RAB27A

Summary

RAB27A (RAB27A, member RAS oncogene family, HGNC:9766) is a protein-coding gene on chromosome 15q21.3, encoding Ras-related protein Rab-27A (P51159). The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes.

The protein encoded by this gene belongs to the small GTPase superfamily, Rab family. The protein is membrane-bound and may be involved in protein transport and small GTPase mediated signal transduction. Mutations in this gene are associated with Griscelli syndrome type 2. Alternative splicing occurs at this locus and four transcript variants encoding the same protein have been identified.

Source: NCBI Gene 5873 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Griscelli syndrome type 2 (Definitive, ClinGen)
• GWAS associations: 2
• Clinical variants (ClinVar): 351 total — 44 pathogenic, 18 likely-pathogenic
• Phenotypes (HPO): 31
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_183235

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9766
Approved symbol	RAB27A
Name	RAB27A, member RAS oncogene family
Location	15q21.3
Locus type	gene with protein product
Status	Approved
Aliases	RAB27, RAM, GS2, HsT18676
Ensembl gene	ENSG00000069974
Ensembl biotype	protein_coding
OMIM	603868
Entrez	5873

Gene structure

Transcript identifiers

Ensembl transcripts: 43 — 38 protein_coding, 4 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000336787, ENST00000396307, ENST00000561545, ENST00000563262, ENST00000564609, ENST00000565776, ENST00000565972, ENST00000566877, ENST00000567380, ENST00000567639, ENST00000568803, ENST00000569493, ENST00000697641, ENST00000697642, ENST00000697643, ENST00000697644, ENST00000899597, ENST00000899598, ENST00000899599, ENST00000899600, ENST00000899601, ENST00000899602, ENST00000899603, ENST00000899604, ENST00000899605, ENST00000899606, ENST00000899607, ENST00000899608, ENST00000899609, ENST00000899610, ENST00000899611, ENST00000899612, ENST00000915166, ENST00000915167, ENST00000915168, ENST00000915169, ENST00000915170, ENST00000915171, ENST00000942609, ENST00000942610, ENST00000942611, ENST00000942612, ENST00000942613

RefSeq mRNA: 4 — MANE Select: NM_183235 NM_004580, NM_183234, NM_183235, NM_183236

CCDS: CCDS10153

Canonical transcript exons

ENST00000336787 — 7 exons

Exon	Start	End
ENSE00001362392	55270165	55270284
ENSE00002586804	55289716	55289813
ENSE00003890957	55223889	55224012
ENSE00003891228	55234782	55234956
ENSE00003892515	55230401	55230486
ENSE00003892805	55202966	55205705
ENSE00003893822	55228609	55228712

Expression profiles

Bgee: expression breadth ubiquitous, 275 present calls, max score 97.91.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 12.1395 / max 125.6237, expressed in 1805 samples.

FANTOM5 promoters (15 alternative TSS)

Promoter ID	TPM avg	Samples expressed
150088	12.1395	1805
150085	9.7194	1631
150081	0.2416	43
150084	0.1677	71
150074	0.0930	29
150079	0.0798	25
150082	0.0752	36
150072	0.0739	37
150073	0.0710	20
150076	0.0556	22

Top tissues by expression

289 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
trabecular bone tissue	UBERON:0002483	97.91	gold quality
monocyte	CL:0000576	97.22	gold quality
lower lobe of lung	UBERON:0008949	97.13	gold quality
mononuclear cell	CL:0000842	97.12	gold quality
bone marrow	UBERON:0002371	97.07	gold quality
leukocyte	CL:0000738	97.05	gold quality
mucosa of sigmoid colon	UBERON:0004993	96.85	gold quality
bone marrow cell	CL:0002092	96.84	gold quality
blood	UBERON:0000178	96.73	gold quality
secondary oocyte	CL:0000655	96.05	gold quality
pigmented layer of retina	UBERON:0001782	95.82	gold quality
colonic mucosa	UBERON:0000317	95.67	gold quality
rectum	UBERON:0001052	95.19	gold quality
cervix squamous epithelium	UBERON:0006922	94.79	gold quality
oocyte	CL:0000023	94.71	gold quality
ileal mucosa	UBERON:0000331	94.64	gold quality
esophagus squamous epithelium	UBERON:0006920	94.26	gold quality
pylorus	UBERON:0001166	94.25	gold quality
colonic epithelium	UBERON:0000397	94.13	gold quality
granulocyte	CL:0000094	94.09	gold quality
palpebral conjunctiva	UBERON:0001812	93.68	gold quality
epithelium of esophagus	UBERON:0001976	93.51	gold quality
cartilage tissue	UBERON:0002418	92.88	gold quality
body of stomach	UBERON:0001161	92.87	gold quality
islet of Langerhans	UBERON:0000006	92.85	gold quality
vermiform appendix	UBERON:0001154	92.84	gold quality
stomach	UBERON:0000945	92.47	gold quality
jejunal mucosa	UBERON:0000399	92.20	gold quality
lymph node	UBERON:0000029	91.97	gold quality
lung	UBERON:0002048	91.78	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 3.

