HLA-C major histocompatibility complex, class I, C [Homo sapiens (human)] - Gene

Summary

Official Symbol: HLA-Cprovided by HGNC
Official Full Name: major histocompatibility complex, class I, Cprovided by HGNC
Primary source: HGNC:HGNC:4933
See related: Ensembl:ENSG00000204525 MIM:142840; AllianceGenome:HGNC:4933
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: MHC; HLAC; HLC-C; D6S204; PSORS1; HLA-JY3
Summary: HLA-C belongs to the HLA class I heavy chain paralogues. This class I molecule is a heterodimer consisting of a heavy chain and a light chain (beta-2 microglobulin). The heavy chain is anchored in the membrane. Class I molecules play a central role in the immune system by presenting peptides derived from endoplasmic reticulum lumen. They are expressed in nearly all cells. The heavy chain is approximately 45 kDa and its gene contains 8 exons. Exon one encodes the leader peptide, exons 2 and 3 encode the alpha1 and alpha2 domain, which both bind the peptide, exon 4 encodes the alpha3 domain, exon 5 encodes the transmembrane region, and exons 6 and 7 encode the cytoplasmic tail. Polymorphisms within exon 2 and exon 3 are responsible for the peptide binding specificity of each class one molecule. Typing for these polymorphisms is routinely done for bone marrow and kidney transplantation. About 6000 HLA-C alleles have been described. The HLA system plays an important role in the occurrence and outcome of infectious diseases, including those caused by the malaria parasite, the human immunodeficiency virus (HIV), and the severe acute respiratory syndrome coronavirus (SARS-CoV). The structural spike and the nucleocapsid proteins of the novel coronavirus SARS-CoV-2, which causes coronavirus disease 2019 (COVID-19), are reported to contain multiple Class I epitopes with predicted HLA restrictions. Individual HLA genetic variation may help explain different immune responses to a virus across a population.[provided by RefSeq, Aug 2020]
Annotation information: Note: This gene has been reviewed for its involvement in coronavirus biology, and is involved in immune response or antiviral activity.
Expression: Broad expression in lung (RPKM 536.7), bone marrow (RPKM 302.4) and 22 other tissues See more
Orthologs: all
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Genomic context

Location:: 6p21.33

Exon count:: 8

Annotation release	Status	Assembly	Chr	Location
RS_2024_08	current	GRCh38.p14 (GCF_000001405.40)	6	NC_000006.12 (31268749..31272092, complement)
RS_2024_08	current	T2T-CHM13v2.0 (GCF_009914755.1)	6	NC_060930.1 (31134915..31138292, complement)
RS_2024_09	previous assembly	GRCh37.p13 (GCF_000001405.25)	6	NC_000006.11 (31236526..31239869, complement)

Chromosome 6 - NC_000006.12 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into Functions

What's a GeneRIF?

