Familial hemophagocytic lymphohistiocytosis 5

Summary

Familial hemophagocytic lymphohistiocytosis 5 (MONDO:0013135) is a disease caused by STXBP2 (GenCC Definitive), with 4 cohort genes.

At a glance

• Causal gene: STXBP2 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 1,142

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	familial hemophagocytic lymphohistiocytosis 5
Mondo ID	MONDO:0013135
MeSH	C567752
OMIM	613101
DOID	DOID:0110925
UMLS	C2751293
MedGen	416514
GARD	0015614
Is cancer (heuristic)	no

Also known as: familial hemophagocytic lymphohistiocytosis type 5 · FHL5 · genetic hemophagocytic lymphohistiocytosis caused by mutation in STXBP2 · hemophagocytic lymphohistiocytosis, familial, 5 · hemophagocytic lymphohistiocytosis, familial, 5, with or without microvillus inclusion disease · hemophagocytic lymphohistiocytosis, familial, type 5 · STXBP2 genetic hemophagocytic lymphohistiocytosis

Data availability: 1,142 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › immune system disorder › inborn error of immunity › hereditary hemophagocytic lymphohistiocytosis › familial hemophagocytic lymphohistiocytosis 5

Related subtypes (10): Chediak-Higashi syndrome, familial hemophagocytic lymphohistiocytosis type 1, familial hemophagocytic lymphohistiocytosis 4, familial hemophagocytic lymphohistiocytosis 2, Griscelli syndrome type 2, Hermansky-Pudlak syndrome 2, familial hemophagocytic lymphohistiocytosis 3, Hermansky-Pudlak syndrome 9, hemophagocytic lymphohistiocytosis, familial, 6, hemophagocytic lymphohistiocytosis due to RhoG deficiency

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

600 retrieved; paginated sample, class counts are floors:

275 likely benign, 234 uncertain significance, 26 likely pathogenic, 19 benign, 14 benign/likely benign, 13 pathogenic, 9 pathogenic/likely pathogenic, 8 conflicting classifications of pathogenicity, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1029119	NM_006949.4(STXBP2):c.607del (p.His203fs)	STXBP2	Pathogenic	criteria provided, single submitter
1184438	NM_006949.4(STXBP2):c.902+5G>A	STXBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1184439	NM_006949.4(STXBP2):c.1146del (p.Lys383fs)	STXBP2	Pathogenic	criteria provided, single submitter
1385750	NM_006949.4(STXBP2):c.982C>T (p.Gln328Ter)	STXBP2	Pathogenic	criteria provided, single submitter
1410439	NM_006949.4(STXBP2):c.539_540delinsAA (p.Cys180Ter)	STXBP2	Pathogenic	criteria provided, single submitter
1451101	NC_000019.9:g.(?7709480)(7712696_?)del	STXBP2	Pathogenic	criteria provided, single submitter
1454120	NM_006949.4(STXBP2):c.1525C>T (p.Gln509Ter)	STXBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454871	NM_006949.4(STXBP2):c.1213C>T (p.Arg405Trp)	STXBP2	Pathogenic	criteria provided, multiple submitters, no conflicts
1458975	NM_006949.4(STXBP2):c.284del (p.Pro95fs)	STXBP2	Pathogenic	criteria provided, single submitter
1800888	NM_006949.4(STXBP2):c.1697G>A (p.Gly566Asp)	STXBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1988382	NM_006949.4(STXBP2):c.864G>A (p.Trp288Ter)	STXBP2	Pathogenic	criteria provided, single submitter
2034454	NM_006949.4(STXBP2):c.71_72del (p.Lys24fs)	STXBP2	Pathogenic	criteria provided, single submitter
2088755	NM_006949.4(STXBP2):c.420C>A (p.Tyr140Ter)	STXBP2	Pathogenic	criteria provided, single submitter
2120770	NM_006949.4(STXBP2):c.859_883del (p.Leu287fs)	STXBP2	Pathogenic	criteria provided, single submitter
2138203	NM_006949.4(STXBP2):c.1452+1G>A	STXBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2185136	NM_006949.4(STXBP2):c.1009C>T (p.Gln337Ter)	STXBP2	Pathogenic	criteria provided, single submitter
2195438	NM_006949.4(STXBP2):c.560C>T (p.Pro187Leu)	STXBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679076	NM_006949.4(STXBP2):c.430-1G>A	STXBP2	Pathogenic	criteria provided, single submitter
2679077	NM_006949.4(STXBP2):c.1138G>T (p.Glu380Ter)	STXBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679083	NM_006949.4(STXBP2):c.87+2T>C	STXBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679084	NM_006949.4(STXBP2):c.80del (p.Glu27fs)	STXBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679092	NM_006949.4(STXBP2):c.1611T>G (p.Tyr537Ter)	STXBP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1387655	NM_006949.4(STXBP2):c.703C>G (p.Arg235Gly)	STXBP2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1504339	NM_006949.4(STXBP2):c.326-1G>C	STXBP2	Likely pathogenic	criteria provided, single submitter
1516839	NC_000019.9:g.(?7706571)(7712696_?)del	STXBP2	Likely pathogenic	criteria provided, single submitter
1709104	NM_006949.4(STXBP2):c.1279C>T (p.Gln427Ter)	STXBP2	Likely pathogenic	criteria provided, single submitter
1901792	NM_006949.4(STXBP2):c.1214G>C (p.Arg405Pro)	STXBP2	Likely pathogenic	criteria provided, single submitter
1994849	NM_006949.4(STXBP2):c.1026+2T>A	STXBP2	Likely pathogenic	criteria provided, single submitter
2033329	NM_006949.4(STXBP2):c.902+1G>A	STXBP2	Likely pathogenic	criteria provided, single submitter
2048510	NM_006949.4(STXBP2):c.87+1G>A	STXBP2	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · 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
STXBP2	Definitive	Autosomal recessive	familial hemophagocytic lymphohistiocytosis 5	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
STXBP2	Orphanet:540	Familial hemophagocytic lymphohistiocytosis
STX11	Orphanet:540	Familial hemophagocytic lymphohistiocytosis