Experiment	Marker?	Max mean expression
E-GEOD-125970	yes	20.29
E-ANND-3	yes	19.17
E-MTAB-9801	yes	6.58
E-MTAB-7606	no	160.49
E-MTAB-6142	no	39.63

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets.

Target	Regulation
RAB27B	Activation

Upstream regulators (CollecTRI, top): AP1, MITF, RBPJ

miRNA regulators (miRDB)

101 targeting RAB27A, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4715-3P	99.98	66.03	670
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-3910	99.95	71.13	2227
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-3143	99.93	71.96	3104
HSA-MIR-548AE-3P	99.93	72.66	4867
HSA-MIR-548AH-3P	99.93	72.54	4872
HSA-MIR-548AM-3P	99.93	72.54	4872
HSA-MIR-548AQ-3P	99.93	72.66	4867
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-3119	99.92	71.34	2390
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-124-3P	99.89	73.74	3043
HSA-MIR-506-3P	99.89	73.55	3057
HSA-MIR-380-3P	99.89	70.18	1978
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-659-3P	99.85	70.69	1620

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• role in melanosome transport (PMID:11980908)
• Griscelli syndrome with neurological involvement is caused by mutations in RAB27A (PMID:12058346)
• Rab27b is functionally redundant with Rab27a and the pathogenesis of Griscelli syndrome is determined by the relative expression of Rab27a and Rab27b in specialized cell types. (PMID:12122117)
• RAB27A mutations in Griscelli disease (PMID:12148598)
• recognition of the GTP-bound form of Rab27A requires the SHD1 of Slac2-a/melanophilin (PMID:12189142)
• Rab27a mutations occurring in Griscelli syndrome patients reveal structure-activity relationships affecting GTP & GDP binding, melanophilin binding, melanosome distribution, and cytotoxic granule exocytosis. (PMID:12446441)
• characterization of molecular defects in patients with Griscelli syndrome (PMID:12531900)
• Rab27 regulates the dense core granule secretion in platelets by employing its binding protein, Munc13-4 (PMID:14699162)
• JFC1 differentially regulates the secretion of PSAP and PSA, and Rab27a and PI3K play a central role in the exocytosis of prostate-specific markers. (PMID:16004602)
• Extensive genetic and allelic heterogeneity in Familial hemophagocytic lymphohistiocytosis (FHL) and delineate an approach for functionally characterizing missense mutations in RAB27A and UNC13D. (PMID:16278825)
• These observations decisively prove that Rab27a inhibits ENaC function through a complex mechanism that involves GTP/GDP status, and protein-protein interactions involving Munc13-4 and SLP-5 effector proteins. (PMID:16630545)
• findings show that Rab27a is involved in CFTR channel regulation through protein-protein interactions involving Munc13-4 and SLP-5 effector proteins (PMID:16762324)
• Rab27 is maintained in the active status in unstimulated platelets, which could function to keep dense granules in a preparative status for secretion (PMID:16880209)
• EPI64 is a GTPase-activating protein specific for Rab27A (PMID:16923811)
• Rab7 controls microtubule-mediated transport of early and Rab27a the subsequent actin-dependent transport of mature melanosomes. (PMID:16965270)
• Rab27a and JFC1/Slp1 permit myeloperoxidase release into the surrounding milieu and constitute key components of the secretory machinery of azurophilic granules in granulocytes (PMID:17090228)
• A novel homozygous mutation in the RAB27A gene of a new Griscelli syndrome patient. (PMID:17255357)
• The present results provide evidence from live retinal pigment epithelium cells that the RAB27A-MYRIP-MYO7A complex functions in melanosome motility. (PMID:17352418)
• These results show that RAB27A is a new direct transcriptional target of MITF and link MITF to melanosome transport, another key parameter of melanocyte differentiation and skin pigmentation. (PMID:18281284)
• The genes PRF1, GZMB, UNC13D, and Rab27a involved in hemophagocytic lymphohistiocytosis do not confer a significant risk of association with systemic-onset juvenile idiopathic arthritis. (PMID:18311812)
• Rab27A is associated with invasive and metastatic potentials of human breast cancer cells. (PMID:18337447)
• We present four novel mutations including a deletion hot spot in RAB27A gene in Griscelli syndrome type 2 (PMID:18350256)
• Study reports a novel homozygous missense mutation of the RAB27A gene of an Afghani GSII patient; G43S mutation located in the highly conserved switch I region of Rab27A induces perinuclear localization of melanosomes in normal melanocytes. (PMID:18397837)
• Mutation analysis in family members revealed the presence of a missense mutation in Rab27a gene. In addition to the rare presentation, this is the first case of Griscelli syndrome to be reported from Jordan. (PMID:18403584)
• Rab3GEP has a role as the non-redundant guanine nucleotide exchange factor for Rab27a in melanocytes (PMID:18559336)
• Rab27A mRNA and protein are expressed in human eosinophils. (PMID:18571497)
• Rab27a is a major component of the exocytic machinery of human neutrophils, modulating the secretion of tertiary and specific granules that are readily mobilized upon neutrophil activation. (PMID:18768832)
• Rab27a recruits Slp2a-hem on vesicular structures in peripheral CTLs and following CTL-target cell conjugate formation, the Slp2a-hem/Rab27a complex colocalizes with perforin-containing granules at the immunologic synapse (PMID:18812475)
• Rab27A/Slp2a expression in limb girdle muscular dystrophy 2B muscle provides a compensatory vesicular trafficking pathway that is able to repair membrane damage in the absence of dysferlin. (PMID:18832576)
• Rab27a and MyRIP regulate the amount and multimeric state of VWF released from endothelial cells. (PMID:19270261)
• Rab27a or Munc13-4 recruitment to lytic granules is preferentially regulated by different receptor signals, demonstrating that individual target cell ligands regulate discrete molecular events for lytic granule maturation. (PMID:19704116)
• RAB27A mutations were found in 1 of the 21 families with haemophagocytic syndromes without mutations in familial HLH (FHL) causing genes (PMID:19953648)
• The Rab27A(K22R) mutant normally binds Munc13-4, but not Slp2-a or Slp4-a, whereas the Rab27A(I44T) mutant shows reduced binding activity to Slp2-a and Munc13-4 but normally binds Slp4-a. (PMID:20370853)
• Loss of Rab27a increased the fraction of mobile lytic granules and the extent of their movement in the cytosol. (PMID:20877725)
• TBC1D16 and RAB27A, were identified known drivers of melanoma both are involved in the regulation of vesicular trafficking, which highlights this process as important for proliferation in melanoma. (PMID:21129771)
• Rab27a plays a direct regulatory role in the nascent process of phagocytosis by prolongation of the stage of actin coating via suppression of Coronin 1A. (PMID:21169636)
• Rab27a hasa role in the CMV life cycle and CMV and LRO biogenesis share common molecular mechanisms (PMID:21170347)
• Molecular analysis revealed a novel homozygous mutation in exon 5, namely, a single-base substitution (g.42996 A>G) leading to an amino acid change (S115G) and thus confirming the diagnosis of Griscelli syndrome type 2. (PMID:21314004)
• Upregulated expression of rab4, rab5, rab7, and rab27 correlates with antemortem measures of cognitive decline in individuals with mild cognitve impairment and Alzheimer disease. (PMID:21669283)
• Data show that point mutations in the binding motif of munc13-4 have severely impaired rab27a binding, allowing dissection of rab27a requirements in munc13-4 function. (PMID:21693760)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	rab27a	ENSDARG00000103935
mus_musculus	Rab27a	ENSMUSG00000032202
rattus_norvegicus	Rab27a	ENSRNOG00000052499
drosophila_melanogaster	Rab27	FBGN0025382
caenorhabditis_elegans	aex-6	WBGENE00000089

Paralogs (68): RAB27B (ENSG00000041353), RAB7A (ENSG00000075785), RABL2B (ENSG00000079974), RAB21 (ENSG00000080371), RAB10 (ENSG00000084733), RAB18 (ENSG00000099246), RAB36 (ENSG00000100228), IFT27 (ENSG00000100360), RAB40AL (ENSG00000102128), RAB11A (ENSG00000103769), RAB2A (ENSG00000104388), RAB3D (ENSG00000105514), RAB3A (ENSG00000105649), RAB5C (ENSG00000108774), RAB34 (ENSG00000109113), RAB5B (ENSG00000111540), RAB35 (ENSG00000111737), RAB23 (ENSG00000112210), DNAJC27 (ENSG00000115137), RAB29 (ENSG00000117280), RAB32 (ENSG00000118508), RAB14 (ENSG00000119396), RAB9B (ENSG00000123570), RAB9A (ENSG00000123595), RAB38 (ENSG00000123892), RAB22A (ENSG00000124209), RAB17 (ENSG00000124839), RAB2B (ENSG00000129472), RAB25 (ENSG00000132698), RAB33A (ENSG00000134594), RAB30 (ENSG00000137502), RAB1A (ENSG00000138069), RAB20 (ENSG00000139832), RAB15 (ENSG00000139998), RAB40B (ENSG00000141542), RAB13 (ENSG00000143545), RABL2A (ENSG00000144134), RAB5A (ENSG00000144566), RAB19 (ENSG00000146955), RAB41 (ENSG00000147127)

Protein

Protein identifiers

Ras-related protein Rab-27A — P51159 (reviewed: P51159)

Alternative names: GTP-binding protein Ram

All UniProt accessions (7): P51159, A2RU94, H3BN55, H3BS49, H3BU81, H3BUD9, H3BVH7

UniProt curated annotations — full annotation on UniProt →

Function. The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes. Rabs cycle between an inactive GDP-bound form and an active GTP-bound form that is able to recruit to membranes different sets of downstream effectors directly responsible for vesicle formation, movement, tethering and fusion. RAB27A regulates homeostasis of late endocytic pathway, including endosomal positioning, maturation and secretion. Plays a role in cytotoxic granule exocytosis in lymphocytes. Required for both granule maturation and granule docking and priming at the immunologic synapse.