Association of the Genetic Diversity of Killer Cell Immunoglobulin-like Receptor Genes and HLA-C Ligand in Saudi Women With Thyroid Cancer.
Title: Association of the Genetic Diversity of Killer Cell Immunoglobulin-like Receptor Genes and HLA-C Ligand in Saudi Women With Thyroid Cancer.
HLA-Cw6 Polymorphism in Autoimmune Blistering Diseases.
Title: HLA-Cw6 Polymorphism in Autoimmune Blistering Diseases.
Insights into PCSK9-LDLR Regulation and Trafficking via the Differential Functions of MHC-I Proteins HFE and HLA-C.
Title: Insights into PCSK9-LDLR Regulation and Trafficking via the Differential Functions of MHC-I Proteins HFE and HLA-C.
Impact of HLA Class I Antigen, Killer Inhibitory Receptor, and FCGR3A Genotypes on Breast Cancer Susceptibility and Tumor Stage.
Title: Impact of HLA Class I Antigen, Killer Inhibitory Receptor, and FCGR3A Genotypes on Breast Cancer Susceptibility and Tumor Stage.
The protective association of HLA-C*12:02 and HLA-DQB1*06:01 with severe acute hepatitis of unknown origin in the Japanese population.
Title: The protective association of HLA-C*12:02 and HLA-DQB1*06:01 with severe acute hepatitis of unknown origin in the Japanese population.
[Genetic study of a rare Chinese pedigree with a recombination occurring between the HLA-A/C loci in both parents].
Title: [Genetic study of a rare Chinese pedigree with a recombination occurring between the HLA-A/C loci in both parents].
Establishing association between HLA-C*04:01 and severe COVID-19.
Title: Establishing association between HLA-C*04:01 and severe COVID-19.
HLA-B and C Expression Contributes to COVID-19 Disease Severity within a South African Cohort.
Title: HLA-B and C Expression Contributes to COVID-19 Disease Severity within a South African Cohort.
HLA-G isoforms, HLA-C allotype and their expressions differ between early abortus and placenta in relation to spontaneous abortions.
Title: HLA-G isoforms, HLA-C allotype and their expressions differ between early abortus and placenta in relation to spontaneous abortions.
Helicobacter pylori enhances HLA-C expression in the human gastric adenocarcinoma cells AGS and can protect them from the cytotoxicity of natural killer cells.
Title: Helicobacter pylori enhances HLA-C expression in the human gastric adenocarcinoma cells AGS and can protect them from the cytotoxicity of natural killer cells.

Submit: New GeneRIF Correction See all GeneRIFs (386)

Phenotypes

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Review eQTL and phenotype association data in this region using PheGenI

Associated conditions

Description	Tests
Psoriasis 1, susceptibility to MedGen: C1867449 OMIM: 177900 GeneReviews: Not available	not available
Susceptibility to HIV infection MedGen: C1836230 OMIM: 609423 GeneReviews: Not available	not available

EBI GWAS Catalog

Description
A genome-wide association meta-analysis of self-reported allergy identifies shared and allergy-specific susceptibility loci. EBI GWAS Catalog EBI GWAS CatalogPubMed
A genome-wide association study for coronary artery disease identifies a novel susceptibility locus in the major histocompatibility complex. EBI GWAS Catalog EBI GWAS CatalogPubMed
A genome-wide association study identifies new psoriasis susceptibility loci and an interaction between HLA-C and ERAP1. EBI GWAS Catalog EBI GWAS CatalogPubMed
A genome-wide association study identifies protein quantitative trait loci (pQTLs). EBI GWAS Catalog EBI GWAS CatalogPubMed
A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci. EBI GWAS Catalog EBI GWAS CatalogPubMed
A genome-wide association study of psoriasis and psoriatic arthritis identifies new disease loci. EBI GWAS Catalog EBI GWAS CatalogPubMed
A whole-genome association study of major determinants for allopurinol-related Stevens-Johnson syndrome and toxic epidermal necrolysis in Japanese patients. EBI GWAS Catalog EBI GWAS CatalogPubMed
Association study of common genetic variants and HIV-1 acquisition in 6,300 infected cases and 7,200 controls. EBI GWAS Catalog EBI GWAS CatalogPubMed
Common genetic variation and the control of HIV-1 in humans. EBI GWAS Catalog EBI GWAS CatalogPubMed
Common variants at TRAF3IP2 are associated with susceptibility to psoriatic arthritis and psoriasis. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genetic variants at 6p21.33 are associated with susceptibility to follicular lymphoma. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association analysis of blood biomarkers in chronic obstructive pulmonary disease. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association study for levels of total serum IgE identifies HLA-C in a Japanese population. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association study for serum complement C3 and C4 levels in healthy Chinese subjects. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association study for vitiligo identifies susceptibility loci at 6q27 and the MHC. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association study identified the human leukocyte antigen region as a novel locus for plasma beta-2 microglobulin. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association study identifies a psoriasis susceptibility locus at TRAF3IP2. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide association study identifies eight new susceptibility loci for atopic dermatitis in the Japanese population. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genome-wide scan reveals association of psoriasis with IL-23 and NF-kappaB pathways. EBI GWAS Catalog EBI GWAS CatalogPubMed
Genomewide association study of an AIDS-nonprogression cohort emphasizes the role played by HLA genes (ANRS Genomewide Association Study 02). EBI GWAS Catalog EBI GWAS CatalogPubMed
Host-microbe interactions have shaped the genetic architecture of inflammatory bowel disease. EBI GWAS Catalog EBI GWAS CatalogPubMed
Identification of ZNF313/RNF114 as a novel psoriasis susceptibility gene. EBI GWAS Catalog EBI GWAS CatalogPubMed
Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization. EBI GWAS Catalog EBI GWAS CatalogPubMed
Multiple loci are associated with white blood cell phenotypes. EBI GWAS Catalog EBI GWAS CatalogPubMed
New loci associated with chronic hepatitis B virus infection in Han Chinese. EBI GWAS Catalog EBI GWAS CatalogPubMed
Novel associations for hypothyroidism include known autoimmune risk loci. EBI GWAS Catalog EBI GWAS CatalogPubMed
The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. EBI GWAS Catalog EBI GWAS CatalogPubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

