HPS4

Chr 22AR

HPS4 biogenesis of lysosomal organelles complex 3 subunit 2

NCBI Gene: 89781ENSG00000100099UniProt: Q9NQG7

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. The BLOC-3 complex plays an important role in the control of melanin production and melanosome biogenesis and promotes the membrane localization of RAB32 and RAB38 (PubMed:23084991)

Primary Disease Associations & Inheritance

Hermansky-Pudlak syndrome 4MIM #614073
AR
Hermansky-Pudlak syndrome 4MIM #614073
AR
976
ClinVar variants
68
Pathogenic / LP
0.00
pLI score
0
Active trials
Clinical Summary— HPS4
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
68 Pathogenic / Likely Pathogenic· 114 VUS of 976 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.63LOEUF
pLI 0.000
Z-score 3.13
OE 0.39 (0.25–0.63)
Tolerant

Typical tolerance to LoF variation

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.80Z-score
OE missense 1.11 (1.03–1.21)
436 obs / 391.3 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.39 (0.25–0.63)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.11 (1.03–1.21)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.26
0≤1.21.6
LoF obs/exp: 12 / 30.7Missense obs/exp: 436 / 391.3Syn Z: -2.64

ClinVar Variant Classifications

976 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic23
Likely Pathogenic45
VUS114
Likely Benign301
Benign1
Conflicting3
23
Pathogenic
45
Likely Pathogenic
114
VUS
301
Likely Benign
1
Benign
3
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
11
0
12
0
23
Likely Pathogenic
28
1
16
0
45
VUS
1
105
7
1
114
Likely Benign
1
25
105
170
301
Benign
0
0
1
0
1
Conflicting
—3
Total41131141171487

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

HPS4 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

HPS4-related Hermansky-Pudlak syndrome

definitive
ARLoss Of FunctionAbsent Gene Product
EyeSkin
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

2 OMIM entries

OMIM

Hermansky-Pudlak syndrome 4

MIM #614073

Molecular basis of disorder known

Autosomal recessive

Hermansky-Pudlak syndrome 4

MIM #614073

Molecular basis of disorder known

Autosomal recessive
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Hermansky-Pudlak Syndrome.
El-Chemaly S et al.·Clin Chest Med
2016Review
Cryo-EM structure of the BLOC-3 complex provides insights into the pathogenesis of Hermansky-Pudlak syndrome.
Yong X et al.·Nat Commun
2025
A novel homozygous HPS4 mutation in Hermansky-Pudlak syndrome: case report and literature review.
Liu Q et al.·Ther Adv Respir Dis
2025Review
Current landscape of Oculocutaneous Albinism in Japan.
Okamura K et al.·Pigment Cell Melanoma Res
2021Review
Report of Hermansky-Pudlak Syndrome in Two Families with Novel Variants in HPS3 and HPS4 Genes.
Zaman Q et al.·Genes (Basel)
2023Case report
Pulmonary Fibrosis in Hermansky-Pudlak Syndrome.
Vicary GW et al.·Ann Am Thorac Soc
2016Review
Hermansky-Pudlak syndrome is caused by mutations in HPS4, the human homolog of the mouse light-ear gene.
Suzuki T et al.·Nat Genet
2002Functional
A novel 5bp deletion in HPS4 gene associates with Hermansky-Pudlak Syndrome.
Premkumar S et al.·Ophthalmic Genet
2025Case report
Biogenesis of lysosome-related organelles complex 3 (BLOC-3): a complex containing the Hermansky-Pudlak syndrome (HPS) proteins HPS1 and HPS4.
Nazarian R et al.·Proc Natl Acad Sci U S A
2003
Association of the Hermansky-Pudlak syndrome type 4 (HPS4) gene variants with cognitive function in patients with schizophrenia and healthy subjects.
Kuratomi G et al.·BMC Psychiatry
2013Cohort
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools