HPS3

Chr 3AR

HPS3 biogenesis of lysosomal organelles complex 2 subunit 1

Also known as: BLOC2S1, SUTAL

NCBI Gene: 84343 ENSG00000163755 UniProt: Q969F9 OMIM: 614072

The HPS3 protein contains clathrin-binding motifs and sorting signals that direct vesicle trafficking to melanosomes, platelet dense granules, and lysosomes, functioning in the early stages of melanosome biogenesis and maturation. Mutations cause Hermansky-Pudlak syndrome type 3, an autosomal recessive disorder affecting pigmentation, bleeding due to platelet storage pool deficiency, and lysosomal function. The gene shows tolerance to loss-of-function variation (pLI near zero), consistent with the recessive inheritance pattern where both alleles must be affected to cause disease.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a protein containing a potential clathrin-binding motif, consensus dileucine signals, and tyrosine-based sorting signals for targeting to vesicles of lysosomal lineage. The encoded protein may play a role in organelle biogenesis associated with melanosomes, platelet dense granules, and lysosomes. Mutations in this gene are associated with Hermansky-Pudlak syndrome type 3. [provided by RefSeq, Apr 2015]

GeneReviews OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Hermansky-Pudlak syndrome 3MIM #614072

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · Hermansky-Pudlak syndrome 3 · AR · ClinGen 2020

Interpreting a novel variant

Loss of function is the curated mechanism (Gene2Phenotype), though the gene is not strongly LoF-constrained in the population — weigh truncating variants against that tolerance.Curated gene-level mechanism — a prior for triage, not a per-variant call.

Active trials

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Pubs (1 yr)

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P/LP submissions

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P/LP missense

1.02

LOEUF

LOF

Mechanism· G2P

📖

GeneReview available — HPS3

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.02LOEUF

pLI 0.000

Z-score 1.44

OE 0.78 (0.60–1.02)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.16Z-score

OE missense 0.98 (0.91–1.05)

525 obs / 535.4 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.78 (0.60–1.02)

0≤0.351.4

Missense OE?0.98 (0.91–1.05)

0≤0.61.4

Synonymous OE?1.03

0≤1.21.6

LoF obs/exp: 38 / 48.9Missense obs/exp: 525 / 535.4Syn Z: -0.38

Background carrier burden — how many people carry a rare variant somewhere in HPS3?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 45

1,279 rare PASS variants

Rare truncating (LoF)

1 in 700

203 rare PASS variants

Rare synonymous (reference)

1 in 130

459 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for HPS3. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 76	1 in 830
South Asian	~43k	1 in 46	1 in 420
Remaining (unassigned)	~30k	1 in 42	1 in 850
European (Finnish)	~27k	1 in 170	1 in 1,900
Admixed American	~22k	1 in 46	1 in 1,400
African / African American	~21k	1 in 45	1 in 580
East Asian	~20k	1 in 49	1 in 260
Ashkenazi Jewish	~13k	1 in 150	≈ 1 in 6,500
Middle Eastern	~2,884	1 in 49	≈ 1 in 960

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 14 of 17 coding exons well covered in gnomAD exomes; exons 8, 14, 16 marginal. Genomes: all 17.? see exons ↓