Subunit / interactions. Binds SYTL1, SLAC2B, MYRIP, SYTL3, SYTL4 and SYTL5. Interacts with RPH3A and RPH3A. Interacts with MLPH. Interacts with SYTL2. Interacts with UNC13D. Does not interact with the BLOC-3 complex (heterodimer of HPS1 and HPS4). Interacts (GDP-bound form preferentially) with DENND10. Interacts with FBXO28; this interaction promotes RAB27A ubiquitination and proteasomal degradation.

Subcellular location. Membrane. Melanosome. Late endosome. Lysosome.

Tissue specificity. Found in all the examined tissues except in brain. Low expression was found in thymus, kidney, muscle and placenta. Detected in melanocytes, and in most tumor cell lines examined. Expressed in cytotoxic T-lymphocytes (CTL) and mast cells.

Post-translational modifications. Ubiquitinated in a FBXO28-dependent manner; leading to proteasomal degradation.

Disease relevance. Griscelli syndrome 2 (GS2) [MIM:607624] Rare autosomal recessive disorder that results in pigmentary dilution of the skin and hair, the presence of large clumps of pigment in hair shafts, and an accumulation of melanosomes in melanocytes. GS2 patients also develop an uncontrolled T-lymphocyte and macrophage activation syndrome, known as hemophagocytic syndrome, leading to death in the absence of bone marrow transplantation. Neurological impairment is present in some patients, likely as a result of hemophagocytic syndrome. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Regulated by guanine nucleotide exchange factors (GEFs) including DENND10, which promote the exchange of bound GDP for free GTP. Regulated by GTPase activating proteins (GAPs) which increase the GTP hydrolysis activity. Inhibited by GDP dissociation inhibitors (GDIs).

Domain organisation. Switch I, switch II and the interswitch regions are characteristic of Rab GTPases and mediate the interactions with Rab downstream effectors. The switch regions undergo conformational changes upon nucleotide binding which drive interaction with specific sets of effector proteins, with most effectors only binding to GTP-bound Rab.

Similarity. Belongs to the small GTPase superfamily. Rab family.

Isoforms (2)

UniProt ID	Names	Canonical?
P51159-1	Long	yes
P51159-2	Short

RefSeq proteins (4): NP_004571, NP_899057, NP_899058, NP_899059 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001806	Small_GTPase	Family
IPR005225	Small_GTP-bd	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily
IPR041837	Rab27a/b	Family
IPR050305	Small_GTPase_Rab	Family

Pfam: PF00071

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (59 total): binding site 18, helix 10, strand 7, sequence variant 6, mutagenesis site 4, modified residue 3, region of interest 2, lipid moiety-binding region 2, sequence conflict 2, initiator methionine 1, chain 1, disulfide bond 1, splice variant 1, turn 1

Structure

Experimental structures (PDB)

11 structures.

PDB	Method	Resolution (Å)
8P3I	X-RAY DIFFRACTION	2
9GVU	X-RAY DIFFRACTION	2.1
8P3G	X-RAY DIFFRACTION	2.13
8P3J	X-RAY DIFFRACTION	2.16
7OPQ	X-RAY DIFFRACTION	2.23
7OPP	X-RAY DIFFRACTION	2.32
7OPR	X-RAY DIFFRACTION	2.32
8P3K	X-RAY DIFFRACTION	2.58
8P3H	X-RAY DIFFRACTION	2.76
6HUF	X-RAY DIFFRACTION	2.82
9LA9	ELECTRON MICROSCOPY	4.38

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P51159-F1	84.69	0.63

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (18): 35; 36; 40; 41; 41; 74; 77; 133; 134; 136; 164; 165 …

Post-translational modifications (5): 2, 2, 221, 219, 221

Disulfide bonds (1): 123–188

Mutagenesis-validated functional residues (4):

Position	Phenotype
23	gdp-locked. abolishes interaction with unc13d and localization to lysosomes. increases interaction with dennd10. disrupt
70	abolishes interaction with sytl2.
76	abolishes interaction with sytl2.
78	gtp-locked. decreases interaction with dennd10.

Function

Pathways and Gene Ontology

Reactome pathways

5 pathways

ID	Pathway
R-HSA-264876	Insulin processing
R-HSA-6798695	Neutrophil degranulation
R-HSA-8873719	RAB geranylgeranylation
R-HSA-8876198	RAB GEFs exchange GTP for GDP on RABs
R-HSA-9824585	Regulation of MITF-M-dependent genes involved in pigmentation

