Familial hemophagocytic lymphohistiocytosis 2

Summary

Familial hemophagocytic lymphohistiocytosis 2 (MONDO:0011337) is a disease caused by PRF1 (GenCC Strong), with 4 cohort genes.

At a glance

• Causal gene: PRF1 (GenCC Strong)
• Cohort genes: 4
• ClinVar variants: 671

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	familial hemophagocytic lymphohistiocytosis 2
Mondo ID	MONDO:0011337
MeSH	C537250
OMIM	603553
DOID	DOID:0110922
UMLS	C1863727
MedGen	400366
GARD	0009922
Is cancer (heuristic)	no

Also known as: familial hemophagocytic lymphohistiocytosis type 2 · FHL2 · genetic hemophagocytic lymphohistiocytosis caused by mutation in PRF1 · hemophagocytic lymphohistiocytosis, familial, 2 · hemophagocytic lymphohistiocytosis, familial, type 2 · HLH2 · HPLH2 · PRF1 genetic hemophagocytic lymphohistiocytosis

Data availability: 671 ClinVar variants · 2 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 2

Related subtypes (10): Chediak-Higashi syndrome, familial hemophagocytic lymphohistiocytosis type 1, familial hemophagocytic lymphohistiocytosis 4, 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

600 retrieved; paginated sample, class counts are floors:

237 likely benign, 183 uncertain significance, 52 pathogenic, 49 conflicting classifications of pathogenicity, 37 pathogenic/likely pathogenic, 21 likely pathogenic, 11 benign/likely benign, 9 benign, 1 conflicting classifications of pathogenicity; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
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
1069592	NM_001083116.3(PRF1):c.1168C>T (p.Arg390Ter)	PRF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1069593	NM_001083116.3(PRF1):c.185_195del (p.Asp62fs)	PRF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1072304	NM_001083116.3(PRF1):c.1103_1110dup (p.Arg371Ter)	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
1334600	NM_001083116.3(PRF1):c.963del (p.Glu323fs)	PRF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13709	NM_001083116.3(PRF1):c.1122G>A (p.Trp374Ter)	PRF1	Pathogenic	criteria provided, multiple submitters, no conflicts
13710	NM_001083116.3(PRF1):c.190C>T (p.Gln64Ter)	PRF1	Pathogenic	criteria provided, single submitter
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
13715	NM_001083116.3(PRF1):c.548T>G (p.Val183Gly)	PRF1	Pathogenic	no assertion criteria provided
13721	NM_001083116.3(PRF1):c.1090_1091del (p.Leu364fs)	PRF1	Pathogenic	criteria provided, multiple submitters, no conflicts
13722	NM_001083116.3(PRF1):c.207del (p.Asp70fs)	PRF1	Pathogenic	criteria provided, single submitter
13723	NM_001083116.3(PRF1):c.1246C>T (p.Gln416Ter)	PRF1	Pathogenic	criteria provided, single submitter
1393918	NM_001083116.3(PRF1):c.501C>G (p.Tyr167Ter)	PRF1	Pathogenic	criteria provided, single submitter
1406224	NM_001083116.3(PRF1):c.902C>A (p.Ser301Ter)	PRF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1427863	NM_001083116.3(PRF1):c.2T>C (p.Met1Thr)	PRF1	Pathogenic	criteria provided, single submitter
1446910	NM_001083116.3(PRF1):c.563dup (p.Leu189fs)	PRF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1457555	NM_001083116.3(PRF1):c.808_812del (p.Gly270fs)	PRF1	Pathogenic	criteria provided, single submitter
1460060	NM_001083116.3(PRF1):c.1267C>T (p.Gln423Ter)	PRF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1678093	NM_001083116.3(PRF1):c.1314T>A (p.Tyr438Ter)	PRF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686096	NM_001083116.3(PRF1):c.1016T>G (p.Val339Gly)	PRF1	Pathogenic	criteria provided, single submitter
2005802	NM_001083116.3(PRF1):c.1406_1428del (p.Asp469fs)	PRF1	Pathogenic	criteria provided, single submitter
2029973	NM_001083116.3(PRF1):c.1126del (p.Asp376fs)	PRF1	Pathogenic	criteria provided, single submitter
2031901	NM_001083116.3(PRF1):c.1422del (p.Pro477_Leu478insTer)	PRF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2032770	NM_001083116.3(PRF1):c.329_330del (p.Lys110fs)	PRF1	Pathogenic	criteria provided, single submitter
2055336	NM_001083116.3(PRF1):c.449C>A (p.Ser150Ter)	PRF1	Pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 6 · 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
PRF1	Strong	Autosomal recessive	familial hemophagocytic lymphohistiocytosis 2	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRF1	Orphanet:391343	Fatal post-viral neurodegenerative disorder
PRF1	Orphanet:540	Familial hemophagocytic lymphohistiocytosis
PRF1	Orphanet:88	Idiopathic aplastic anemia
RANBP2	Orphanet:178342	Inflammatory myofibroblastic tumor
RANBP2	Orphanet:263524	Acute necrotizing encephalopathy of childhood
RANBP2	Orphanet:88619	Familial acute necrotizing encephalopathy

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
PRF1	HGNC:9360	ENSG00000180644	P14222	Perforin-1	gencc,clinvar
PALD1	HGNC:23530	ENSG00000107719	Q9ULE6	Paladin	clinvar
EIF4EBP2	HGNC:3289	ENSG00000148730	Q13542	Eukaryotic translation initiation factor 4E-binding protein 2	clinvar
RANBP2	HGNC:9848	ENSG00000153201	P49792	E3 SUMO-protein ligase RanBP2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
EIF4EBP2	Eukaryotic translation initiation factor 4E-binding protein 2	Repressor of translation initiation involved in synaptic plasticity, learning and memory formation.
RANBP2	E3 SUMO-protein ligase RanBP2	E3 SUMO-protein ligase which facilitates SUMO1 and SUMO2 conjugation by UBE2I.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.5

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	67.0×	0.059
Phosphatase	1	21.0×	0.094
Transcription factor	1	2.1×	0.538
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRF1	Complement	yes		C2_dom, MACPF_CS, MACPF
PALD1	Phosphatase	yes		Tyr_Pase_cat, Prot-tyrosine_phosphatase-like, PTP
EIF4EBP2	Other/Unknown	no		EIF4EBP
RANBP2	Transcription factor	no		Ran_bind_dom, Znf_RanBP2, Cyclophilin-type_PPIase_dom

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
blood	1
granulocyte	1
spleen	1
medial globus pallidus	1
right lung	1
tendon of biceps brachii	1
buccal mucosa cell	1
epithelium of esophagus	1
esophagus squamous epithelium	1
endothelial cell	1
mucosa of paranasal sinus	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRF1	220	broad	marker	granulocyte, blood, spleen
PALD1	194	broad	marker	tendon of biceps brachii, medial globus pallidus, right lung
EIF4EBP2	292	ubiquitous	marker	buccal mucosa cell, esophagus squamous epithelium, epithelium of esophagus
RANBP2	294	ubiquitous	marker	endothelial cell, sperm, mucosa of paranasal sinus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
RANBP2	7,348
PRF1	3,299
PALD1	652
EIF4EBP2	542

Structural data

PDB: 2 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
RANBP2	P49792	33
EIF4EBP2	Q13542	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PRF1	P14222	91.01
PALD1	Q9ULE6	84.20

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 38. 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
IPs transport between nucleus and cytosol	1	190.3×	0.015	RANBP2
IP3 and IP4 transport between cytosol and nucleus	1	190.3×	0.015	RANBP2
IP6 and IP7 transport between cytosol and nucleus	1	190.3×	0.015	RANBP2
Transport of Ribonucleoproteins into the Host Nucleus	1	178.4×	0.015	RANBP2
Regulation of Glucokinase by Glucokinase Regulatory Protein	1	178.4×	0.015	RANBP2
Defective TPR may confer susceptibility towards thyroid papillary carcinoma (TPC)	1	178.4×	0.015	RANBP2
NEP/NS2 Interacts with the Cellular Export Machinery	1	173.0×	0.015	RANBP2
Nuclear import of Rev protein	1	167.9×	0.015	RANBP2
Vpr-mediated nuclear import of PICs	1	167.9×	0.015	RANBP2
Transport of the SLBP independent Mature mRNA	1	163.1×	0.015	RANBP2
SUMOylation of SUMOylation proteins	1	163.1×	0.015	RANBP2
Nuclear events stimulated by ALK signaling in cancer	1	163.1×	0.015	PRF1
Transport of the SLBP Dependant Mature mRNA	1	158.6×	0.015	RANBP2
Rev-mediated nuclear export of HIV RNA	1	158.6×	0.015	RANBP2
Nuclear Pore Complex (NPC) Disassembly	1	154.3×	0.015	RANBP2
SUMOylation of ubiquitinylation proteins	1	146.4×	0.015	RANBP2
NS1 Mediated Effects on Host Pathways	1	142.8×	0.015	RANBP2
Transport of Mature mRNA Derived from an Intronless Transcript	1	135.9×	0.015	RANBP2
Viral Messenger RNA Synthesis	1	129.8×	0.015	RANBP2
SUMOylation of DNA replication proteins	1	124.1×	0.015	RANBP2
SUMOylation of RNA binding proteins	1	119.0×	0.015	RANBP2
snRNP Assembly	1	105.7×	0.016	RANBP2
tRNA processing in the nucleus	1	98.5×	0.017	RANBP2
SUMOylation of chromatin organization proteins	1	79.3×	0.018	RANBP2
Transport of Mature mRNA derived from an Intron-Containing Transcript	1	76.1×	0.018	RANBP2
ISG15 antiviral mechanism	1	75.1×	0.018	RANBP2
Signaling by ALK fusions and activated point mutants	1	75.1×	0.018	RANBP2
SUMOylation of DNA damage response and repair proteins	1	73.2×	0.018	RANBP2
Regulation of HSF1-mediated heat shock response	1	69.6×	0.019	RANBP2
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal	1	58.3×	0.022	RANBP2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of killing of cells of another organism	1	5617.3×	0.006	PRF1
immune response to tumor cell	1	1872.4×	0.010	PRF1
granzyme-mediated programmed cell death signaling pathway	1	702.2×	0.010	PRF1
protein import	1	561.7×	0.010	PRF1
nuclear export	1	510.7×	0.010	RANBP2
immunological synapse formation	1	432.1×	0.010	PRF1
defense response to tumor cell	1	432.1×	0.010	PRF1
protein transmembrane transport	1	432.1×	0.010	PRF1
T cell mediated cytotoxicity	1	374.5×	0.010	PRF1
regulation of gluconeogenesis	1	374.5×	0.010	RANBP2
negative regulation of translational initiation	1	295.6×	0.010	EIF4EBP2
centrosome localization	1	295.6×	0.010	RANBP2
NLS-bearing protein import into nucleus	1	267.5×	0.010	RANBP2
TOR signaling	1	255.3×	0.010	EIF4EBP2
intracellular glucose homeostasis	1	193.7×	0.012	RANBP2
plasma membrane repair	1	193.7×	0.012	PRF1
response to amphetamine	1	165.2×	0.013	RANBP2
ceramide biosynthetic process	1	140.4×	0.014	PRF1
nucleocytoplasmic transport	1	130.6×	0.014	RANBP2
protein sumoylation	1	108.0×	0.016	RANBP2
cellular defense response	1	106.0×	0.016	PRF1
killing of cells of another organism	1	90.6×	0.016	PRF1
social behavior	1	90.6×	0.016	EIF4EBP2
protein secretion	1	87.8×	0.016	PRF1
mRNA transport	1	87.8×	0.016	RANBP2
regulation of synaptic plasticity	1	86.4×	0.016	EIF4EBP2
insulin receptor signaling pathway	1	73.9×	0.018	EIF4EBP2
memory	1	61.1×	0.020	EIF4EBP2
modulation of chemical synaptic transmission	1	61.1×	0.020	EIF4EBP2
protein maturation	1	54.5×	0.022	PRF1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PRF1	0	0
PALD1	0	0
EIF4EBP2	0	0
RANBP2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
PRF1	34	Binding:34
RANBP2	1	Binding:1

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	2	PRF1, PALD1
E	Difficult family or no structure, no drug	2	EIF4EBP2, RANBP2

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)
PRF1	34	—
PALD1	0	—
EIF4EBP2	0	—
RANBP2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.