HLA-F

Summary

HLA-F (major histocompatibility complex, class I, F, HGNC:4963) is a protein-coding gene on chromosome 6p22.1, encoding HLA class I histocompatibility antigen, alpha chain F (P30511). Non-classical major histocompatibility class Ib molecule postulated to play a role in immune surveillance, immune tolerance and inflammation.

This gene belongs to the HLA class I heavy chain paralogues. It encodes a non-classical heavy chain that forms a heterodimer with a beta-2 microglobulin light chain, with the heavy chain anchored in the membrane. Unlike most other HLA heavy chains, this molecule is localized in the endoplasmic reticulum and Golgi apparatus, with a small amount present at the cell surface in some cell types. It contains a divergent peptide-binding groove, and is thought to bind a restricted subset of peptides for immune presentation. This gene exhibits few polymorphisms. Multiple transcript variants encoding different isoforms have been found for this gene. These variants lack a coding exon found in transcripts from other HLA paralogues due to an altered splice acceptor site, resulting in a shorter cytoplasmic domain.

Source: NCBI Gene 3134 — RefSeq curated summary.

At a glance

• GWAS associations: 21
• Clinical variants (ClinVar): 13 total
• MANE Select transcript: NM_001098479

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4963
Approved symbol	HLA-F
Name	major histocompatibility complex, class I, F
Location	6p22.1
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000204642
Ensembl biotype	protein_coding
OMIM	143110
Entrez	3134

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 9 protein_coding, 8 protein_coding_CDS_not_defined

ENST00000259951, ENST00000334668, ENST00000376861, ENST00000429294, ENST00000434407, ENST00000444621, ENST00000462777, ENST00000465459, ENST00000475996, ENST00000482257, ENST00000484704, ENST00000485513, ENST00000486194, ENST00000489502, ENST00000606273, ENST00000899563, ENST00000957138

RefSeq mRNA: 3 — MANE Select: NM_001098479 NM_001098478, NM_001098479, NM_018950

CCDS: CCDS43437, CCDS43438, CCDS43439

Canonical transcript exons

ENST00000259951 — 7 exons

Exon	Start	End
ENSE00001594762	29726883	29727296
ENSE00001607867	29723434	29723527
ENSE00003463156	29725031	29725306
ENSE00003483699	29725447	29725563
ENSE00003513573	29724173	29724448
ENSE00003633056	29723658	29723927
ENSE00003641304	29726011	29726043

Expression profiles

Bgee: expression breadth ubiquitous, 139 present calls, max score 99.57.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 26.3062 / max 513.6224, expressed in 1325 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
66662	20.8004	1165
66661	5.2642	976
66663	0.2415	137

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
granulocyte	CL:0000094	99.57	gold quality
spleen	UBERON:0002106	99.48	gold quality
blood	UBERON:0000178	99.14	gold quality
lymph node	UBERON:0000029	99.03	gold quality
vermiform appendix	UBERON:0001154	98.95	gold quality
leukocyte	CL:0000738	98.84	gold quality
monocyte	CL:0000576	98.78	gold quality
right lung	UBERON:0002167	98.67	gold quality
duodenum	UBERON:0002114	98.46	gold quality
upper lobe of left lung	UBERON:0008952	98.26	gold quality
bone marrow cell	CL:0002092	98.24	gold quality
mucosa of transverse colon	UBERON:0004991	98.21	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.17	gold quality
small intestine	UBERON:0002108	98.01	gold quality
gall bladder	UBERON:0002110	97.96	gold quality
apex of heart	UBERON:0002098	97.73	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	97.67	gold quality
bone marrow	UBERON:0002371	97.51	gold quality
bone element	UBERON:0001474	97.50	gold quality
subcutaneous adipose tissue	UBERON:0002190	97.34	gold quality
adipose tissue	UBERON:0001013	97.20	gold quality
endocervix	UBERON:0000458	97.16	gold quality
thoracic mammary gland	UBERON:0005200	97.16	gold quality
omental fat pad	UBERON:0010414	97.06	gold quality
transverse colon	UBERON:0001157	97.03	gold quality
ectocervix	UBERON:0012249	96.97	gold quality
body of uterus	UBERON:0009853	96.91	gold quality
left uterine tube	UBERON:0001303	96.83	gold quality
myometrium	UBERON:0001296	96.79	gold quality
right coronary artery	UBERON:0001625	96.47	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	14.52