MSigDB gene sets: 494 (showing top): GOBP_SYNAPTIC_VESICLE_LOCALIZATION, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_PIGMENT_GRANULE_LOCALIZATION, GOBP_POSITIVE_REGULATION_OF_ENDOCYTOSIS, GOBP_ENDOSOME_ORGANIZATION, BOYAULT_LIVER_CANCER_SUBCLASS_G56_DN, GOBP_VESICLE_LOCALIZATION, GOCC_SECRETORY_GRANULE, GOBP_T_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_VESICLE_ORGANIZATION, GOBP_POSITIVE_REGULATION_OF_REACTIVE_OXYGEN_SPECIES_BIOSYNTHETIC_PROCESS, HALMOS_CEBPA_TARGETS_UP, GOBP_REGULATION_OF_EXOCYTOSIS, GOBP_CELLULAR_PIGMENTATION

GO Biological Process (24): exocytosis (GO:0006887), blood coagulation (GO:0007596), protein secretion (GO:0009306), positive regulation of gene expression (GO:0010628), antigen processing and presentation (GO:0019882), melanocyte differentiation (GO:0030318), melanosome localization (GO:0032400), melanosome transport (GO:0032402), multivesicular body organization (GO:0036257), cytotoxic T cell degranulation (GO:0043316), natural killer cell degranulation (GO:0043320), positive regulation of exocytosis (GO:0045921), synaptic vesicle transport (GO:0048489), positive regulation of phagocytosis (GO:0050766), multivesicular body sorting pathway (GO:0071985), complement-dependent cytotoxicity (GO:0097278), positive regulation of regulated secretory pathway (GO:1903307), positive regulation of reactive oxygen species biosynthetic process (GO:1903428), positive regulation of constitutive secretory pathway (GO:1903435), exosomal secretion (GO:1990182), vesicle-mediated transport (GO:0016192), pigmentation (GO:0043473), pigment granule localization (GO:0051875), pigment granule transport (GO:0051904)

GO Molecular Function (9): GTPase activity (GO:0003924), G protein activity (GO:0003925), GTP binding (GO:0005525), GDP binding (GO:0019003), protein domain specific binding (GO:0019904), myosin V binding (GO:0031489), nucleotide binding (GO:0000166), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (18): photoreceptor outer segment (GO:0001750), extracellular region (GO:0005576), lysosome (GO:0005764), late endosome (GO:0005770), Golgi apparatus (GO:0005794), cytosol (GO:0005829), apical plasma membrane (GO:0016324), secretory granule (GO:0030141), dendrite (GO:0030425), multivesicular body membrane (GO:0032585), Weibel-Palade body (GO:0033093), melanosome membrane (GO:0033162), specific granule lumen (GO:0035580), melanosome (GO:0042470), extracellular exosome (GO:0070062), exocytic vesicle (GO:0070382), endosome (GO:0005768), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Peptide hormone metabolism	1
Innate Immune System	1
Post-translational protein modification	1
Rab regulation of trafficking	1
MITF-M-dependent gene expression	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
endomembrane system	3
vesicle-mediated transport	2
secretion by cell	2
leukocyte degranulation	2
exocytosis	2
establishment of vesicle localization	2
positive regulation of exocytosis	2
guanyl ribonucleotide binding	2
cytoplasm	2
secretory vesicle	2
vesicle fusion to plasma membrane	1
hemostasis	1
wound healing	1
coagulation	1
protein transport	1
establishment of protein localization to extracellular region	1
protein localization to extracellular region	1
gene expression	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
immune system process	1
pigment cell differentiation	1
pigment granule localization	1
melanosome localization	1
establishment of melanosome localization	1
pigment granule transport	1
endosome organization	1
T cell mediated cytotoxicity	1
T cell activation involved in immune response	1
natural killer cell activation involved in immune response	1
natural killer cell mediated cytotoxicity	1
regulation of exocytosis	1
positive regulation of secretion by cell	1
transport	1
cellular process	1
synaptic vesicle localization	1
phagocytosis	1
positive regulation of endocytosis	1
regulation of phagocytosis	1

Protein interactions and networks

STRING

1766 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RAB27A	UNC13D	Q70J99	999
RAB27A	MLPH	Q9BV36	999
RAB27A	MYO5A	Q9Y4I1	999
RAB27A	MYRIP	Q8NFW9	997
RAB27A	SYTL4	Q96C24	997
RAB27A	SYTL2	Q9HCH5	991
RAB27A	SYTL1	Q8IYJ3	983
RAB27A	EXPH5	Q8NEV8	970
RAB27A	STX11	O75558	929
RAB27A	RPH3A	Q9Y2J0	915
RAB27A	TBC1D10A	Q9BXI6	900
RAB27A	DPYSL2	Q16555	862
RAB27A	MYO7A	P78427	857
RAB27A	CHM	P24386	852
RAB27A	TBC1D10B	Q4KMP7	851

IntAct

57 interactions, top by confidence:

