Griscelli syndrome type 2

Summary

Griscelli syndrome type 2 (MONDO:0011872) is a disease caused by RAB27A (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: RAB27A (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 309
• Phenotypes (HPO): 19

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		102	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

19 HPO clinical features (Orphanet curated; top 19 by frequency):

HPO ID	Term	Frequency
HP:0001744	Splenomegaly	Very frequent (80-99%)
HP:0001876	Pancytopenia	Very frequent (80-99%)
HP:0002216	Premature graying of hair	Very frequent (80-99%)
HP:0002240	Hepatomegaly	Very frequent (80-99%)
HP:0002721	Immunodeficiency	Very frequent (80-99%)
HP:0005599	Hypopigmentation of hair	Very frequent (80-99%)
HP:0007443	Partial albinism	Very frequent (80-99%)
HP:0012156	Hemophagocytosis	Very frequent (80-99%)
HP:0000952	Jaundice	Frequent (30-79%)
HP:0001875	Decreased total neutrophil count	Frequent (30-79%)
HP:0002716	Lymphadenopathy	Frequent (30-79%)
HP:0003077	Hyperlipidemia	Frequent (30-79%)
HP:0000967	Petechiae	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001276	Hypertonia	Occasional (5-29%)
HP:0001945	Fever	Occasional (5-29%)
HP:0002017	Nausea and vomiting	Occasional (5-29%)
HP:0002113	Pulmonary infiltrates	Occasional (5-29%)
HP:0007730	Iris hypopigmentation	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Griscelli syndrome type 2
Mondo ID	MONDO:0011872
MeSH	C537302
OMIM	607624
Orphanet	79477
DOID	DOID:0060833
ICD-11	1836541365
NCIT	C111814
UMLS	C1868679
MedGen	357030
GARD	0004483
Is cancer (heuristic)	no

Also known as: Griscelli syndrome type 2 · Griscelli syndrome with hemophagocytic syndrome · Griscelli syndrome, type 2 · Griscelli-PruniC)ras syndrome type 2 · Griscelli-Pruniéras syndrome type 2 · Griscelli-Pruni��ras syndrome type 2 · GS2 · hypopigmentation-immunodeficiency with or without neurologic impairment syndrome · PAID syndrome · partial albinism and immunodeficiency syndrome

Data availability: 309 ClinVar variants · 3 GenCC gene-disease records.

Disease family

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

Related subtypes (12): cyclic hematopoiesis, Chediak-Higashi syndrome, Cohen syndrome, glycogen storage disease Ib, Lichtenstein syndrome, Barth syndrome, poikiloderma with neutropenia, Hermansky-Pudlak syndrome 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

309 retrieved; paginated sample, class counts are floors:

120 uncertain significance, 86 likely benign, 42 pathogenic, 23 benign, 15 conflicting classifications of pathogenicity, 15 likely pathogenic, 5 pathogenic/likely pathogenic, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1073444	NC_000015.9:g.(?55497685)(55527152_?)del	RAB27A	Pathogenic	criteria provided, single submitter
1074135	NM_183235.3(RAB27A):c.400_401del (p.Lys134fs)	RAB27A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074152	NM_183235.3(RAB27A):c.439G>T (p.Glu147Ter)	RAB27A	Pathogenic	criteria provided, single submitter
1339548	NM_183235.3(RAB27A):c.137T>G (p.Phe46Cys)	RAB27A	Pathogenic	criteria provided, single submitter
1408103	NM_183235.3(RAB27A):c.227C>T (p.Ala76Val)	RAB27A	Pathogenic	criteria provided, single submitter
1409958	NM_183235.3(RAB27A):c.335del (p.Asn112fs)	RAB27A	Pathogenic	criteria provided, multiple submitters, no conflicts
1453208	NM_183235.3(RAB27A):c.460A>T (p.Lys154Ter)	RAB27A	Pathogenic	criteria provided, single submitter
1459351	NC_000015.9:g.(?55526960)(55613608_?)del	RAB27A	Pathogenic	criteria provided, single submitter
1519012	NM_183235.3(RAB27A):c.239G>C (p.Arg80Thr)	RAB27A	Pathogenic	criteria provided, single submitter
1690307	NM_183235.3(RAB27A):c.598C>T (p.Arg200Ter)	RAB27A	Pathogenic	no assertion criteria provided
1690308	NM_183235.3(RAB27A):c.400A>G (p.Lys134Glu)	RAB27A	Pathogenic	criteria provided, single submitter
1690310	NM_183235.3(RAB27A):c.467+5G>A	RAB27A	Pathogenic	no assertion criteria provided
1690311	NC_000015.9:g.55514530_55552423dup	RAB27A	Pathogenic	no assertion criteria provided
1694156	NM_183235.3(RAB27A):c.239+1G>T	RAB27A	Pathogenic	criteria provided, multiple submitters, no conflicts
2010396	NC_000015.10:g.55224013del	RAB27A	Pathogenic	criteria provided, single submitter
2047437	NM_183235.3(RAB27A):c.147_148del (p.Arg50fs)	RAB27A	Pathogenic	criteria provided, single submitter
2078065	NM_183235.3(RAB27A):c.638_642del (p.Glu213fs)	RAB27A	Pathogenic	criteria provided, single submitter
2137718	NM_183235.3(RAB27A):c.240-2A>C	RAB27A	Pathogenic	criteria provided, single submitter
2501797	NM_183235.3(RAB27A):c.467+3_467+6del	RAB27A	Pathogenic	criteria provided, single submitter
2710378	NM_183235.3(RAB27A):c.465T>A (p.Tyr155Ter)	RAB27A	Pathogenic	criteria provided, single submitter
2852056	NM_183235.3(RAB27A):c.467+1G>T	RAB27A	Pathogenic	criteria provided, single submitter
3064868	NM_183235.3(RAB27A):c.148del (p.Arg50fs)	RAB27A	Pathogenic	criteria provided, single submitter
3243801	NC_000015.9:g.(?55522579)(55522704_?)del	RAB27A	Pathogenic	criteria provided, single submitter
3243802	NC_000015.9:g.(?55520787)(55522704_?)del	RAB27A	Pathogenic	criteria provided, single submitter
3363143	NM_183235.3(RAB27A):c.514C>T (p.Gln172Ter)	RAB27A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3572949	NM_183235.3(RAB27A):c.240-5_242del	RAB27A	Pathogenic	criteria provided, single submitter
417958	NM_183235.3(RAB27A):c.514_518del (p.Gln172fs)	RAB27A	Pathogenic	criteria provided, multiple submitters, no conflicts
419794	NM_183235.3(RAB27A):c.244C>T (p.Arg82Cys)	RAB27A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
436458	NM_183235.3(RAB27A):c.550C>T (p.Arg184Ter)	RAB27A	Pathogenic	criteria provided, multiple submitters, no conflicts
451279	NM_183235.3(RAB27A):c.18_19del (p.Tyr6_Asp7delinsTer)	RAB27A	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · Orphanet: 2 · 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
RAB27A	Strong	Autosomal recessive	Griscelli syndrome type 2	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RAB27A	Orphanet:79477	Griscelli syndrome type 2
DNAAF4	Orphanet:244	Primary ciliary dyskinesia

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RAB27A	HGNC:9766	ENSG00000069974	P51159	Ras-related protein Rab-27A	gencc,clinvar
DNAAF4	HGNC:21493	ENSG00000256061	Q8WXU2	Dynein axonemal assembly factor 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RAB27A	Ras-related protein Rab-27A	The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes.
DNAAF4	Dynein axonemal assembly factor 4	Axonemal dynein assembly factor required for ciliary motility.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 2 · 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	2	1.8×	0.312

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RAB27A	Other/Unknown	no		Small_GTPase, Small_GTP-bd, P-loop_NTPase
DNAAF4	Other/Unknown	no		CS_dom, HSP20-like_chaperone, TPR-like_helical_dom_sf

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lower lobe of lung	1
monocyte	1
trabecular bone tissue	1
bronchial epithelial cell	1
bronchus	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RAB27A	275	ubiquitous	marker	trabecular bone tissue, monocyte, lower lobe of lung
DNAAF4	188	ubiquitous	marker	bronchial epithelial cell, bronchus, secondary oocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RAB27A	1,970
DNAAF4	1,742

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RAB27A	P51159	11

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DNAAF4	Q8WXU2	84.00

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 2 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
Insulin processing	1	456.8×	0.009	RAB27A
Regulation of MITF-M-dependent genes involved in pigmentation	1	265.6×	0.009	RAB27A
RAB geranylgeranylation	1	173.0×	0.010	RAB27A
RAB GEFs exchange GTP for GDP on RABs	1	124.1×	0.010	RAB27A
Neutrophil degranulation	1	23.1×	0.043	RAB27A

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
multivesicular body organization	1	8426.0×	0.001	RAB27A
cytotoxic T cell degranulation	1	8426.0×	0.001	RAB27A
positive regulation of constitutive secretory pathway	1	8426.0×	0.001	RAB27A
complement-dependent cytotoxicity	1	4213.0×	0.002	RAB27A
exosomal secretion	1	2106.5×	0.003	RAB27A
melanosome localization	1	1685.2×	0.003	RAB27A
positive regulation of regulated secretory pathway	1	1685.2×	0.003	RAB27A
natural killer cell degranulation	1	1203.7×	0.003	RAB27A
regulation of intracellular estrogen receptor signaling pathway	1	936.2×	0.004	DNAAF4
positive regulation of reactive oxygen species biosynthetic process	1	561.7×	0.005	RAB27A
inner dynein arm assembly	1	443.5×	0.005	DNAAF4
synaptic vesicle transport	1	421.3×	0.005	RAB27A
melanocyte differentiation	1	401.2×	0.005	RAB27A
multivesicular body sorting pathway	1	401.2×	0.005	RAB27A
epithelial cilium movement involved in extracellular fluid movement	1	383.0×	0.005	DNAAF4
melanosome transport	1	383.0×	0.005	RAB27A
regulation of proteasomal protein catabolic process	1	383.0×	0.005	DNAAF4
outer dynein arm assembly	1	366.4×	0.005	DNAAF4
antigen processing and presentation	1	351.1×	0.005	RAB27A
positive regulation of exocytosis	1	300.9×	0.005	RAB27A
cilium movement	1	195.9×	0.008	DNAAF4
positive regulation of phagocytosis	1	159.0×	0.009	RAB27A
protein secretion	1	131.7×	0.010	RAB27A
determination of left/right symmetry	1	127.7×	0.010	DNAAF4
learning or memory	1	120.4×	0.010	DNAAF4
blood coagulation	1	86.9×	0.014	RAB27A
establishment of localization in cell	1	80.2×	0.014	DNAAF4
exocytosis	1	75.9×	0.015	RAB27A
neuron migration	1	66.9×	0.016	DNAAF4
heart development	1	39.4×	0.026	DNAAF4

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
RAB27A	COPANLISIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RAB27A	1	4
DNAAF4	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
COPANLISIB	4	RAB27A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
RAB27A	3	Binding:3

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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)
COPANLISIB	4	RAB27A

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	RAB27A
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	DNAAF4

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)
DNAAF4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.