Hereditary hemophagocytic lymphohistiocytosis

Summary

Hereditary hemophagocytic lymphohistiocytosis (MONDO:0015541) is a disease (an umbrella term covering 11 Mondo subtypes) caused by NBAS (GenCC Strong), with 7 cohort genes and 6 clinical trials. Top therapeutic interventions include emapalumab, alemtuzumab, and cyclophosphamide anhydrous.

At a glance

• Prevalence: 1-9 / 100 000 (Sweden) [Orphanet-validated]
• Causal gene: NBAS (GenCC Strong)
• Umbrella term: 11 Mondo subtypes
• Cohort genes: 7
• ClinVar variants: 82
• Phenotypes (HPO): 45
• Clinical trials: 6

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Annual incidence	1-9 / 1 000 000	0.104	China	Validated
Prevalence at birth	1-9 / 100 000	2	Sweden	Validated

Signs & symptoms

Clinical features (HPO)

45 HPO clinical features (Orphanet curated; top 45 by frequency):

HPO ID	Term	Frequency
HP:0001873	Thrombocytopenia	Very frequent (80-99%)
HP:0001903	Anemia	Very frequent (80-99%)
HP:0001945	Fever	Very frequent (80-99%)
HP:0002910	Elevated circulating hepatic transaminase concentration	Very frequent (80-99%)
HP:0002958	Immune dysregulation	Very frequent (80-99%)
HP:0003073	Hypoalbuminemia	Very frequent (80-99%)
HP:0003281	Increased circulating ferritin concentration	Very frequent (80-99%)
HP:0011112	Abnormality of serum cytokine level	Very frequent (80-99%)
HP:0011118	Abnormality of tumor necrosis factor secretion	Very frequent (80-99%)
HP:0012145	Abnormality of multiple cell lineages in the bone marrow	Very frequent (80-99%)
HP:0012156	Hemophagocytosis	Very frequent (80-99%)
HP:0030356	Increased serum interferon-gamma level	Very frequent (80-99%)
HP:0012177	Abnormal natural killer cell physiology	Frequent (30-79%)
HP:0000967	Petechiae	Frequent (30-79%)
HP:0000979	Purpura	Frequent (30-79%)
HP:0000988	Skin rash	Frequent (30-79%)
HP:0001019	Erythroderma	Frequent (30-79%)
HP:0001410	Decreased liver function	Frequent (30-79%)
HP:0001744	Splenomegaly	Frequent (30-79%)
HP:0001875	Decreased total neutrophil count	Frequent (30-79%)
HP:0002086	Abnormality of the respiratory system	Frequent (30-79%)
HP:0002155	Hypertriglyceridemia	Frequent (30-79%)
HP:0002240	Hepatomegaly	Frequent (30-79%)
HP:0002611	Cholestatic liver disease	Frequent (30-79%)
HP:0002716	Lymphadenopathy	Frequent (30-79%)
HP:0003256	Abnormality of the coagulation cascade	Frequent (30-79%)
HP:0011121	Abnormal skin morphology	Frequent (30-79%)
HP:0011900	Hypofibrinogenemia	Frequent (30-79%)
HP:0012211	Abnormal renal physiology	Frequent (30-79%)
HP:0012229	CSF pleocytosis	Frequent (30-79%)
HP:0030783	Increased circulating interleukin 6 concentration	Frequent (30-79%)
HP:0031364	Ecchymosis	Frequent (30-79%)
HP:0000707	Abnormality of the nervous system	Occasional (5-29%)
HP:0000952	Jaundice	Occasional (5-29%)
HP:0000978	Bruising susceptibility	Occasional (5-29%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001259	Coma	Occasional (5-29%)
HP:0002383	Infectious encephalitis	Occasional (5-29%)
HP:0002500	Abnormal cerebral white matter morphology	Occasional (5-29%)
HP:0002583	Colitis	Occasional (5-29%)
HP:0004302	Functional motor deficit	Occasional (5-29%)
HP:0004313	Decreased circulating antibody level	Occasional (5-29%)
HP:0009830	Peripheral neuropathy	Occasional (5-29%)
HP:0040186	Maculopapular exanthema	Occasional (5-29%)
HP:0000407	Sensorineural hearing impairment	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary hemophagocytic lymphohistiocytosis
Mondo ID	MONDO:0015541
OMIM	267700
Orphanet	540
SNOMED CT	398250003
UMLS	C0272199
MedGen	78797
GARD	0006589
MedDRA	10070904
Is cancer (heuristic)	no

Also known as: familial hemophagocytic lymphohistiocytosis · genetic hemophagocytic lymphohistiocytosis · genetic hemophagocytic syndrome · primary hemophagocytic lymphohistiocytosis

Data availability: 82 ClinVar variants · 6 GenCC gene-disease records · 4 cell lines.

Disease family

An umbrella term covering 11 Mondo subtypes.

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

Related subtypes (40): B cell deficiency, complement deficiency, phagocyte bactericidal dysfunction, trichohepatoenteric syndrome, hepatic veno-occlusive disease-immunodeficiency syndrome, immunodeficiency with defective T-cell response to interleukin 1, Say-Barber-Miller syndrome, familial isolated congenital asplenia, X-linked immunoneurologic disorder, ectodermal dysplasia and immune deficiency, immunodeficiency 33, immunodeficiency 47, combined immunodeficiency due to moesin deficiency, immunodeficiency, X-linked, with deficiency of 115,000 Dalton surface glycoprotein, properdin deficiency, X-linked, combined immunodeficiency with faciooculoskeletal anomalies, recurrent infections associated with rare immunoglobulin isotypes deficiency, immunodeficiency 28, autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity, immunodeficiency 37, immunodeficiency 39, BENTA disease, primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection, immunodeficiency 49, chronic mucocutaneous candidiasis, immunoglobulin heavy chain deficiency, immuno-osseous dysplasia, lymphoproliferative syndrome, IL10-related early-onset inflammatory bowel disease, T-cell immunodeficiency with epidermodysplasia verruciformis, Aicardi-Goutieres syndrome, immune dysregulation-inflammatory bowel disease-arthritis-recurrent infections-lymphopenia syndrome, inflammatory bowel disease-recurrent sinopulmonary infections syndrome, A20 haploinsufficiency, NK cell deficiency, T cell and NK cell immunodeficiency, dendritic cell deficiency, immunodysregulation with variable immunodeficiency and autoimmunity, immune dysregulation with immunodeficiency due to AIOLOS haploinsufficiency, STAT5 haploinsufficiency

Subtypes (11): 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, familial hemophagocytic lymphohistiocytosis 5, 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

82 retrieved; paginated sample, class counts are floors:

31 pathogenic/likely pathogenic, 25 pathogenic, 16 likely pathogenic, 10 conflicting classifications of pathogenicity