A	B	Type	Score
MLPH	RAB27A	psi-mi:“MI:0915”(physical association)	0.830
RAB27A	MLPH	psi-mi:“MI:0915”(physical association)	0.830
MLPH	RAB27A	psi-mi:“MI:0914”(association)	0.830
RAB27A	MLPH	psi-mi:“MI:0407”(direct interaction)	0.830
RAB27A	SYTL1	psi-mi:“MI:0915”(physical association)	0.740
RAB27A	SYTL3	psi-mi:“MI:0915”(physical association)	0.740
RAB27A	SYTL4	psi-mi:“MI:0915”(physical association)	0.740
UNC13D	RAB27A	psi-mi:“MI:0915”(physical association)	0.570
RAB27A	MYRIP	psi-mi:“MI:0915”(physical association)	0.560
RAB27A	SYTL5	psi-mi:“MI:0915”(physical association)	0.560
SH3BGRL3	PCP4	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
DDX21	MED19	psi-mi:“MI:2364”(proximity)	0.480
PCP4	RAB27A	psi-mi:“MI:0915”(physical association)	0.400
ACTA1	RAB27A	psi-mi:“MI:0915”(physical association)	0.400
RAB27A	DKC1	psi-mi:“MI:0914”(association)	0.350
RPH3A	RAB27A	psi-mi:“MI:0914”(association)	0.350
SYTL5	CCDC85C	psi-mi:“MI:0914”(association)	0.350
RAB27A	GTPBP1	psi-mi:“MI:0914”(association)	0.350
KLK10	IGLL5	psi-mi:“MI:0914”(association)	0.350
CHI3L1	IGF1R	psi-mi:“MI:0914”(association)	0.350
RAB27A	ATE1	psi-mi:“MI:0914”(association)	0.350
RAB27B	MYH7B	psi-mi:“MI:0914”(association)	0.350
FASTKD2	MED19	psi-mi:“MI:2364”(proximity)	0.270
GPKOW	ESYT2	psi-mi:“MI:2364”(proximity)	0.270

BioGRID (147): RAB27A (Affinity Capture-MS), RAB27A (Affinity Capture-MS), RAB27A (Affinity Capture-MS), RAB27A (Affinity Capture-Western), RAB27A (Reconstituted Complex), RAB27A (Proximity Label-MS), RAB27A (Proximity Label-MS), RAB27A (Proximity Label-MS), RPH3AL (Reconstituted Complex), RAB27A (Reconstituted Complex), SYTL1 (Affinity Capture-Western), SYTL5 (Affinity Capture-Western), MYRIP (Affinity Capture-Western), SYTL2 (Affinity Capture-Western), SYTL3 (Affinity Capture-Western)

ESM2 similar proteins: A4D1S5, O13876, O80501, P05714, P10948, P10949, P20337, P20338, P34213, P35289, P35293, P35294, P51152, P51159, P56371, P62823, P90726, Q05976, Q0IIG8, Q15771, Q17QB7, Q18969, Q1HE58, Q28IZ3, Q2TBH7, Q32NQ0, Q3ZC27, Q53B90, Q54E92, Q55FK2, Q5EB77, Q5KTJ7, Q5M7U5, Q5R5H5, Q63941, Q68EK7, Q6DHC1, Q6PHI9, Q8CG50, Q923S9

Diamond homologs: A4IHM6, F1PTE3, F4KFD8, O13876, O23657, O49841, P35286, P51153, P51157, P51158, P51159, Q14964, Q17QU4, Q18969, Q32LJ6, Q3SWY9, Q58DS5, Q5HYI8, Q5KTJ6, Q5RFI2, Q5UQ27, Q5ZKR4, Q6GPS4, Q6TNS7, Q7T3A4, Q7Z6P3, Q8BHC1, Q8BHD0, Q8N4Z0, Q948K8, Q96DA2, Q99KL7, Q9C5J9, Q9D4V7, Q9DD03, Q9SJ11, A4FV54, C4YL11, O00194, O24466

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 46 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
exocytosis	5	17.6×	1e-03
intracellular protein transport	7	10.6×	1e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

351 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	44
Likely pathogenic	18
Uncertain significance	142
Likely benign	89
Benign	30

