPS4):c.45G>A (p.Trp15Ter)	HPS4	Pathogenic	criteria provided, single submitter
3645167	NM_022081.6(HPS4):c.1184del (p.Pro395fs)	HPS4	Pathogenic	criteria provided, multiple submitters, no conflicts
4073703	NM_022081.6(HPS4):c.1739del (p.Asn580fs)	HPS4	Pathogenic	criteria provided, single submitter
4073704	NM_022081.6(HPS4):c.133-570_502-34del	HPS4	Pathogenic	criteria provided, single submitter
4077105	NM_022081.6(HPS4):c.1693_1694del (p.Ser565fs)	HPS4	Pathogenic	criteria provided, single submitter
4125	NM_022081.6(HPS4):c.1891C>T (p.Gln631Ter)	HPS4	Pathogenic	criteria provided, single submitter
4126	NM_022081.6(HPS4):c.2089_2093dup (p.Lys699fs)	HPS4	Pathogenic	no assertion criteria provided
4127	NM_022081.6(HPS4):c.57del (p.Leu20fs)	HPS4	Pathogenic	no assertion criteria provided
4128	NM_022081.6(HPS4):c.541C>T (p.Gln181Ter)	HPS4	Pathogenic	no assertion criteria provided
4130	NM_022081.6(HPS4):c.649C>T (p.Arg217Ter)	HPS4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4131	NM_022081.6(HPS4):c.412G>T (p.Glu138Ter)	HPS4	Pathogenic	no assertion criteria provided
4132	NM_022081.6(HPS4):c.664G>T (p.Glu222Ter)	HPS4	Pathogenic	no assertion criteria provided
593813	NM_022081.6(HPS4):c.148C>T (p.Gln50Ter)	HPS4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1684588	NM_022081.6(HPS4):c.502-1G>A	HPS4	Likely pathogenic	criteria provided, single submitter
1698570	NM_022081.6(HPS4):c.1535C>G (p.Ser512Ter)	HPS4	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2502839	NM_022081.6(HPS4):c.133-2A>T	HPS4	Likely pathogenic	criteria provided, single submitter
2676113	NM_022081.6(HPS4):c.133-1G>A	HPS4	Likely pathogenic	criteria provided, single submitter
2676114	NM_022081.6(HPS4):c.348dup (p.Asn117Ter)	HPS4	Likely pathogenic	criteria provided, single submitter
2676115	NM_022081.6(HPS4):c.1409T>G (p.Leu470Ter)	HPS4	Likely pathogenic	criteria provided, single submitter
2676116	NM_022081.6(HPS4):c.316A>T (p.Lys106Ter)	HPS4	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 5 · Orphanet: 1 · 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
HPS4	Definitive	Autosomal recessive	Hermansky-Pudlak syndrome 4	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
HPS4	Orphanet:231500	Hermansky-Pudlak syndrome due to BLOC-3 deficiency

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
HPS4	HGNC:15844	ENSG00000100099	Q9NQG7	BLOC-3 complex member HPS4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · 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	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
HPS4	Other/Unknown	no		HPS4, CCZ1/INTU/HSP4_longin_1, CCZ1/INTU/HSP4_longin_3

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
HPS4	261	ubiquitous	marker	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HPS4	623

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HPS4	Q9NQG7	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 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
RAB GEFs exchange GTP for GDP on RABs	1	124.1×	0.008	HPS4

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of eye pigmentation	1	16852.0×	7e-04	HPS4
hemostasis	1	1685.2×	0.003	HPS4
melanosome assembly	1	887.0×	0.003	HPS4
melanocyte differentiation	1	802.5×	0.003	HPS4
platelet dense granule organization	1	674.1×	0.003	HPS4
obsolete positive regulation of protein targeting to mitochondrion	1	495.6×	0.004	HPS4
protein targeting	1	366.4×	0.004	HPS4
lysosome organization	1	306.4×	0.004	HPS4
blood coagulation	1	173.7×	0.007	HPS4
vesicle-mediated transport	1	96.3×	0.011	HPS4
protein stabilization	1	66.9×	0.015	HPS4

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 1 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
HPS4	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	HPS4

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)
HPS4	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