ClinVar	Variant (HGVS)	Gene	Classification	Review
1916169	NM_001791.4(CDC42):c.556C>T (p.Arg186Cys)	CDC42	Pathogenic	criteria provided, multiple submitters, no conflicts
1022083	NM_001083116.3(PRF1):c.895C>T (p.Arg299Cys)	PRF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1027586	NM_001083116.3(PRF1):c.1189_1190dup (p.His398fs)	PRF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1029054	NM_001083116.3(PRF1):c.1A>G (p.Met1Val)	PRF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1067731	NM_001083116.3(PRF1):c.1228C>T (p.Arg410Trp)	PRF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1192232	NM_001083116.3(PRF1):c.91T>G (p.Cys31Gly)	PRF1	Pathogenic	criteria provided, single submitter
1301336	NM_001083116.3(PRF1):c.3G>A (p.Met1Ile)	PRF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13711	NM_001083116.3(PRF1):c.673C>T (p.Arg225Trp)	PRF1	Pathogenic	criteria provided, multiple submitters, no conflicts
13714	NM_001083116.3(PRF1):c.836G>A (p.Cys279Tyr)	PRF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13721	NM_001083116.3(PRF1):c.1090_1091del (p.Leu364fs)	PRF1	Pathogenic	criteria provided, multiple submitters, no conflicts
2055336	NM_001083116.3(PRF1):c.449C>A (p.Ser150Ter)	PRF1	Pathogenic	criteria provided, multiple submitters, no conflicts
2136869	NM_001083116.3(PRF1):c.1229G>C (p.Arg410Pro)	PRF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2136871	NM_001083116.3(PRF1):c.949G>A (p.Gly317Arg)	PRF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2445916	NM_001083116.3(PRF1):c.116C>A (p.Pro39His)	PRF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2498463	NM_001083116.3(PRF1):c.150del (p.Thr51fs)	PRF1	Pathogenic	criteria provided, multiple submitters, no conflicts
2678052	NM_001083116.3(PRF1):c.694C>T (p.Arg232Cys)	PRF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2678058	NM_001083116.3(PRF1):c.394G>A (p.Gly132Arg)	PRF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2678060	NM_001083116.3(PRF1):c.916G>T (p.Gly306Cys)	PRF1	Pathogenic	criteria provided, multiple submitters, no conflicts
2678062	NM_001083116.3(PRF1):c.941_948delinsA (p.Leu314fs)	PRF1	Pathogenic	criteria provided, multiple submitters, no conflicts
280112	NM_001083116.3(PRF1):c.666C>A (p.His222Gln)	PRF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3385197	NM_001083116.3(PRF1):c.665A>G (p.His222Arg)	PRF1	Pathogenic	criteria provided, single submitter
468305	NM_001083116.3(PRF1):c.50del (p.Leu17fs)	PRF1	Pathogenic	criteria provided, multiple submitters, no conflicts
468311	NM_001083116.3(PRF1):c.916G>A (p.Gly306Ser)	PRF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
520942	NM_001083116.3(PRF1):c.445G>A (p.Gly149Ser)	PRF1	Pathogenic	criteria provided, multiple submitters, no conflicts
548929	NM_001083116.3(PRF1):c.386G>C (p.Trp129Ser)	PRF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
645064	NM_001083116.3(PRF1):c.658G>C (p.Gly220Arg)	PRF1	Pathogenic	criteria provided, multiple submitters, no conflicts
802582	NM_001083116.3(PRF1):c.659G>A (p.Gly220Asp)	PRF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
802583	NM_001083116.3(PRF1):c.160C>T (p.Arg54Cys)	PRF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
802584	NM_001083116.3(PRF1):c.148G>A (p.Val50Met)	PRF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
961631	NM_001083116.3(PRF1):c.658G>A (p.Gly220Ser)	PRF1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 31 · Orphanet: 10 · 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
STX11	Definitive	Autosomal recessive	familial hemophagocytic lymphohistiocytosis 4	4
STXBP2	Definitive	Autosomal recessive	familial hemophagocytic lymphohistiocytosis 5	7
UNC13D	Definitive	Autosomal recessive	familial hemophagocytic lymphohistiocytosis 3	5
NBAS	Strong	Autosomal recessive	hereditary hemophagocytic lymphohistiocytosis	8
PRF1	Strong	Autosomal recessive	familial hemophagocytic lymphohistiocytosis 2	6
RHOG	Moderate	Autosomal recessive	hereditary hemophagocytic lymphohistiocytosis

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
STX11	Orphanet:540	Familial hemophagocytic lymphohistiocytosis
STXBP2	Orphanet:540	Familial hemophagocytic lymphohistiocytosis
UNC13D	Orphanet:540	Familial hemophagocytic lymphohistiocytosis
PRF1	Orphanet:391343	Fatal post-viral neurodegenerative disorder
PRF1	Orphanet:540	Familial hemophagocytic lymphohistiocytosis
PRF1	Orphanet:88	Idiopathic aplastic anemia
NBAS	Orphanet:391677	Short stature-optic atrophy-Pelger-Huët anomaly syndrome
NBAS	Orphanet:464724	Fever-associated acute infantile liver failure syndrome
CDC42	Orphanet:487796	Takenouchi-Kosaki syndrome
CDC42	Orphanet:619363	NOCARH syndrome

Cohort genes → proteins

7 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	7

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
STX11	HGNC:11429	ENSG00000135604	O75558	Syntaxin-11	gencc,clinvar
STXBP2	HGNC:11445	ENSG00000076944	Q15833	Syntaxin-binding protein 2	gencc,clinvar
UNC13D	HGNC:23147	ENSG00000092929	Q70J99	Protein unc-13 homolog D	gencc,clinvar
PRF1	HGNC:9360	ENSG00000180644	P14222	Perforin-1	gencc,clinvar
NBAS	HGNC:15625	ENSG00000151779	A2RRP1	NBAS subunit of NRZ tethering complex	gencc
RHOG	HGNC:672	ENSG00000177105	P84095	Rho-related GTP-binding protein RhoG	gencc
CDC42	HGNC:1736	ENSG00000070831	P60953	Cell division control protein 42 homolog	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
STX11	Syntaxin-11	SNARE that acts to regulate protein transport between late endosomes and the trans-Golgi network.
STXBP2	Syntaxin-binding protein 2	Involved in intracellular vesicle trafficking and vesicle fusion with membranes.
UNC13D	Protein unc-13 homolog D	Plays a role in cytotoxic granule exocytosis in lymphocytes.
PRF1	Perforin-1	Pore-forming protein that plays a key role in granzyme-mediated programmed cell death, and in defense against virus-infected or neoplastic cells.
NBAS	NBAS subunit of NRZ tethering complex	Involved in Golgi-to-endoplasmic reticulum (ER) retrograde transport; the function is proposed to depend on its association in the NRZ complex which is believed to play a role in SNARE assembly at the ER.
RHOG	Rho-related GTP-binding protein RhoG	Plays a role in immunological synaptic F-actin density and architecture organization.
CDC42	Cell division control protein 42 homolog	Plasma membrane-associated small GTPase which cycles between an active GTP-bound and an inactive GDP-bound state.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 4 · Druggable fraction: 0.29

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
Complement	1	38.3×	0.103
Scaffold/PPI	1	2.5×	0.609
Enzyme (other)	1	1.7×	0.609
Other/Unknown	4	1.0×	0.626

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
STX11	Other/Unknown	no		T_SNARE_dom, Syntaxin_N, Syntaxin/epimorphin_CS
STXBP2	Other/Unknown	no		Sec1-like, Sec1-like_dom2, Sec1-like_sf
UNC13D	Other/Unknown	no		C2_dom, MUN_dom, Munc13_1
PRF1	Complement	yes		C2_dom, MACPF_CS, MACPF
NBAS	Scaffold/PPI	no		Quino_amine_DH_bsu, Sec39_domain, WD40/YVTN_repeat-like_dom_sf
RHOG	Other/Unknown	no		Small_GTPase, Small_GTPase_Rho, Small_GTP-bd
CDC42	Enzyme (other)	yes	3.6.5.2	Small_GTPase, Small_GTPase_Rho, Small_GTP-bd

Expression context

Cohort genes with no expression data: 0.

7 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)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
granulocyte	4
leukocyte	3
monocyte	3
mononuclear cell	2
spleen	2
blood	2
bone marrow cell	1
calcaneal tendon	1
primordial germ cell in gonad	1
ventricular zone	1
cortical plate	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
STX11	193	broad	marker	monocyte, mononuclear cell, leukocyte
STXBP2	227	ubiquitous	marker	granulocyte, monocyte, leukocyte
UNC13D	195	ubiquitous	marker	granulocyte, bone marrow cell, spleen
PRF1	220	broad	marker	granulocyte, blood, spleen
NBAS	293	ubiquitous	marker	calcaneal tendon, primordial germ cell in gonad, ventricular zone
RHOG	287	ubiquitous	marker	granulocyte, blood, leukocyte
CDC42	301	ubiquitous	marker	cortical plate, monocyte, mononuclear cell

Protein interactions among cohort

Intra-cohort edges: 7.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PRF1	3,299
CDC42	2,537
STX11	2,409
STXBP2	1,556
NBAS	1,134
RHOG	1,024
UNC13D	907

Intra-cohort edges

A	B	Sources
PRF1	STX11	string_interaction
PRF1	STXBP2	string_interaction
PRF1	UNC13D	string_interaction
RHOG	UNC13D	intact
STX11	STXBP2	intact, string_interaction
STX11	UNC13D	string_interaction
STXBP2	UNC13D	string_interaction

Structural data

PDB: 4 · AlphaFold-only: 3 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CDC42	P60953	48
RHOG	P84095	6
STXBP2	Q15833	1
UNC13D	Q70J99	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PRF1	P14222	91.01
STX11	O75558	79.08
NBAS	A2RRP1	74.42

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 79. Enrichment computed across 7 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
RHO GTPases activate KTN1	2	346.1×	1e-03	CDC42, RHOG
GPVI-mediated activation cascade	2	102.9×	0.006	CDC42, RHOG
RHOG GTPase cycle	2	49.4×	0.017	CDC42, RHOG
Platelet activation, signaling and aggregation	2	35.2×	0.026	STXBP2, CDC42
G-protein beta:gamma signalling	1	317.2×	0.046	CDC42
Signaling by Interleukins	2	21.4×	0.046	STXBP2, CDC42
Inactivation of CDC42 and RAC1	1	237.9×	0.047	CDC42
CD28 dependent Vav1 pathway	1	146.4×	0.053	CDC42
DCC mediated attractive signaling	1	119.0×	0.053	CDC42
G beta:gamma signalling through CDC42	1	95.2×	0.053	CDC42
RHO GTPases activate PAKs	1	90.6×	0.053	CDC42
SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)	1	82.8×	0.053	CDC42
Interleukin-12 family signaling	1	79.3×	0.053	CDC42
Other interleukin signaling	1	79.3×	0.053	STXBP2
Netrin-1 signaling	1	73.2×	0.053	CDC42
Regulation of T cell activation by CD28 family	1	70.5×	0.053	CDC42
Interleukin-12 signaling	1	68.0×	0.053	CDC42
Co-stimulation by CD28	1	63.4×	0.053	CDC42
Myogenesis	1	63.4×	0.053	CDC42
EGFR downregulation	1	57.7×	0.053	CDC42
RHO GTPases activate IQGAPs	1	57.7×	0.053	CDC42
Parasite infection	1	57.7×	0.053	CDC42
Leishmania phagocytosis	1	57.7×	0.053	CDC42
Signaling by EGFR	1	54.4×	0.053	CDC42
Nuclear events stimulated by ALK signaling in cancer	1	54.4×	0.053	PRF1
RHO GTPases Activate WASPs and WAVEs	1	52.9×	0.053	CDC42
Gene and protein expression by JAK-STAT signaling after Interleukin-12 stimulation	1	50.1×	0.053	CDC42
RHOV GTPase cycle	1	47.6×	0.053	CDC42
Fcgamma receptor (FCGR) dependent phagocytosis	1	46.4×	0.053	CDC42
RHOU GTPase cycle	1	46.4×	0.053	CDC42

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 7 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of mast cell degranulation	2	535.0×	5e-04	STXBP2, UNC13D
establishment or maintenance of cell polarity	2	114.6×	0.005	CDC42, RHOG
positive regulation of substrate adhesion-dependent cell spreading	2	107.0×	0.005	UNC13D, CDC42
leukocyte mediated cytotoxicity	1	2407.4×	0.008	STXBP2
positive regulation of killing of cells of another organism	1	2407.4×	0.008	PRF1
cellular response to type II interferon	2	59.4×	0.008	STXBP2, CDC42
immune response to tumor cell	1	802.5×	0.011	PRF1
granuloma formation	1	802.5×	0.011	UNC13D
neuropilin signaling pathway	1	802.5×	0.011	CDC42
endothelin receptor signaling pathway involved in heart process	1	802.5×	0.011	CDC42
regulation of actin cytoskeleton organization	2	45.0×	0.011	CDC42, RHOG
presynaptic dense core vesicle exocytosis	1	601.9×	0.012	STXBP2
neutrophil degranulation	1	481.5×	0.012	STXBP2
positive regulation of pinocytosis	1	481.5×	0.012	CDC42
positive regulation of regulated secretory pathway	1	481.5×	0.012	UNC13D
cardiac neural crest cell migration involved in outflow tract morphogenesis	1	343.9×	0.012	CDC42
natural killer cell degranulation	1	343.9×	0.012	UNC13D
positive regulation of epithelial cell proliferation involved in lung morphogenesis	1	343.9×	0.012	CDC42
secretion	1	300.9×	0.012	UNC13D
neuron fate determination	1	300.9×	0.012	CDC42
granzyme-mediated programmed cell death signaling pathway	1	300.9×	0.012	PRF1
regulation of ruffle assembly	1	300.9×	0.012	RHOG
regulation of lamellipodium assembly	1	267.5×	0.012	CDC42
dendritic cell migration	1	267.5×	0.012	CDC42
host-mediated perturbation of viral process	1	267.5×	0.012	CDC42
establishment of Golgi localization	1	267.5×	0.012	CDC42
negative regulation of nuclear-transcribed mRNA catabolic process, nonsense-mediated decay	1	267.5×	0.012	NBAS
germinal center formation	1	240.7×	0.012	UNC13D
protein import	1	240.7×	0.012	PRF1
cortical cytoskeleton organization	1	240.7×	0.012	RHOG

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 6

Druggability breadth: 3 of 7 evidence-associated genes (43%) 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
CDC42	KETOROLAC

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CDC42	3	4
STX11	0	0
STXBP2	0	0
UNC13D	0	0
PRF1	0	0
NBAS	0	0
RHOG	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
KETOROLAC	4	CDC42
SANGUINARIUM CHLORIDE	2	CDC42
MBQ-167	1	CDC42

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
CDC42	76	Binding:76
PRF1	34	Binding:34
NBAS	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CDC42	3.6.5.2	small monomeric GTPase

Pharmacogenomics

Cohort genes with a PharmGKB record: 7; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

3 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)
KETOROLAC	4	CDC42
SANGUINARIUM CHLORIDE	2	CDC42
MBQ-167	1	CDC42

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CDC42
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	PRF1
E	Difficult family or no structure, no drug	5	STX11, STXBP2, UNC13D, NBAS, RHOG

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
STX11	0	—
STXBP2	0	—
UNC13D	0	—
PRF1	34	—
NBAS	1	—
RHOG	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 6.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2
PHASE4	1
PHASE3	1
PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05744063	PHASE4	COMPLETED	A Post-authorization Study to Describe the Safety and Efficacy of Emapalumab for the Treatment of pHLH in Treatment Experienced Chinese Patients
NCT03312751	PHASE3	COMPLETED	Study to Assess the Efficacy and Safety of Emapalumab in Primary Haemophagocytic Lymphohistiocytosis
NCT00368355	PHASE2	COMPLETED	T Cell Depletion for Recipients of HLA Haploidentical Related Donor Stem Cell Grafts
NCT01494103	PHASE1	ACTIVE_NOT_RECRUITING	Administration of Donor T Cells With the Caspase-9 Suicide Gene
NCT03827343	Not specified	ACTIVE_NOT_RECRUITING	Retrospective Study of Immunotherapy Related Toxicities and Factors Impacting Outcomes in Children and Adults With Cancer
NCT06587191	Not specified	ACTIVE_NOT_RECRUITING	Emapalumab Efficacy in Children With Primary Hemophagocytic Lymphohistiocytosis

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
EMAPALUMAB	4	2
ALEMTUZUMAB	4	1
CYCLOPHOSPHAMIDE ANHYDROUS	4	1
RIMIDUCID	2	1