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1073444	NC_000015.9:g.(?55497685)(55527152_?)del	Pathogenic
1074152	NM_183235.3(RAB27A):c.439G>T (p.Glu147Ter)	Pathogenic
1339548	NM_183235.3(RAB27A):c.137T>G (p.Phe46Cys)	Pathogenic
1408103	NM_183235.3(RAB27A):c.227C>T (p.Ala76Val)	Pathogenic
1409958	NM_183235.3(RAB27A):c.335del (p.Asn112fs)	Pathogenic
1453208	NM_183235.3(RAB27A):c.460A>T (p.Lys154Ter)	Pathogenic
1459351	NC_000015.9:g.(?55526960)(55613608_?)del	Pathogenic
1519012	NM_183235.3(RAB27A):c.239G>C (p.Arg80Thr)	Pathogenic
1690307	NM_183235.3(RAB27A):c.598C>T (p.Arg200Ter)	Pathogenic
1690308	NM_183235.3(RAB27A):c.400A>G (p.Lys134Glu)	Pathogenic
1690310	NM_183235.3(RAB27A):c.467+5G>A	Pathogenic
1690311	NC_000015.9:g.55514530_55552423dup	Pathogenic
1694156	NM_183235.3(RAB27A):c.239+1G>T	Pathogenic
2010396	NC_000015.10:g.55224013del	Pathogenic
2047437	NM_183235.3(RAB27A):c.147_148del (p.Arg50fs)	Pathogenic
2078065	NM_183235.3(RAB27A):c.638_642del (p.Glu213fs)	Pathogenic
2137718	NM_183235.3(RAB27A):c.240-2A>C	Pathogenic
2501797	NM_183235.3(RAB27A):c.467+3_467+6del	Pathogenic
2710378	NM_183235.3(RAB27A):c.465T>A (p.Tyr155Ter)	Pathogenic
2852056	NM_183235.3(RAB27A):c.467+1G>T	Pathogenic
3064868	NM_183235.3(RAB27A):c.148del (p.Arg50fs)	Pathogenic
3243801	NC_000015.9:g.(?55522579)(55522704_?)del	Pathogenic
3243802	NC_000015.9:g.(?55520787)(55522704_?)del	Pathogenic
3353400	NM_183235.3(RAB27A):c.586del (p.Glu196fs)	Pathogenic
3572949	NM_183235.3(RAB27A):c.240-5_242del	Pathogenic
3767552	NM_183235.3(RAB27A):c.148_149delinsC (p.Arg50fs)	Pathogenic
417958	NM_183235.3(RAB27A):c.514_518del (p.Gln172fs)	Pathogenic
436458	NM_183235.3(RAB27A):c.550C>T (p.Arg184Ter)	Pathogenic
451279	NM_183235.3(RAB27A):c.18_19del (p.Tyr6_Asp7delinsTer)	Pathogenic
468590	NC_000015.10:g.(?55228589)(55234954_?)del	Pathogenic

SpliceAI

2217 predictions. Top by Δscore:

Variant	Effect	Δscore
15:55223881:ATACT:A	donor_loss	1.0000
15:55223883:ACTC:A	donor_loss	1.0000
15:55223884:CTCA:C	donor_loss	1.0000
15:55223885:T:TA	donor_loss	1.0000
15:55223886:CA:C	donor_loss	1.0000
15:55223887:A:AC	donor_gain	1.0000
15:55223887:A:T	donor_loss	1.0000
15:55223887:AC:A	donor_gain	1.0000
15:55223887:ACC:A	donor_gain	1.0000
15:55223888:C:CA	donor_loss	1.0000
15:55223888:C:CC	donor_gain	1.0000
15:55223888:CC:C	donor_gain	1.0000
15:55223888:CCC:C	donor_gain	1.0000
15:55223888:CCCAT:C	donor_gain	1.0000
15:55228607:A:AC	donor_gain	1.0000
15:55228608:C:CC	donor_gain	1.0000
15:55228608:CTTAT:C	donor_gain	1.0000
15:55228611:AT:A	donor_gain	1.0000
15:55228612:T:C	donor_gain	1.0000
15:55234781:CCA:C	donor_gain	1.0000
15:55234781:CCACT:C	donor_gain	1.0000
15:55234957:C:CC	acceptor_gain	1.0000
15:55270164:CCT:C	donor_gain	1.0000
15:55270285:C:CC	acceptor_gain	1.0000
15:55270288:A:AC	acceptor_gain	1.0000
15:55270288:A:C	acceptor_gain	1.0000
15:55223880:AATAC:A	donor_loss	0.9900
15:55223882:TAC:T	donor_loss	0.9900
15:55224008:CTGGC:C	acceptor_gain	0.9900
15:55224011:GCC:G	acceptor_loss	0.9900

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000002083 (15:55240113 T>C), RS1000024271 (15:55264845 T>C), RS1000033285 (15:55240472 T>C), RS1000037843 (15:55277260 G>T), RS1000040114 (15:55269471 G>A,T), RS1000109343 (15:55276036 G>A,T), RS1000187918 (15:55232639 T>A), RS1000191324 (15:55221678 A>G), RS1000236474 (15:55222786 C>T), RS1000300719 (15:55234322 C>T), RS1000339633 (15:55219866 T>C), RS1000392795 (15:55277122 T>C,G), RS1000404549 (15:55228358 G>A), RS1000418257 (15:55264259 C>G), RS1000441904 (15:55258625 A>G)

Disease associations

OMIM: gene MIM:603868 | disease phenotypes: MIM:607624, MIM:214450

GenCC curated gene-disease

Disease	Classification	Inheritance
Griscelli syndrome type 2	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
Griscelli syndrome type 2	Definitive	AR

Mondo (3): Griscelli syndrome type 2 (MONDO:0011872), autoinflammatory syndrome (MONDO:0019751), Griscelli syndrome (MONDO:0018306)

Orphanet (3): Griscelli syndrome (Orphanet:381), Griscelli syndrome type 2 (Orphanet:79477), Autoinflammatory syndrome (Orphanet:93665)

