Griscelli syndrome type 3

Summary

Griscelli syndrome type 3 (MONDO:0012220) is a disease caused by MLPH (GenCC Strong), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: MLPH (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 16
• Phenotypes (HPO): 3

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		13	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

3 HPO clinical features (Orphanet curated; top 3 by frequency):

HPO ID	Term	Frequency
HP:0005599	Hypopigmentation of hair	Very frequent (80-99%)
HP:0007443	Partial albinism	Occasional (5-29%)
HP:0007730	Iris hypopigmentation	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Griscelli syndrome type 3
Mondo ID	MONDO:0012220
MeSH	C537303
OMIM	609227
Orphanet	79478
DOID	DOID:0060834
ICD-11	1959052636
UMLS	C1836573
MedGen	373124
GARD	0009715
Is cancer (heuristic)	no

Also known as: Griscelli syndrome type 3 · Griscelli syndrome, type 3 · Griscelli-PruniC)ras syndrome type 3 · Griscelli-Pruniéras syndrome type 3 · Griscelli-Pruni��ras syndrome type 3 · GS3 · hypomelanosis with no immunologic or neurologic manifestations

Data availability: 16 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › syndromic oculocutaneous albinism › Griscelli syndrome › Griscelli syndrome type 3

Related subtypes (2): Griscelli syndrome type 1, Griscelli syndrome type 2

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

16 retrieved; paginated sample, class counts are floors:

4 uncertain significance, 3 benign, 3 likely pathogenic, 3 pathogenic, 1 pathogenic/likely pathogenic, 1 conflicting classifications of pathogenicity, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1686914	NM_024101.7(MLPH):c.292G>T (p.Glu98Ter)	MLPH	Pathogenic	no assertion criteria provided
191157	NM_024101.7(MLPH):c.104G>A (p.Arg35Gln)	MLPH	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
191315	NM_024101.7(MLPH):c.987del (p.Lys330fs)	MLPH	Pathogenic	criteria provided, single submitter
14071	NM_001382347.1(MYO5A):c.4239+871_4315-331del	MYO5A	Pathogenic	no assertion criteria provided
1324723	NM_024101.7(MLPH):c.332+1G>T	MLPH	Likely pathogenic	criteria provided, single submitter
3891697	NM_024101.7(MLPH):c.963_966del (p.Ala321_His322insTer)	MLPH	Likely pathogenic	criteria provided, single submitter
4268	NM_024101.7(MLPH):c.103C>T (p.Arg35Trp)	MLPH	Likely pathogenic	criteria provided, single submitter
636328	NM_024101.7(MLPH):c.70C>T (p.Arg24Ter)	MLPH	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2222959	NM_024101.7(MLPH):c.1552C>G (p.Arg518Gly)	MLPH	Uncertain significance	criteria provided, multiple submitters, no conflicts
3068068	NM_024101.7(MLPH):c.523GCCCAG[4] (p.Gln180_Pro181insAlaGln)	MLPH	Uncertain significance	criteria provided, single submitter
3235066	NM_024101.7(MLPH):c.1135_1136del (p.Asp379fs)	MLPH	Uncertain significance	criteria provided, single submitter
3250415	NM_024101.7(MLPH):c.959G>A (p.Arg320Gln)	MLPH	Uncertain significance	criteria provided, single submitter
1275303	NM_024101.7(MLPH):c.333-21A>G	MIR6811	Benign	criteria provided, multiple submitters, no conflicts
1287353	NM_024101.7(MLPH):c.1221A>G (p.Glu407=)	MLPH	Benign	criteria provided, multiple submitters, no conflicts
1321173	NM_024101.7(MLPH):c.1121T>C (p.Val374Ala)	MLPH	Benign	criteria provided, multiple submitters, no conflicts
728022	NM_024101.7(MLPH):c.522G>A (p.Glu174=)	MLPH	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 4 · 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
MYO5A	Definitive	Autosomal recessive	Griscelli syndrome type 1	6
MLPH	Strong	Autosomal recessive	Griscelli syndrome type 3	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
MLPH	Orphanet:79478	Griscelli syndrome type 3
MYO5A	Orphanet:33445	Neuroectodermal melanolysosomal disease
MYO5A	Orphanet:79476	Griscelli syndrome type 1
MYO5A	Orphanet:79478	Griscelli syndrome type 3

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MLPH	HGNC:29643	ENSG00000115648	Q9BV36	Melanophilin	gencc,clinvar
MYO5A	HGNC:7602	ENSG00000197535	Q9Y4I1	Unconventional myosin-Va	gencc,clinvar
MIR6811	HGNC:49944	ENSG00000277842		microRNA 6811	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MLPH	Melanophilin	Rab effector protein involved in melanosome transport.
MYO5A	Unconventional myosin-Va	Processive actin-based motor that can move in large steps approximating the 36-nm pseudo-repeat of the actin filament.

Protein-family classification

Druggable: 0 · Difficult: 2 · 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
Scaffold/PPI	1	5.8×	0.482
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MLPH	Transcription factor	no		Myrip/Melanophilin, Rab_BD, Znf_FYVE_PHD
MYO5A	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Dilute_dom
MIR6811	Other/Unknown	no

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)	1
broad (>20)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
pancreatic ductal cell	1
parotid gland	1
right uterine tube	1
endothelial cell	1
lateral nuclear group of thalamus	1
substantia nigra pars compacta	1
gastrocnemius	1
heart left ventricle	1
right frontal lobe	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MLPH	236	ubiquitous	marker	pancreatic ductal cell, parotid gland, right uterine tube
MYO5A	277	ubiquitous	marker	lateral nuclear group of thalamus, endothelial cell, substantia nigra pars compacta
MIR6811	18		yes	gastrocnemius, heart left ventricle, right frontal lobe

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MYO5A	4,333
MLPH	549
MIR6811	0

Intra-cohort edges

A	B	Sources
MLPH	MYO5A	biogrid_interaction, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MYO5A	Q9Y4I1	7

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
MLPH	Q9BV36	61.58

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 21. Enrichment computed across 3 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of MITF-M-dependent genes involved in pigmentation	2	265.6×	3e-04	MLPH, MYO5A
MITF-M-dependent gene expression	2	181.3×	3e-04	MLPH, MYO5A
MITF-M-regulated melanocyte development	2	114.2×	5e-04	MLPH, MYO5A
Insulin processing	1	228.4×	0.017	MYO5A
Parasite infection	1	173.0×	0.017	MYO5A
Leishmania phagocytosis	1	173.0×	0.017	MYO5A
Fcgamma receptor (FCGR) dependent phagocytosis	1	139.3×	0.017	MYO5A
Peptide hormone metabolism	1	135.9×	0.017	MYO5A
Developmental Biology	2	14.5×	0.017	MLPH, MYO5A
FCGR3A-mediated phagocytosis	1	93.6×	0.019	MYO5A
Regulation of actin dynamics for phagocytic cup formation	1	92.1×	0.019	MYO5A
Leishmania infection	1	81.6×	0.019	MYO5A
Parasitic Infection Pathways	1	81.6×	0.019	MYO5A
Translocation of SLC2A4 (GLUT4) to the plasma membrane	1	77.2×	0.019	MYO5A
Membrane Trafficking	1	18.5×	0.074	MYO5A
Vesicle-mediated transport	1	17.4×	0.074	MYO5A
Innate Immune System	1	12.8×	0.092	MYO5A
Infectious disease	1	12.4×	0.092	MYO5A
Disease	1	6.5×	0.155	MYO5A
Immune System	1	6.5×	0.155	MYO5A
Metabolism of proteins	1	6.2×	0.155	MYO5A

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
melanosome transport	2	766.0×	2e-05	MLPH, MYO5A
vesicle transport along actin filament	1	1203.7×	0.005	MYO5A
post-Golgi vesicle-mediated transport	1	526.6×	0.007	MYO5A
actin filament-based movement	1	401.2×	0.007	MYO5A
cellular response to insulin stimulus	1	85.1×	0.026	MYO5A
actin filament organization	1	59.3×	0.026	MYO5A
protein localization to plasma membrane	1	54.4×	0.026	MYO5A
vesicle-mediated transport	1	48.1×	0.026	MYO5A
endocytosis	1	47.6×	0.026	MYO5A
intracellular protein transport	1	32.4×	0.034	MLPH
protein transport	1	21.9×	0.045	MYO5A

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 3 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
MLPH	0	0
MYO5A	0	0
MIR6811	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

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	3	MLPH, MYO5A, MIR6811

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
MLPH	0	—
MYO5A	0	—
MIR6811	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.