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): CIITA, HIVEP2, MYC, MYCN, NFKB1, RELA, RFX5

miRNA regulators (miRDB)

8 targeting HLA-F, 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-3924	100.00	72.09	2394
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-221-3P	99.86	71.56	1329
HSA-MIR-222-3P	99.86	71.35	1337
HSA-MIR-567	99.63	68.57	1219
HSA-MIR-4316	99.37	65.75	1360
HSA-MIR-4433A-5P	96.79	65.01	599
HSA-MIR-4264	96.35	64.76	1480

Literature-anchored findings (GeneRIF, showing 40)

• This is the first example of placental HLA-F expression–primarily in trophoblasts that have invaded the maternal decidua–in the same cells that simultaneously express the other two nonclassical class I antigens HLA-E and HLA-G. (PMID:12874228)
• HLA-F surface expression on B cell and monocyte cell lines correlates with the presence of a limited amount of endoglycosidase H (Endo H)-resistant HLA-F; however, clearly not all surface-expressed HLA-F is fully glycosylated. (PMID:14607927)
• The results of this analysis confirmed several previously reported coding sequence variants, identified several new allelic variants, and also defined extensive variation in intron and flanking sequences. (PMID:16570139)
• HLA-F is entirely dependent on its cytoplasmic tail for export from the endoplasmic reticulum. (PMID:16709803)
• strong positive directional selection is acting for maintaining the observed low polymorphism on HLA-E, -F and -G loci (PMID:17157219)
• the role of NKG2D and 2B4 is not focussed on trophoblast recognition in normal pregnancy, but is more likely involved in cross-talk among maternal cells of the placental bed (PMID:18658158)
• Across HIV Gag protein, the rise of polymorphisms from independent origin during the last twenty years of epidemic was related to an association with an HLA allele accumulated in one of either B or F subtypes (PMID:18941505)
• These data suggest that HLA-F is expressed independently of peptide and that a physical interaction specific to MHC-I HC plays a role in the function of MHC-I HC expression in activated lymphocytes. (PMID:20483783)
• surface marker on activated lymphocytes (PMID:20865824)
• Mifepristone can inhibit the effects of progesterone by down-regulating the expressions of HLA-G, HLA-E and HLA-F mRNA in trophoblasts during the first trimester. (PMID:22490650)
• Upregulated HLA-F expression (p = 0.026) and downregulated HLA I expression (p = 0.013) could be an independent unfavorable prognostic factor. (PMID:22544725)
• expression in gastric cancer lesion was unrelated to patient prognosis (PMID:23542057)
• A previously unrecognized model of Ag cross-presentation mediated by HLA-F & MHC-I open conformers on activated lymphocytes & monocytes may significantly contribute to the regulation of immune system functions & the immune defense. (PMID:23851683)
• HLA-F and MHC class I open conformers are ligands for NK cell Ig-like receptors. (PMID:24018270)
• This is the first study regarding HLA-F polymorphisms in a Euro-Brazilian population contributing to the Southern Brazilian genetic characterization. (PMID:25413105)
• Review of the impact of human leukocyte antigen molecules E, F, and G on the outcome of transplantation. (PMID:25420801)
• The effect of Japanese encephalitis virus and TNF-alpha exposure on NFkappaB-mediated induction of HLA-F is reported. (PMID:25461528)
• We identified that the HLA-E and HLA-F in gastric cancer independently affected clinical factors, including postoperative outcome (PMID:25862890)
• provides substantial evidence that the rs7903146 variant is significantly associated with the risk of diabetic retinopathy in Caucasian populations (PMID:26332651)