HPO phenotypes

31 total (30 of 31 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000952	Jaundice
HP:0000967	Petechiae
HP:0001008	Accumulation of melanosomes in melanocytes
HP:0001010	Hypopigmentation of the skin
HP:0001250	Seizure
HP:0001257	Spasticity
HP:0001276	Hypertonia
HP:0001433	Hepatosplenomegaly
HP:0001744	Splenomegaly
HP:0001875	Decreased total neutrophil count
HP:0001876	Pancytopenia
HP:0001945	Fever
HP:0002017	Nausea and vomiting
HP:0002113	Pulmonary infiltrates
HP:0002216	Premature graying of hair
HP:0002218	Silver-gray hair
HP:0002220	Melanin pigment aggregation in hair shafts
HP:0002240	Hepatomegaly
HP:0002344	Progressive neurologic deterioration
HP:0002716	Lymphadenopathy
HP:0002718	Recurrent bacterial infections
HP:0002721	Immunodeficiency
HP:0002972	Reduced delayed hypersensitivity
HP:0003077	Hyperlipidemia
HP:0003593	Infantile onset
HP:0003819	Death in childhood
HP:0005599	Hypopigmentation of hair
HP:0007443	Partial albinism
HP:0007730	Iris hypopigmentation

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST002704_2	Fractional exhaled nitric oxide levels	2.000000e-07
GCST007842_5	Glioma	6.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0005536	nitric oxide exhalation measurement

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
C537302	Griscelli syndrome type 2 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4105702 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 4,529 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL3218576	COPANLISIB	4	4,529

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB variants

2 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs4261468	RAB27A		0.00	0
rs12050885	RAB27A		0.00	0

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — RAB subfamily

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
Nexinhib20	Inhibition	5.59	pIC50

ChEMBL bioactivities

3 potent at pChembl≥5 of 4 total, top 3 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
5.58	IC50	2600	nM	CHEMBL6160892
5.58	IC50	2600	nM	CHEMBL1459140
5.35	Kd	4493	nM	COPANLISIB

PubChem BioAssay actives

1 with measured affinity, of 223 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
2-amino-N-[7-methoxy-8-(3-morpholin-4-ylpropoxy)-2,3-dihydro-1H-imidazo[1,2-c]quinazolin-5-ylidene]pyrimidine-5-carboxamide	1425149: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	4.4930	uM

CTD chemical–gene interactions

42 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases expression	5
sodium arsenite	affects expression, increases expression	4
Cyclosporine	increases expression	3
bisphenol A	affects cotreatment, decreases methylation, increases expression	2
cobaltous chloride	decreases expression	2
entinostat	decreases expression, affects cotreatment	2
(+)-JQ1 compound	decreases expression	2
Acetaminophen	decreases expression, increases expression	2
Benzo(a)pyrene	affects methylation, increases expression, increases methylation	2
Nickel	increases expression	2
Silicon Dioxide	decreases expression	2
testosterone enanthate	affects expression	1
methylmercuric chloride	decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	decreases expression	1
perfluorooctanoic acid	increases expression	1
ochratoxin A	affects binding	1
potassium chromate(VI)	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, decreases expression, increases expression	1
Sunitinib	decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation	1
Leflunomide	decreases expression	1
Alitretinoin	decreases expression, decreases response to substance	1
Arsenic	affects methylation	1
Cisplatin	increases expression	1
Ethyl Methanesulfonate	increases expression	1
Ivermectin	decreases expression	1
Methyl Methanesulfonate	increases expression	1

ChEMBL screening assays

3 unique, capped per target: 3 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3991862	Binding	Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by ma	The target landscape of clinical kinase drugs. — Science

Cellosaurus cell lines

6 cell lines: 6 cancer cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2D1	Abcam HeLa RAB27A KO	Cancer cell line	Female
CVCL_B2PQ	Abcam A-549 RAB27A KO	Cancer cell line	Male
CVCL_D7Z4	Ubigene A-549 RAB27A KO	Cancer cell line	Male
CVCL_E0MF	Ubigene HeLa RAB27A KO	Cancer cell line	Female
CVCL_TI06	HAP1 RAB27A (-) 1	Cancer cell line	Male
CVCL_TI07	HAP1 RAB27A (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

8 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00442182	PHASE2	UNKNOWN	The Efficacy and Safety of ITF2357 in AIS
NCT00176865	PHASE2	COMPLETED	Stem Cell Transplant for Immunologic or Histiocytic Disorders
NCT00887939	Not specified	COMPLETED	Pathogenesis of Physical Induced Urticarial Syndromes
NCT03510442	Not specified	RECRUITING	Natural History, Genetics, and Pathophysiology of Systemic Juvenile Idiopathic Arthritis, Adult-Onset Still’s Disease, and Related Conditions
NCT06248957	Not specified	RECRUITING	SYSTEMS-LEVEL ANALYSES OF IMMUNE DYSREGULATION
NCT00176826	PHASE2/PHASE3	TERMINATED	T-Cell Depletion and Stem Cell Transplant for Immune Deficiencies and Histiocytic Disorders
NCT01652092	Not specified	ACTIVE_NOT_RECRUITING	Allogeneic Hematopoietic Stem Cell Transplant for Patients With Primary Immune Deficiencies
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening