STX11

Summary

STX11 (syntaxin 11, HGNC:11429) is a protein-coding gene on chromosome 6q24.2, encoding Syntaxin-11 (O75558). SNARE that acts to regulate protein transport between late endosomes and the trans-Golgi network.

This gene encodes a member of the syntaxin family. Syntaxins have been implicated in the targeting and fusion of intracellular transport vesicles. This family member may regulate protein transport among late endosomes and the trans-Golgi network. Mutations in this gene have been associated with familial hemophagocytic lymphohistiocytosis.

Source: NCBI Gene 8676 — RefSeq curated summary.

At a glance

• Gene–disease (curated): familial hemophagocytic lymphohistiocytosis 4 (Definitive, ClinGen) — +1 more curated relationship
• GWAS associations: 2
• Clinical variants (ClinVar): 417 total — 15 pathogenic, 11 likely-pathogenic
• Phenotypes (HPO): 53
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity unscored
• MANE Select transcript: NM_003764

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11429
Approved symbol	STX11
Name	syntaxin 11
Location	6q24.2
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000135604
Ensembl biotype	protein_coding
OMIM	605014
Entrez	8676

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 17 protein_coding

ENST00000367568, ENST00000698355, ENST00000698356, ENST00000698357, ENST00000872511, ENST00000872512, ENST00000872513, ENST00000872514, ENST00000872515, ENST00000872516, ENST00000872517, ENST00000872518, ENST00000872519, ENST00000951880, ENST00000951881, ENST00000951882, ENST00000951883

RefSeq mRNA: 1 — MANE Select: NM_003764 NM_003764

CCDS: CCDS5205

Canonical transcript exons

ENST00000367568 — 2 exons

Exon	Start	End
ENSE00001445051	144150517	144150703
ENSE00003973398	144186623	144191939

Expression profiles

Bgee: expression breadth ubiquitous, 193 present calls, max score 95.97.

FANTOM5 (CAGE): breadth broad, TPM avg 27.5652 / max 2201.4719, expressed in 900 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
70280	23.0853	704
70278	2.9853	552
70279	1.0244	283
70286	0.2651	117
70287	0.1121	53
70285	0.0930	45

Top tissues by expression

287 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	95.97	gold quality
mononuclear cell	CL:0000842	95.44	gold quality
leukocyte	CL:0000738	95.07	gold quality
granulocyte	CL:0000094	88.60	gold quality
blood	UBERON:0000178	88.47	gold quality
bone marrow	UBERON:0002371	85.20	gold quality
bone marrow cell	CL:0002092	83.51	gold quality
right lung	UBERON:0002167	80.58	gold quality
omental fat pad	UBERON:0010414	80.54	gold quality
peritoneum	UBERON:0002358	80.43	gold quality
adipose tissue of abdominal region	UBERON:0007808	80.35	gold quality
lower lobe of lung	UBERON:0008949	80.29	gold quality
upper lobe of left lung	UBERON:0008952	80.16	gold quality
upper lobe of lung	UBERON:0008948	79.83	gold quality
adipose tissue	UBERON:0001013	78.64	gold quality
connective tissue	UBERON:0002384	77.84	gold quality
subcutaneous adipose tissue	UBERON:0002190	76.56	gold quality
spleen	UBERON:0002106	75.79	gold quality
lung	UBERON:0002048	74.11	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	72.43	gold quality
left coronary artery	UBERON:0001626	71.63	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	71.02	gold quality
skin of abdomen	UBERON:0001416	70.74	gold quality
left lobe of thyroid gland	UBERON:0001120	70.35	gold quality
heart left ventricle	UBERON:0002084	70.05	gold quality
skin of leg	UBERON:0001511	70.01	gold quality
vermiform appendix	UBERON:0001154	69.90	gold quality
lymph node	UBERON:0000029	69.83	gold quality
coronary artery	UBERON:0001621	69.73	gold quality
cardiac ventricle	UBERON:0002082	69.50	gold quality

Single-cell (SCXA)

Detected in 6 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-CURD-89	yes	433.16
E-HCAD-4	yes	35.48
E-MTAB-6678	yes	24.66
E-MTAB-9467	yes	20.48
E-ANND-3	yes	12.14
E-MTAB-9801	yes	6.16

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): E2F1

miRNA regulators (miRDB)

147 targeting STX11, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-511-3P	99.99	68.85	1467
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-548AN	99.97	70.91	2817
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-493-5P	99.96	72.47	2382
HSA-MIR-548J-3P	99.94	72.61	4881
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-6845-3P	99.94	66.88	1439

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity Not yet evaluated (unscored). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 24)

• A large group of 63 unrelated patients with Familial hemophagocytic lymphohistiocytosis (FHL) was analysed for mutations in STX11, PRF1, and UNC13D. (PMID:16278825)
• Defective cytotoxic lymphocyte degranulation is associated with syntaxin-11 deficient familial hemophagocytic lymphohistiocytosis 4 patients (PMID:17525286)
• Syntaxin 11 plays a role in natural killer (NK) cell granule exocytosis and in the generation of cell-mediated killing. (PMID:17785771)
• DNA methylation of Stx11 contribute to disease susceptibility at the 6q24 locus in humans. (PMID:19169743)
• These data indicate that human neutrophils express syntaxin 11 and call attention to the possible involvement of neutrophils in familial hemophagocytic lymphohistiocytosis pathology (PMID:19259622)
• Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11 (PMID:19804848)
• a novel homozygous deletion (c. 581_584delTGCC; p.Leu194ProfsX2) in the gene-encoding syntaxin 11 (STX11), causing a premature termination codon in hemophagocytic lymphohistiocytosis (PMID:19967551)
• The mutations in STX11 are responsible for HLH in approximately 1% of North American patients and can cause variable defects in syntaxin 11 expression and function with resultant impact on clinical phenotype. (PMID:20486178)
• STX11 should be sequenced in HLH patients even when impaired NK cell degranulation is not found (PMID:21298754)
• Data suggest that syntaxin 11 promotes the fusion of Rab27a-expressing vesicles with cytotoxic granules and reveal additional complexity in spatial/temporal segregation of subcellular structures involved in granule-mediated cytotoxicity. (PMID:21342435)
• No detrimental mutations were identified in STX11 in Chinese children with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. (PMID:21674762)
• Platelets deficient in syntaxin-11 from a Familial Hemophagocytic Lymphohistiocytosis type 4 had secretion defect. (PMID:22767500)
• Distinct severity of HLH in both human and murine mutants with complete loss of cytotoxic effector PRF1, RAB27A, and STX11. (PMID:23160464)
• Stx11 functions as a t-SNARE for the final fusion of LG at the IS. (PMID:24227526)
• a pivotal role for S-acylation in the function of syntaxin 11 in NK cells (PMID:24910990)
• The results suggest that STX11 plays an important role in the pathogenesis of Peripheral T-cell lymphomas and they may contribute to the future development of new drugs for the treatment of Peripheral T-cell lymphomas. (PMID:26176172)
• Neonatal platelets exhibit low levels of the Stx11-Munc18b complex (essential component of the SNARE machinery) and of beta1-tubulin. These developmental deficiencies are associated with defects in platelet adhesion, spreading and secretion. (PMID:29044293)
• Data suggest that acylation of SNAP23 (synaptosome associated protein 23) and STX11 (syntaxin-11) regulates exocytosis in platelets; maintaining acylation states of SNAP23 and STX11 is important for platelet function. (PMID:29352103)
• STX11-deficient familial hemophagocytic lymphohistiocytosis type 4 is associated with self-resolving flares and a milder clinical course. (PMID:31207086)
• Spectrum mutations of PRF1, UNC13D, STX11, and STXBP2 genes in Vietnamese patients with hemophagocytic lymphohistiocytosis. (PMID:34339548)
• Familial Hemophagocytic Lymphohistiocytosis With Heterozygous STX11 and Homozygous UNC13D Mutations Diagnosed in the Neonatal Period. (PMID:35293882)
• Syntaxin 11 Contributes to the Interferon-Inducible Restriction of Coxiella burnetii Intracellular Infection. (PMID:36728431)
• Dynamic palmitoylation of STX11 controls injury-induced fatty acid uptake to promote muscle regeneration. (PMID:38198890)
• Patients and mice with deficiency in the SNARE protein SYNTAXIN-11 have a secondary B cell defect. (PMID:38722309)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	stx11b.1	ENSDARG00000029290
danio_rerio	stx11b.2	ENSDARG00000042231
danio_rerio	stx11a	ENSDARG00000044039
mus_musculus	Stx11	ENSMUSG00000039232
rattus_norvegicus	Stx11	ENSRNOG00000014902
caenorhabditis_elegans		WBGENE00006371
caenorhabditis_elegans		WBGENE00006372
caenorhabditis_elegans		WBGENE00006374

Paralogs (12): STX7 (ENSG00000079950), STX1B (ENSG00000099365), STX4 (ENSG00000103496), STX1A (ENSG00000106089), STX2 (ENSG00000111450), STX12 (ENSG00000117758), STX16 (ENSG00000124222), STX17 (ENSG00000136874), STX5 (ENSG00000162236), STX3 (ENSG00000166900), TSNARE1 (ENSG00000171045), STX19 (ENSG00000178750)

Protein

Protein identifiers

Syntaxin-11 — O75558 (reviewed: O75558)

All UniProt accessions (1): O75558

UniProt curated annotations — full annotation on UniProt →

Function. SNARE that acts to regulate protein transport between late endosomes and the trans-Golgi network.

Subunit / interactions. Interacts with the SNARE proteins SNAP-23 and VAMP.

Subcellular location. Membrane. Golgi apparatus. trans-Golgi network membrane.

Disease relevance. Hemophagocytic lymphohistiocytosis, familial, 4 (FHL4) [MIM:603552] A rare disorder characterized by immune dysregulation with hypercytokinemia, defective function of natural killer cell, and massive infiltration of several organs by activated lymphocytes and macrophages. The clinical features of the disease include fever, hepatosplenomegaly, cytopenia, and less frequently neurological abnormalities ranging from irritability and hypotonia to seizures, cranial nerve deficits and ataxia. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the syntaxin family.

RefSeq proteins (1): NP_003755* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000727	T_SNARE_dom	Domain
IPR006011	Syntaxin_N	Domain
IPR006012	Syntaxin/epimorphin_CS	Conserved_site
IPR010989	SNARE	Homologous_superfamily
IPR042781	Syntaxin11_SNARE	Domain
IPR045242	Syntaxin	Family

Pfam: PF00804

UniProt features (16 total): sequence conflict 9, sequence variant 4, chain 1, domain 1, coiled-coil region 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-O75558-F1	79.08	0.25

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 428 (showing top): GSE45365_NK_CELL_VS_CD11B_DC_DN, BEGUM_TARGETS_OF_PAX3_FOXO1_FUSION_UP, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, GOBP_VESICLE_ORGANIZATION, ENK_UV_RESPONSE_KERATINOCYTE_UP, MODULE_45, GOBP_MEMBRANE_FUSION, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, IVANOVA_HEMATOPOIESIS_MATURE_CELL, GOBP_NEUROTRANSMITTER_TRANSPORT, GOBP_VESICLE_MEDIATED_TRANSPORT, BROWNE_HCMV_INFECTION_12HR_UP, GOBP_CELL_CELL_SIGNALING, GOBP_MEMBRANE_DOCKING, IRF7_01

GO Biological Process (7): intracellular protein transport (GO:0006886), exocytosis (GO:0006887), synaptic vesicle fusion to presynaptic active zone membrane (GO:0031629), obsolete vesicle docking (GO:0048278), membrane fusion (GO:0061025), protein transport (GO:0015031), vesicle-mediated transport (GO:0016192)

GO Molecular Function (3): SNARE binding (GO:0000149), SNAP receptor activity (GO:0005484), protein binding (GO:0005515)

GO Cellular Component (6): Golgi apparatus (GO:0005794), plasma membrane (GO:0005886), endomembrane system (GO:0012505), SNARE complex (GO:0031201), presynaptic active zone membrane (GO:0048787), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular protein localization	2
vesicle fusion to plasma membrane	2
transport	2
cytoplasm	2
cellular anatomical structure	2
protein transport	1
intracellular transport	1
vesicle-mediated transport	1
secretion by cell	1
synaptic vesicle exocytosis	1
synaptic vesicle membrane organization	1
membrane organization	1
establishment of protein localization	1
cellular process	1
protein binding	1
protein-macromolecule adaptor activity	1
membrane fusion	1
fusogenic activity	1
binding	1
endomembrane system	1
intracellular membrane-bounded organelle	1
membrane	1
cell periphery	1
vacuole	1
plasma membrane	1
membrane protein complex	1
presynaptic membrane	1
presynaptic active zone	1
synaptic membrane	1

Protein interactions and networks

STRING

1799 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
STX11	STXBP2	Q15833	996
STX11	UNC13D	Q70J99	989
STX11	SNAP23	O00161	989
STX11	VAMP8	Q9BV40	929
STX11	RAB27A	P51159	929
STX11	FHL2	Q14192	880
STX11	LYST	Q99698	809
STX11	PRF1	P14222	807
STX11	STXBP1	P61764	786
STX11	SH2D1A	O60880	767
STX11	VAMP2	P19065	737
STX11	AP3B1	O00203	720
STX11	GNLY	P09325	683
STX11	STXBP5	Q5T5C0	650
STX11	STX12	Q86Y82	641

IntAct

393 interactions, top by confidence:

A	B	Type	Score
STX11	SNAP23	psi-mi:“MI:0915”(physical association)	0.900
STX11	STXBP1	psi-mi:“MI:0915”(physical association)	0.830
STXBP1	STX11	psi-mi:“MI:0915”(physical association)	0.830
STXBP2	STX11	psi-mi:“MI:0915”(physical association)	0.770
STXBP2	STX11	psi-mi:“MI:0403”(colocalization)	0.770
PRPF31	STX11	psi-mi:“MI:0915”(physical association)	0.720
CCDC184	STX11	psi-mi:“MI:0915”(physical association)	0.720
STX11	BLOC1S6	psi-mi:“MI:0915”(physical association)	0.720
STX11	BYSL	psi-mi:“MI:0915”(physical association)	0.720
PPP1R18	STX11	psi-mi:“MI:0915”(physical association)	0.720
STX11	EIF1AD	psi-mi:“MI:0915”(physical association)	0.720
STX11	ZNF417	psi-mi:“MI:0915”(physical association)	0.720
STX11	KAT5	psi-mi:“MI:0915”(physical association)	0.720
STX11	ZNF587	psi-mi:“MI:0915”(physical association)	0.720
STX11	AIRIM	psi-mi:“MI:0915”(physical association)	0.720
STX11	CCDC184	psi-mi:“MI:0915”(physical association)	0.720
BLOC1S6	STX11	psi-mi:“MI:0915”(physical association)	0.720
BYSL	STX11	psi-mi:“MI:0915”(physical association)	0.720
STX11	PPP1R18	psi-mi:“MI:0915”(physical association)	0.720
EIF1AD	STX11	psi-mi:“MI:0915”(physical association)	0.720

BioGRID (217): STX11 (Two-hybrid), STX11 (Two-hybrid), STX11 (Two-hybrid), STX11 (Two-hybrid), STX11 (Two-hybrid), STX11 (Two-hybrid), STX11 (Two-hybrid), STX11 (Two-hybrid), STX11 (Two-hybrid), STX11 (Two-hybrid), STX11 (Two-hybrid), SNAP23 (Two-hybrid), NDC80 (Two-hybrid), KAT5 (Two-hybrid), FARS2 (Two-hybrid)

ESM2 similar proteins: A8WVD0, O15400, O16000, O35526, O64791, O70257, O70439, O75558, P32850, P32851, P32856, P32867, P50279, P61264, P61265, P61266, P61267, P61268, P70452, Q00262, Q08849, Q08850, Q0VCI2, Q12846, Q13277, Q16623, Q16932, Q24547, Q3SWZ3, Q3ZBT5, Q42374, Q5R4L2, Q5R602, Q5RAL4, Q5TX47, Q64704, Q7XIE2, Q8N4C7, Q8R1Q0, Q8VZU2

Diamond homologs: A8WVD0, O16000, O35526, O75558, P32850, P32851, P32854, P32856, P50279, P61264, P61265, P61266, P61267, P61268, P70452, P91409, Q00262, Q08849, Q08850, Q12846, Q13277, Q16623, Q16932, Q20797, Q24547, Q3SWZ3, Q5R4L2, Q5TX47, Q64704, Q6F3B4, Q8R1Q0, Q9D3G5, G3V7P1, Q08144, Q3ZBT5, Q5RBW6, Q9ER00, O15400, O64791, O65359

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
STX11	up-regulates	Platelet_degranulation
STX11	“form complex”	“STX11-SNAP23 SNARE complex”	binding
STX11	“form complex”	“STX11-VAMP8 SNARE complex”	binding
STXBP2	“up-regulates activity”	STX11	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

417 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	11
Uncertain significance	205
Likely benign	142
Benign	19

Top pathogenic / likely-pathogenic (26)

Variant ID	HGVS	Classification
1455186	NM_003764.4(STX11):c.599_602del (p.Ala200fs)	Pathogenic
1686234	NM_003764.4(STX11):c.448G>T (p.Glu150Ter)	Pathogenic
1686235	NM_003764.4(STX11):c.554dup (p.Trp186fs)	Pathogenic
2679062	NM_003764.4(STX11):c.748C>T (p.Gln250Ter)	Pathogenic
2679068	NM_003764.4(STX11):c.73G>T (p.Glu25Ter)	Pathogenic
2744743	NM_003764.4(STX11):c.127_133del (p.Ser43fs)	Pathogenic
2771358	NM_003764.4(STX11):c.334G>T (p.Glu112Ter)	Pathogenic
2829742	NM_003764.4(STX11):c.490C>T (p.Gln164Ter)	Pathogenic
5263	NM_003764.4(STX11):c.369_376delinsTGG (p.Val124fs)	Pathogenic
5264	NC_000006.12:g.144176889_144196077del	Pathogenic
5265	NM_003764.4(STX11):c.802C>T (p.Gln268Ter)	Pathogenic
545749	NM_003764.4(STX11):c.687dup (p.Gln230fs)	Pathogenic
583514	NC_000006.12:g.(?144186608)(144187511_?)del	Pathogenic
802280	NM_003764.4(STX11):c.581_584del (p.Leu194fs)	Pathogenic
97001	NM_003764.4(STX11):c.173T>C (p.Leu58Pro)	Pathogenic
1878417	NM_003764.4(STX11):c.822del (p.Cys275fs)	Likely pathogenic
2679060	NM_003764.4(STX11):c.568dup (p.Ser190fs)	Likely pathogenic
2679064	NM_003764.4(STX11):c.807C>A (p.Tyr269Ter)	Likely pathogenic
2679065	NM_003764.4(STX11):c.551del (p.Gly184fs)	Likely pathogenic
2679067	NM_003764.4(STX11):c.325G>T (p.Glu109Ter)	Likely pathogenic
2679070	NM_003764.4(STX11):c.397_398del (p.Asn133fs)	Likely pathogenic
3240549	NM_003764.4(STX11):c.337_352dup (p.His118delinsArgGlyTer)	Likely pathogenic
3240550	NM_003764.4(STX11):c.157_160del (p.Asp53fs)	Likely pathogenic
3593213	NM_003764.4(STX11):c.794del (p.Lys265fs)	Likely pathogenic
4077673	NM_003764.4(STX11):c.785_791del (p.Gln262fs)	Likely pathogenic
502219	NM_003764.4(STX11):c.473del (p.Lys158fs)	Likely pathogenic

SpliceAI

913 predictions. Top by Δscore:

Variant	Effect	Δscore
6:144186618:TGCA:T	acceptor_loss	1.0000
6:144186620:CA:C	acceptor_loss	1.0000
6:144186621:A:AG	acceptor_gain	1.0000
6:144186621:A:T	acceptor_loss	1.0000
6:144186622:G:GA	acceptor_gain	1.0000
6:144186622:GGC:G	acceptor_gain	1.0000
6:144186622:GGCA:G	acceptor_gain	1.0000
6:144186622:GGCAA:G	acceptor_gain	1.0000
6:144150602:G:GT	donor_gain	0.9900
6:144150700:CCAG:C	donor_loss	0.9900
6:144150701:CAGGT:C	donor_loss	0.9900
6:144150702:AG:A	donor_loss	0.9900
6:144150703:GG:G	donor_loss	0.9900
6:144150704:GTTT:G	donor_loss	0.9900
6:144165754:T:TA	donor_gain	0.9900
6:144165755:A:AA	donor_gain	0.9900
6:144168606:T:TA	acceptor_gain	0.9900
6:144186616:C:G	acceptor_gain	0.9900
6:144186621:AG:A	acceptor_gain	0.9900
6:144186622:GG:G	acceptor_gain	0.9900
6:144186615:A:AG	acceptor_gain	0.9800
6:144186615:ACTT:A	acceptor_gain	0.9800
6:144186618:T:TA	acceptor_gain	0.9800
6:144158260:AT:A	donor_gain	0.9500
6:144151094:AGTAG:A	acceptor_gain	0.9400
6:144151095:GTAGG:G	acceptor_gain	0.9400
6:144171439:G:GT	donor_gain	0.9400
6:144150681:T:A	donor_gain	0.9200
6:144168612:AC:A	acceptor_gain	0.9200
6:144168613:C:CA	acceptor_gain	0.9100

AlphaMissense

1908 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:144187115:G:C	R163P	0.994
6:144187192:T:C	F189L	0.990
6:144187194:T:A	F189L	0.990
6:144187194:T:G	F189L	0.990
6:144187088:G:C	R154P	0.989
6:144187256:G:C	R210P	0.989
6:144187072:G:C	A149P	0.987
6:144187121:T:C	L165P	0.987
6:144187106:G:C	R160P	0.986
6:144187268:T:C	L214P	0.983
6:144186865:A:C	S80R	0.982
6:144186867:C:A	S80R	0.982
6:144186867:C:G	S80R	0.982
6:144187114:C:A	R163S	0.982
6:144187286:G:C	R220P	0.982
6:144187309:T:C	F228L	0.981
6:144187311:C:A	F228L	0.981
6:144187311:C:G	F228L	0.981
6:144187109:T:C	I161T	0.977
6:144186841:T:C	F72L	0.976
6:144186843:C:A	F72L	0.976
6:144186843:C:G	F72L	0.976
6:144187127:T:C	I167T	0.974
6:144187238:T:C	L204P	0.973
6:144186938:T:C	L104P	0.972
6:144186868:A:C	S81R	0.971
6:144186870:C:A	S81R	0.971
6:144186870:C:G	S81R	0.971
6:144187004:G:C	R126P	0.971
6:144186821:T:C	L65P	0.970

dbSNP variants (sampled 300 via entrez): RS1000071651 (6:144153601 A>G,T), RS1000127999 (6:144182466 T>C,G), RS1000133418 (6:144139068 A>T), RS1000173871 (6:144156555 T>A,C), RS1000200851 (6:144140444 G>A,T), RS1000224843 (6:144156223 C>A,T), RS1000243403 (6:144188212 T>C), RS1000253302 (6:144138815 G>A), RS1000334363 (6:144144233 G>A), RS1000341811 (6:144188000 G>A), RS1000392000 (6:144150582 C>T), RS1000418365 (6:144174559 G>C), RS1000490094 (6:144150785 G>T), RS1000498549 (6:144155174 G>T), RS1000550632 (6:144154933 G>A)

Disease associations

OMIM: gene MIM:605014 | disease phenotypes: MIM:603552, MIM:613101, MIM:267700

GenCC curated gene-disease

Disease	Classification	Inheritance
familial hemophagocytic lymphohistiocytosis 4	Definitive	Autosomal recessive
hereditary hemophagocytic lymphohistiocytosis	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
familial hemophagocytic lymphohistiocytosis 4	Definitive	AR

Mondo (4): familial hemophagocytic lymphohistiocytosis 4 (MONDO:0011336), familial hemophagocytic lymphohistiocytosis 5 (MONDO:0013135), autoinflammatory syndrome (MONDO:0019751), hereditary hemophagocytic lymphohistiocytosis (MONDO:0015541)

Orphanet (3): Familial hemophagocytic lymphohistiocytosis (Orphanet:540), Autoinflammatory syndrome (Orphanet:93665), Primary hemophagocytic lymphohistiocytosis (Orphanet:158038)

HPO phenotypes

53 total (30 of 53 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000407	Sensorineural hearing impairment
HP:0000509	Conjunctivitis
HP:0000707	Abnormality of the nervous system
HP:0000952	Jaundice
HP:0000967	Petechiae
HP:0000969	Edema
HP:0000978	Bruising susceptibility
HP:0000979	Purpura
HP:0000988	Skin rash
HP:0001019	Erythroderma
HP:0001250	Seizure
HP:0001252	Hypotonia
HP:0001259	Coma
HP:0001263	Global developmental delay
HP:0001410	Decreased liver function
HP:0001744	Splenomegaly
HP:0001873	Thrombocytopenia
HP:0001875	Decreased total neutrophil count
HP:0001903	Anemia
HP:0001945	Fever
HP:0001954	Recurrent fever
HP:0002086	Abnormality of the respiratory system
HP:0002155	Hypertriglyceridemia
HP:0002240	Hepatomegaly
HP:0002383	Infectious encephalitis
HP:0002500	Abnormal cerebral white matter morphology
HP:0002583	Colitis
HP:0002611	Cholestatic liver disease
HP:0002716	Lymphadenopathy

GWAS associations

2 associations (top):

Study	Trait	p-value
GCST008758_59	Pre-treatment viral load in HIV-1 infection	2.000000e-17
GCST010105_79	Nicotine dependence symptom count	2.000000e-06

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0010125	viral load
EFO:0009262	nicotine dependence symptom count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C567752	Hemophagocytic Lymphohistiocytosis, Familial, 5 (supp.)
C537252	Hemophagocytic lymphohistiocytosis, familial, 4 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

56 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
potassium chromate(VI)	affects cotreatment, decreases expression	2
nickel sulfate	increases expression	2
Benzo(a)pyrene	increases expression, increases methylation, affects methylation, decreases methylation	2
Cisplatin	affects cotreatment, decreases expression, increases expression	2
Nickel	increases expression	2
Tetrachlorodibenzodioxin	affects expression, decreases expression	2
Valproic Acid	affects cotreatment, increases expression, increases methylation	2
aristolochic acid I	increases expression	1
ginger extract	decreases expression, increases abundance	1
ethylbenzene	increases expression	1
triphenyl phosphate	affects expression	1
bisphenol A	decreases expression	1
2-methyl-4-isothiazolin-3-one	increases expression	1
sodium arsenite	increases expression	1
2-xylene	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression, affects cotreatment	1
epigallocatechin gallate	decreases expression, affects cotreatment	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
CGP 52608	affects binding, increases reaction	1
abrine	increases expression	1
licochalcone B	increases expression	1
bisphenol S	decreases methylation	1
jinfukang	affects cotreatment, decreases expression	1
(+)-JQ1 compound	decreases expression	1
NSC668394	increases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Troglitazone	increases expression	1

Clinical trials (associated diseases)

10 trials via MONDO — disease-level, not drug-specific.

Trial	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
NCT00442182	PHASE2	UNKNOWN	The Efficacy and Safety of ITF2357 in AIS
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
NCT00887939	Not specified	COMPLETED	Pathogenesis of Physical Induced Urticarial Syndromes
NCT03510442	Not specified	RECRUITING	Natural History, Genetics, and Pathophysiology of Systemic Juvenile Idiopathic Arthritis, Adult-Onset Still’s Disease, and Related Conditions
NCT06248957	Not specified	RECRUITING	SYSTEMS-LEVEL ANALYSES OF IMMUNE DYSREGULATION