• Overexpression of a single MHCI molecule, HLA-F, protects human MNs from ALS astrocyte-mediated toxicity, whereas knockdown of its receptor, the killer cell immunoglobulin-like receptor KIR3DL2, on human astrocytes results in enhanced motor neurons death (PMID:26928464)
• Two eSNPs were associated with fecundability at a FDR of 5%; both were in the HLA region and were eQTLs for the TAP2 gene (P = 1.3x10-4) and the HLA-F gene (P = 4.0x10-4), respectively. (PMID:27447835)
• this study established HLA-F as a ligand of KIR3DS1 and have demonstrated cell-context-dependent expression of HLA-F that might explain the widespread influence of KIR3DS1 in human disease, including delayed progression of disease caused by human immunodeficiency virus type 1 (PMID:27455421)
• Data suggest that the immunoproteasome is involved in pathologic MHC class I (HLA-A, B, C, F and G) expression and maintenance of myokine production in Idiopathic inflammatory myopathies (IIMs). (PMID:27522114)
• In this study, we describe and confirm the distinct expression of HLA-F, HLA-G, HLA-E, and HLA-C in placental tissue (PMID:28185362)
• the results of this study provide a blueprint of the molecular details of HLA-F, which will inform future exploration of its roles in human health and allow for the development of additional, targeted therapeutics (PMID:28636952)
• interactions between KIR3DS1 and HLA-F contribute to NK cell-mediated control of HCV. (PMID:30031767)
• The rs2523393 A allele creates a GATA2 binding site in a progesterone-responsive distal enhancer that loops to the HLA-F promoter. (PMID:30245028)
• high HLA-F expression is associated with Nasopharyngeal Carcinoma (NPC) local recurrence and distant metastasis and may be regarded as a poor prognostic factor for NPC patients. (PMID:30510890)
• This study showed that the HLA-F expression was positively correlated with malignant phenotype and negatively correlated with overall survival. (PMID:30755240)
• HLA-F variants bound to selected peptides, were structurally compared. (PMID:31717259)
• HLA-F-AS1 also enhanced the expressions of PFN1, which was validated as a target gene of miR-330-3p. CONCLUSION: HLA-F-AS1 promoted colorectal cancer progression via regulating miR-330-3p/PFN1 axis (PMID:31863778)
• Variation in the HLA-F gene locus with functional impact is associated with pregnancy success and time-to-pregnancy after fertility treatment. (PMID:32020202)
• Development of a Novel Prognostic Signature Based on Antigen Processing and Presentation in Patients with Breast Cancer. (PMID:34257557)
• HLA-E and HLA-F Are Overexpressed in Glioblastoma and HLA-E Increased After Exposure to Ionizing Radiation. (PMID:35181585)
• LncRNA HLA-F-AS1 attenuates the ovarian cancer development by targeting miR-21-3p/PEG3 axis. (PMID:35276697)
• Evolution and molecular interactions of major histocompatibility complex (MHC)-G, -E and -F genes. (PMID:35925520)
• HLA-F transcriptional and protein differential expression according to its genetic polymorphisms. (PMID:37166140)
• HLA-F and LILRB1 Genetic Polymorphisms Associated with Alloimmunisation in Sickle Cell Disease. (PMID:37686397)
• Single-cell profiling reveals immune disturbances landscape and HLA-F-mediated immune tolerance at the maternal-fetal interface in preeclampsia. (PMID:37854606)
• Association of human leukocyte antigen-G and -F with recurrent miscarriage and implantation failure: A systematic review and meta-analysis. (PMID:38009058)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	si:ch211-147g22.4	ENSDARG00000097275
danio_rerio	mhc1lia	ENSDARG00000097766
danio_rerio		ENSDARG00000115781

Paralogs (22): HFE (ENSG00000010704), FCGRT (ENSG00000104870), ULBP1 (ENSG00000111981), ULBP2 (ENSG00000131015), ULBP3 (ENSG00000131019), MR1 (ENSG00000153029), RAET1L (ENSG00000155918), CD1D (ENSG00000158473), CD1A (ENSG00000158477), CD1C (ENSG00000158481), CD1B (ENSG00000158485), CD1E (ENSG00000158488), AZGP1 (ENSG00000160862), RAET1E (ENSG00000164520), RAET1G (ENSG00000203722), MICB (ENSG00000204516), MICA (ENSG00000204520), HLA-C (ENSG00000204525), HLA-E (ENSG00000204592), HLA-G (ENSG00000204632), HLA-A (ENSG00000206503), HLA-B (ENSG00000234745)

Protein

Protein identifiers

HLA class I histocompatibility antigen, alpha chain F — P30511 (reviewed: P30511)

Alternative names: CDA12, HLA F antigen, Leukocyte antigen F, MHC class I antigen F

All UniProt accessions (6): P30511, A0A0D9SF55, A0A0D9SFW8, H0Y4J4, Q5JZ47, Q5JZ48

UniProt curated annotations — full annotation on UniProt →

Function. Non-classical major histocompatibility class Ib molecule postulated to play a role in immune surveillance, immune tolerance and inflammation. Functions in two forms, as a heterotrimeric complex with B2M/beta-2 microglobulin and a peptide (peptide-bound HLA-F-B2M) and as an open conformer (OC) devoid of peptide and B2M (peptide-free OC). In complex with B2M, presents non-canonical self-peptides carrying post-translational modifications, particularly phosphorylated self-peptides. Peptide-bound HLA-F-B2M acts as a ligand for LILRB1 inhibitory receptor, a major player in maternal-fetal tolerance. Peptide-free OC acts as a ligand for KIR3DS1 and KIR3DL2 receptors. Upon interaction with activating KIR3DS1 receptor on NK cells, triggers NK cell degranulation and anti-viral cytokine production. Through interaction with KIR3DL2 receptor, inhibits NK and T cell effector functions. May interact with other MHC class I OCs to cross-present exogenous viral, tumor or minor histompatibility antigens to cytotoxic CD8+ T cells, triggering effector and memory responses. May play a role in inflammatory responses in the peripheral nervous system. Through interaction with KIR3DL2, may protect motor neurons from astrocyte-induced toxicity.

Subunit / interactions. Forms a heterotrimer with B2M and a self-peptide. Binds a diverse number of peptides ranging from 7 to more than 30 amino acids. Peptide-bound HLA-F-B2M interacts with LILRB1 and LILRB2 but not with KIR3DS1 or KIR3DL2; this interaction is direct. The OC form interacts with KIR3DS1, KIR2DS4 and KIR3DL2; this interaction is direct. Interacts with TAP1-TAP2 complex and CALR; this interaction is required for appropriate folding and peptide loading. Interacts with the coat protein complex II and 14-3-3 proteins; these interactions likely control the anterograde ER-to-Golgi transport of HLA-F. HLA-F-B2M complex interacts with the heavy chain of other MHC class I molecules including HLA-A and HLA-E; this interaction may regulate the intracellular trafficking and the stability of peptide-free MHC class I OCs.

Subcellular location. Cell membrane. Early endosome membrane. Lysosome membrane.

Tissue specificity. Expressed in resting B cells (at protein level). Expressed in secondary lymphoid organs rich in B and T cells such as the tonsils, spleen, and thymus (at protein level). Expressed in the endothelial cells of the tonsils. Expressed on activated lymphoid cells including B cells, NK cells, CD4+ T cells and memory T cells (at protein level). Expressed in motor neurons of spinal cord.

Post-translational modifications. N-glycosylated.

Induction. Up-regulated in CD4+ T cells upon stimulation via TCR and upon HIV-1 infection.

Similarity. Belongs to the MHC class I family.

Isoforms (3)

UniProt ID	Names	Canonical?
P30511-1	1	yes
P30511-2	2
P30511-3	3

RefSeq proteins (3): NP_001091948, NP_001091949, NP_061823 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001039	MHC_I_a_a1/a2	Domain
IPR003006	Ig/MHC_CS	Conserved_site
IPR003597	Ig_C1-set	Domain
IPR007110	Ig-like_dom	Domain
IPR011161	MHC_I-like_Ag-recog	Domain
IPR011162	MHC_I/II-like_Ag-recog	Homologous_superfamily
IPR013783	Ig-like_fold	Homologous_superfamily
IPR036179	Ig-like_dom_sf	Homologous_superfamily
IPR037055	MHC_I-like_Ag-recog_sf	Homologous_superfamily
IPR050208	MHC_class-I_related	Family

Pfam: PF00129, PF07654

UniProt features (57 total): strand 18, helix 7, binding site 5, mutagenesis site 5, region of interest 4, sequence variant 3, disulfide bond 2, splice variant 2, topological domain 2, turn 2, signal peptide 1, chain 1, short sequence motif 1, glycosylation site 1, transmembrane region 1, domain 1, sequence conflict 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
5IUE	X-RAY DIFFRACTION	2.62
5KNM	X-RAY DIFFRACTION	3.3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P30511-F1	90.25	0.80

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Ligand- & substrate-binding residues (5): 91; 105; 164; 168; 176

Disulfide bonds (2): 122–185, 224–280

Glycosylation sites (1): 107

Mutagenesis-validated functional residues (5):

Position	Phenotype
83	impairs peptide binding.
336–338	impairs the interaction with 14-3-3 proteins.
336–338	impairs the anterograde er-to-golgi transport.
346	impairs the anterograde er-to-golgi transport.
346	impairs the interaction with coat protein complex ii; impairs the anterograde er-to-golgi transport.

Function

Pathways and Gene Ontology

Reactome pathways

7 pathways

ID	Pathway
R-HSA-1236974	ER-Phagosome pathway
R-HSA-1236977	Endosomal/Vacuolar pathway
R-HSA-198933	Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell
R-HSA-877300	Interferon gamma signaling
R-HSA-909733	Interferon alpha/beta signaling
R-HSA-9705671	SARS-CoV-2 activates/modulates innate and adaptive immune responses
R-HSA-983170	Antigen Presentation: Folding, assembly and peptide loading of class I MHC

MSigDB gene sets: 375 (showing top): WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, BENPORATH_ES_WITH_H3K27ME3, GOBP_NEGATIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, REACTOME_ANTIGEN_PRESENTATION_FOLDING_ASSEMBLY_AND_PEPTIDE_LOADING_OF_CLASS_I_MHC, REACTOME_CLASS_I_MHC_MEDIATED_ANTIGEN_PROCESSING_PRESENTATION, GOCC_VACUOLAR_MEMBRANE, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_POSITIVE_REGULATION_OF_LEUKOCYTE_DEGRANULATION, ENK_UV_RESPONSE_KERATINOCYTE_UP, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_PRODUCTION_OF_MOLECULAR_MEDIATOR_OF_IMMUNE_RESPONSE, GOBP_NEGATIVE_REGULATION_OF_LEUKOCYTE_MEDIATED_IMMUNITY

GO Biological Process (13): positive regulation of T cell mediated cytotoxicity (GO:0001916), antigen processing and presentation of endogenous peptide antigen via MHC class Ib (GO:0002476), antigen processing and presentation of exogenous peptide antigen via MHC class Ib (GO:0002477), antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-independent (GO:0002486), negative regulation of T cell cytokine production (GO:0002725), negative regulation of natural killer cell cytokine production (GO:0002728), positive regulation of natural killer cell cytokine production (GO:0002729), immune response (GO:0006955), negative regulation of natural killer cell degranulation (GO:0043322), positive regulation of natural killer cell degranulation (GO:0043323), negative regulation of natural killer cell mediated cytotoxicity (GO:0045953), immune system process (GO:0002376), antigen processing and presentation of peptide antigen via MHC class I (GO:0002474)

GO Molecular Function (7): signaling receptor binding (GO:0005102), beta-2-microglobulin binding (GO:0030881), peptide antigen binding (GO:0042605), TAP1 binding (GO:0046978), TAP2 binding (GO:0046979), 14-3-3 protein binding (GO:0071889), protein binding (GO:0005515)

GO Cellular Component (17): Golgi membrane (GO:0000139), obsolete extracellular space (GO:0005615), lysosomal membrane (GO:0005765), endoplasmic reticulum (GO:0005783), plasma membrane (GO:0005886), external side of plasma membrane (GO:0009897), cell surface (GO:0009986), ER to Golgi transport vesicle membrane (GO:0012507), membrane (GO:0016020), phagocytic vesicle membrane (GO:0030670), early endosome membrane (GO:0031901), MHC class Ib protein complex (GO:0032398), MHC class I protein complex (GO:0042612), recycling endosome membrane (GO:0055038), lumenal side of endoplasmic reticulum membrane (GO:0098553), lysosome (GO:0005764), endosome (GO:0005768)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
Antigen processing-Cross presentation	2
Interferon Signaling	2
Adaptive Immune System	1
SARS-CoV-2-host interactions	1
Class I MHC mediated antigen processing & presentation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
protein binding	3
antigen processing and presentation of peptide antigen via MHC class Ib	2
negative regulation of cytokine production involved in immune response	2
natural killer cell cytokine production	2
negative regulation of natural killer cell mediated immunity	2
regulation of natural killer cell cytokine production	2
natural killer cell degranulation	2
regulation of natural killer cell degranulation	2
TAP binding	2
endomembrane system	2
cellular anatomical structure	2
endosome membrane	2
MHC protein complex	2
positive regulation of leukocyte mediated cytotoxicity	1
T cell mediated cytotoxicity	1
regulation of T cell mediated cytotoxicity	1
positive regulation of T cell mediated immunity	1
antigen processing and presentation of endogenous peptide antigen	1
antigen processing and presentation of exogenous peptide antigen	1
antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway	1
T cell cytokine production	1
negative regulation of T cell mediated immunity	1
regulation of T cell cytokine production	1
positive regulation of natural killer cell mediated immunity	1
positive regulation of cytokine production involved in immune response	1
immune system process	1
response to stimulus	1
negative regulation of leukocyte degranulation	1
negative regulation of natural killer cell mediated cytotoxicity	1
positive regulation of leukocyte degranulation	1
positive regulation of natural killer cell mediated cytotoxicity	1
negative regulation of leukocyte mediated cytotoxicity	1
natural killer cell mediated cytotoxicity	1
regulation of natural killer cell mediated cytotoxicity	1
biological_process	1
antigen processing and presentation of peptide antigen	1
antigen binding	1
peptide binding	1
binding	1
Golgi apparatus	1

Protein interactions and networks

STRING

1074 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HLA-F	LILRB1	Q8NHL6	982
HLA-F	LILRB2	Q8N423	968
HLA-F	KIR3DL2	P43630	943
HLA-F	KLRC1	P26715	903
HLA-F	RNF39	Q9H2S5	796
HLA-F	TRIM31	Q9BZY9	742
HLA-F	UBD	O15205	728
HLA-F	KIR3DL1	P43629	703
HLA-F	B2M	P01884	701
HLA-F	KLRD1	Q13241	695
HLA-F	OR2H2	O95918	694
HLA-F	OR1D2	P34982	668
HLA-F	HLA-DMA	P28067	607
HLA-F	KIR2DL1	P43626	588
HLA-F	HLA-E	P13747	583

IntAct

120 interactions, top by confidence:

A	B	Type	Score
KIR3DL2	HLA-F	psi-mi:“MI:0915”(physical association)	0.720
KIR3DL2	HLA-F	psi-mi:“MI:0407”(direct interaction)	0.720
HLA-F	KIR3DL2	psi-mi:“MI:0407”(direct interaction)	0.720
KIR3DS1	HLA-F	psi-mi:“MI:0915”(physical association)	0.710
HLA-F	KIR3DS1	psi-mi:“MI:0407”(direct interaction)	0.710
HLA-A	TAPBP	psi-mi:“MI:0915”(physical association)	0.690
KIR3DL1	HLA-F	psi-mi:“MI:0915”(physical association)	0.680
HLA-F	KIR3DL1	psi-mi:“MI:0407”(direct interaction)	0.680
KIR2DS4	HLA-F	psi-mi:“MI:0915”(physical association)	0.670
KIR2DS4	HLA-F	psi-mi:“MI:0407”(direct interaction)	0.670
HLA-F	HLA-E	psi-mi:“MI:0915”(physical association)	0.660
HLA-F	HLA-E	psi-mi:“MI:0407”(direct interaction)	0.660
B2M	NEMP1	psi-mi:“MI:0914”(association)	0.640
HLA-F	HLA-A	psi-mi:“MI:0407”(direct interaction)	0.610
CFTR	HAX1	psi-mi:“MI:0914”(association)	0.610
B2M	TAPBP	psi-mi:“MI:0915”(physical association)	0.570
CLEC4A	SEMA7A	psi-mi:“MI:0914”(association)	0.530
ADAM21	PLXNA2	psi-mi:“MI:0914”(association)	0.530
FUT3	C1QL1	psi-mi:“MI:0914”(association)	0.530
HLA-G	HLA-B	psi-mi:“MI:0914”(association)	0.530

BioGRID (102): HLA-F (Affinity Capture-MS), HLA-F (Affinity Capture-MS), HLA-F (Affinity Capture-MS), HLA-F (Affinity Capture-MS), HLA-F (Affinity Capture-MS), HLA-F (Affinity Capture-MS), B2M (Affinity Capture-MS), KIAA1549 (Affinity Capture-MS), KDM5C (Affinity Capture-MS), HLA-F (Affinity Capture-MS), HLA-F (Affinity Capture-MS), KDM5C (Affinity Capture-MS), HLA-F (Affinity Capture-MS), HLA-F (Affinity Capture-MS), KIAA1549 (Affinity Capture-MS)

ESM2 similar proteins: O35799, O62848, P01898, P01899, P06126, P06339, P10321, P11609, P11610, P13747, P13752, P13753, P14429, P14430, P15812, P15813, P15978, P16212, P16215, P17693, P23043, P29016, P29017, P30511, P30515, P30516, P30517, P60018, P70387, Q28565, Q29422, Q30201, Q3ZCH5, Q4ACW4, Q5YB65, Q63493, Q95IT1, Q95IT3, Q9GKZ0, Q9GL41

Diamond homologs: A0A0G2K7V7, O19477, O35799, P01896, P01899, P01900, P01901, P10321, P13752, P15979, P16391, P30377, P30379, P30380, P30381, P30386, P30388, P30511, P30516, P60018, P70387, Q29980, Q29983, Q30201, Q60I18, Q8HWE5, Q8HWE7, Q9GKZ0, Q9GL41, Q9GL42, Q9GL43, C1ITJ8, P01888, P01889, P01893, P01894, P01895, P01897, P01898, P01902

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CIITA	“up-regulates quantity by expression”	HLA-F	“transcriptional regulation”
MYC	“down-regulates quantity by repression”	HLA-F	“transcriptional regulation”

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 135 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Antigen Presentation: Folding, assembly and peptide loading of class I MHC	8	37.1×	4e-09
DAP12 interactions	5	28.0×	5e-05
Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell	15	15.4×	1e-11
Interferon gamma signaling	9	13.3×	2e-06
ER-Phagosome pathway	7	10.7×	2e-04
Interferon alpha/beta signaling	5	9.0×	8e-03
SARS-CoV-2 activates/modulates innate and adaptive immune responses	6	6.3×	1e-02
Neutrophil degranulation	12	3.3×	9e-03

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of T cell mediated cytotoxicity	9	38.0×	1e-09
immune response-regulating signaling pathway	5	18.8×	6e-04
immune response	18	7.0×	4e-08
adaptive immune response	10	7.0×	2e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	0
Likely benign	3
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

832 predictions. Top by Δscore:

Variant	Effect	Δscore
6:29724235:G:A	acceptor_gain	1.0000
6:29724426:G:GT	donor_gain	1.0000
6:29724426:G:T	donor_gain	1.0000
6:29724444:CGCAG:C	donor_loss	1.0000
6:29724446:CAGG:C	donor_loss	1.0000
6:29724447:AGGTA:A	donor_loss	1.0000
6:29724448:GGTA:G	donor_loss	1.0000
6:29724449:G:C	donor_loss	1.0000
6:29724450:T:G	donor_loss	1.0000
6:29725446:GAGCA:G	acceptor_gain	1.0000
6:29723523:GGCGG:G	donor_gain	0.9900
6:29723524:GCGG:G	donor_gain	0.9900
6:29723524:GCGGG:G	donor_gain	0.9900
6:29723923:GGCTG:G	donor_gain	0.9900
6:29723924:GCTG:G	donor_gain	0.9900
6:29723924:GCTGG:G	donor_gain	0.9900
6:29724234:C:CA	acceptor_gain	0.9900
6:29724446:C:T	donor_gain	0.9900
6:29725026:CTCA:C	acceptor_loss	0.9900
6:29725027:TCA:T	acceptor_loss	0.9900
6:29725028:CA:C	acceptor_loss	0.9900
6:29725029:A:AC	acceptor_loss	0.9900
6:29725304:GGG:G	donor_gain	0.9900
6:29725305:GG:G	donor_gain	0.9900
6:29725305:GGG:G	donor_gain	0.9900
6:29725306:GG:G	donor_gain	0.9900
6:29725307:GTA:G	donor_loss	0.9900
6:29725308:TAA:T	donor_loss	0.9900
6:29725445:A:AG	acceptor_gain	0.9900
6:29725446:G:GA	acceptor_gain	0.9900

AlphaMissense

2872 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
6:29725105:T:C	F229L	0.990
6:29725107:C:A	F229L	0.990
6:29725107:C:G	F229L	0.990
6:29725204:T:C	F262L	0.978
6:29725206:C:A	F262L	0.978
6:29725206:C:G	F262L	0.978
6:29723762:T:C	F57L	0.972
6:29723764:C:A	F57L	0.972
6:29723764:C:G	F57L	0.972
6:29725132:T:A	W238R	0.967
6:29725132:T:C	W238R	0.967
6:29725134:G:C	W238C	0.966
6:29725134:G:T	W238C	0.966
6:29725215:G:C	W265C	0.959
6:29725215:G:T	W265C	0.959
6:29725090:T:A	C224S	0.957
6:29725091:G:C	C224S	0.957
6:29724300:G:C	W154C	0.952
6:29724300:G:T	W154C	0.952
6:29724298:T:A	W154R	0.951
6:29724298:T:C	W154R	0.951
6:29725090:T:C	C224R	0.944
6:29725106:T:C	F229S	0.942
6:29725258:T:A	C280S	0.942
6:29725259:G:C	C280S	0.942
6:29725258:T:C	C280R	0.941
6:29725213:T:A	W265R	0.929
6:29725213:T:C	W265R	0.929
6:29725260:C:G	C280W	0.929
6:29725092:C:G	C224W	0.928

dbSNP variants (sampled 300 via entrez): RS1000094516 (6:29729008 G>C,T), RS1000962638 (6:29731494 A>G), RS1001133955 (6:29727200 C>T), RS1001467883 (6:29731266 T>C,G), RS1001519169 (6:29728097 T>A,C), RS1001588131 (6:29721510 G>A,C), RS1001681617 (6:29735143 C>A,T), RS1001734998 (6:29732203 A>G), RS1001857636 (6:29726829 C>G), RS1002074339 (6:29733053 G>A,T), RS1002503465 (6:29726723 T>C), RS1002576153 (6:29729540 A>C,G), RS1002994988 (6:29723329 A>C), RS1003460483 (6:29737871 G>A,T), RS1003531518 (6:29737602 G>T)

Disease associations

OMIM: gene MIM:143110 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

21 associations (top):

Study	Trait	p-value
GCST000460_2	Nasopharyngeal carcinoma	7.000000e-11
GCST001438_6	Crohn’s disease	2.000000e-10
GCST004521_12	Autism spectrum disorder or schizophrenia	2.000000e-12
GCST004521_171	Autism spectrum disorder or schizophrenia	4.000000e-14
GCST004521_216	Autism spectrum disorder or schizophrenia	5.000000e-13
GCST004521_218	Autism spectrum disorder or schizophrenia	5.000000e-11
GCST004521_247	Autism spectrum disorder or schizophrenia	4.000000e-09
GCST004521_263	Autism spectrum disorder or schizophrenia	7.000000e-17
GCST004521_268	Autism spectrum disorder or schizophrenia	7.000000e-12
GCST004521_295	Autism spectrum disorder or schizophrenia	6.000000e-18
GCST004521_44	Autism spectrum disorder or schizophrenia	2.000000e-17
GCST004521_56	Autism spectrum disorder or schizophrenia	1.000000e-22
GCST004521_58	Autism spectrum disorder or schizophrenia	1.000000e-17
GCST004521_79	Autism spectrum disorder or schizophrenia	1.000000e-16
GCST004521_80	Autism spectrum disorder or schizophrenia	1.000000e-15
GCST005210_3	Mixed cellularity Hodgkin lymphoma	3.000000e-23
GCST005987_39	Albumin-globulin ratio	3.000000e-11
GCST008363_112	Offspring birth weight	3.000000e-08
GCST011656_13	Lung cancer	7.000000e-09
GCST90020028_885	Hip circumference adjusted for BMI	3.000000e-10
GCST90020028_886	Hip circumference adjusted for BMI	3.000000e-14

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0005128	albumin:globulin ratio measurement
EFO:0004344	birth weight
EFO:0005939	parental genotype effect measurement
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression	7
sodium arsenite	decreases expression, affects splicing	2
Resveratrol	affects cotreatment, increases expression	2
Arsenic Trioxide	decreases expression	2
Cisplatin	decreases expression, increases expression	2
Estradiol	affects cotreatment, decreases expression, increases expression	2
Smoke	decreases expression, increases abundance	2
Tretinoin	increases expression	2
peracetylated N-azidoacetylmannosamine	decreases expression	1
dicrotophos	decreases expression	1
bufotalin	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
bisphenol A	affects cotreatment, increases methylation	1
trichostatin A	increases expression	1
butyraldehyde	increases expression	1
nickel chloride	increases expression, increases reaction	1
ochratoxin A	increases acetylation, increases expression	1
potassium chromate(VI)	decreases expression	1
cadmium acetate	decreases expression	1
nickel sulfate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	affects response to substance, increases expression	1
pentanal	increases expression	1
repaglinide	affects expression	1
entinostat	increases expression	1
pinostrobin	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
ICG 001	increases expression	1
dorsomorphin	affects cotreatment, increases expression	1
eprenetapopt	affects expression	1

Clinical trials (associated diseases)

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