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
STXBP2	HGNC:11445	ENSG00000076944	Q15833	Syntaxin-binding protein 2	gencc,clinvar
STX11	HGNC:11429	ENSG00000135604	O75558	Syntaxin-11	clinvar
CAMSAP3	HGNC:29307	ENSG00000076826	Q9P1Y5	Calmodulin-regulated spectrin-associated protein 3	clinvar
PCP2	HGNC:30209	ENSG00000174788	Q8IVA1	Purkinje cell protein 2 homolog	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
STXBP2	Syntaxin-binding protein 2	Involved in intracellular vesicle trafficking and vesicle fusion with membranes.
STX11	Syntaxin-11	SNARE that acts to regulate protein transport between late endosomes and the trans-Golgi network.
CAMSAP3	Calmodulin-regulated spectrin-associated protein 3	Key microtubule-organizing protein that specifically binds the minus-end of non-centrosomal microtubules and regulates their dynamics and organization.
PCP2	Purkinje cell protein 2 homolog	May function as a cell-type specific modulator for G protein-mediated cell signaling.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 4 · 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	4	1.8×	0.097

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
STXBP2	Other/Unknown	no		Sec1-like, Sec1-like_dom2, Sec1-like_sf
STX11	Other/Unknown	no		T_SNARE_dom, Syntaxin_N, Syntaxin/epimorphin_CS
CAMSAP3	Other/Unknown	no		CH_dom, PRC_barrel-like_sf, CKK_CAMSAP
PCP2	Other/Unknown	no		GoLoco_motif, TPR-like_helical_dom_sf, Pcp2

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
leukocyte	2
monocyte	2
granulocyte	1
mononuclear cell	1
lower esophagus mucosa	1
skin of abdomen	1
zone of skin	1
left testis	1
right hemisphere of cerebellum	1
right testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
STXBP2	227	ubiquitous	marker	granulocyte, monocyte, leukocyte
STX11	193	broad	marker	monocyte, mononuclear cell, leukocyte
CAMSAP3	135	broad	marker	lower esophagus mucosa, skin of abdomen, zone of skin
PCP2	157	tissue_specific	marker	left testis, right testis, right hemisphere of cerebellum

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
STX11	2,409
STXBP2	1,556
CAMSAP3	1,345
PCP2	956

Intra-cohort edges

A	B	Sources
STX11	STXBP2	intact, string_interaction

Structural data

PDB: 1 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
STXBP2	Q15833	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
STX11	O75558	79.08
PCP2	Q8IVA1	70.65
CAMSAP3	Q9P1Y5	60.70

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 9. Enrichment computed across 4 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
Other interleukin signaling	1	237.9×	0.038	STXBP2
Response to elevated platelet cytosolic Ca2+	1	81.6×	0.051	STXBP2
Platelet activation, signaling and aggregation	1	52.9×	0.051	STXBP2
Platelet degranulation	1	43.9×	0.051	STXBP2
Signaling by Interleukins	1	32.1×	0.056	STXBP2
Cytokine Signaling in Immune system	1	20.4×	0.062	STXBP2
G alpha (i) signalling events	1	19.5×	0.062	PCP2
Hemostasis	1	18.0×	0.062	STXBP2
Immune System	1	6.5×	0.148	STXBP2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
leukocyte mediated cytotoxicity	1	4213.0×	0.004	STXBP2
regulation of organelle organization	1	2106.5×	0.004	CAMSAP3
zonula adherens maintenance	1	1404.3×	0.004	CAMSAP3
protein transport along microtubule	1	1404.3×	0.004	CAMSAP3
establishment or maintenance of microtubule cytoskeleton polarity	1	1053.2×	0.004	CAMSAP3
replication fork arrest	1	1053.2×	0.004	CAMSAP3
presynaptic dense core vesicle exocytosis	1	1053.2×	0.004	STXBP2
G protein-coupled opsin signaling pathway	1	842.6×	0.004	PCP2
neutrophil degranulation	1	842.6×	0.004	STXBP2
intracellular protein transport	2	32.4×	0.004	STXBP2, STX11
regulation of mast cell degranulation	1	468.1×	0.006	STXBP2
synaptic vesicle fusion to presynaptic active zone membrane	1	421.3×	0.006	STX11
DNA replication checkpoint signaling	1	324.1×	0.006	CAMSAP3
microtubule anchoring	1	324.1×	0.006	CAMSAP3
epithelial cell-cell adhesion	1	300.9×	0.006	CAMSAP3
regulation of microtubule polymerization	1	280.9×	0.006	CAMSAP3
regulation of Golgi organization	1	280.9×	0.006	CAMSAP3
establishment of epithelial cell apical/basal polarity	1	263.3×	0.007	CAMSAP3
obsolete vesicle docking	1	191.5×	0.008	STX11
embryo development ending in birth or egg hatching	1	183.2×	0.008	CAMSAP3
obsolete vesicle docking involved in exocytosis	1	168.5×	0.009	STXBP2
membrane fusion	1	156.0×	0.009	STX11
regulation of focal adhesion assembly	1	150.5×	0.009	CAMSAP3
regulation of microtubule cytoskeleton organization	1	135.9×	0.009	CAMSAP3
cilium movement	1	98.0×	0.013	CAMSAP3
cellular response to type II interferon	1	52.0×	0.023	STXBP2
regulation of cell migration	1	39.4×	0.029	CAMSAP3
exocytosis	1	38.0×	0.029	STX11
neuron projection development	1	30.5×	0.034	CAMSAP3
microtubule cytoskeleton organization	1	30.3×	0.034	CAMSAP3

Therapeutics

Drug target analysis

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

Druggability breadth: 0 of 4 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
STXBP2	0	0
STX11	0	0
CAMSAP3	0	0
PCP2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	4	STXBP2, STX11, CAMSAP3, PCP2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
STXBP2	0	—
STX11	0	—
CAMSAP3	0	—
PCP2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.