HIV-1 interactions

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Replication interactions

Interaction	Pubs
Capsid expressing (p24+) cells from pleural fluid of HIV-1/TB coinfected patients or in vitro infected PBMC (NL4-3 or NLAD8) downregulate HLA-A/B/C and BST2 (Tetherin) concomitantly with CD4 downregulation	PubMed

Protein interactions

Protein	Gene	Interaction	Pubs
Asp	asp	Antisense reading frame-derived cryptic epitopes from the gag, pol, and nef genes are inhibited by the predicted HLA-I alleles, and presented by HIV-1-infected CD8+ T-cells	PubMed
	asp	Antisense reading frame-derived cryptic epitopes from the env gene are inhibited by the HLA-I alleles in CD8+ T-cells	PubMed
Envelope surface glycoprotein gp120	env	The presence of HLA-C and HLA-E molecules on HIV-infected cells facilitates evasion of NK-mediated killing of anti-gp120-coated HIV-infected cells	PubMed
	env	HLA-C positive cells co-expressing HIV-1 gp120/gp41 fuse more rapidly and produce larger syncytia than HLA-C negative cells	PubMed
	env	Conformational changes in HIV-1 gp120, including an enhanced expression of the V3 loop of gp120 and of epitopes that are exposed upon CD4 binding, are consistent with the formation of a multimolecular complex between HLA class I and gp120/160	PubMed
	env	A highly conserved region of HIV-1 gp120 (amino acids 376 to 383) is recognized by an HLA-C molecule, Cw4	PubMed
	env	Treatment of CD4+ T cells with HIV-1 gp120 significantly increases CD4 association with CD3, CD45RA, CD45RB, CD59, CD38, CD26 and HLA class I, and decreases that with CD45RC	PubMed
Envelope surface glycoprotein gp160, precursor	env	HIV-1 gp160-derived peptide p18 presented by H-2Dd class I major histocompatibility complex molecules is processed by angiotensin-1 converting enzyme (ACE) prior to T cell stimulation by the peptide p18	PubMed
Envelope transmembrane glycoprotein gp41	env	HLA-C positive cells co-expressing HIV-1 gp120/gp41 fuse more rapidly and produce larger syncytia than HLA-C negative cells	PubMed
	env	Soluble HIV-1 gp41 can selectively enhance MHC class I and II expression on human B cells, but does not increase expression of other cell surface antigens such as CD21 and CD54 (ICAM-1)	PubMed
	env	Soluble HIV-1 gp41 enhancement effects on MHC class I and II antigen expression can be inhibited by soluble gp41-binding proteins of 45, 49 and 62 kD from human B cells	PubMed
	env	HIV-1 gp41 selectively enhances MHC class I, ICAM-1, IFN-alpha, IFN-beta, and IFN-omega expression in H9 cells	PubMed
Nef	nef	HIV-1 (SF2) Nef downregulates MHC-I (HLA-A/B/C); downregulation is dependent upon a proline-rich SH3 binding domain in Nef	PubMed
	nef	HIV-1 NL4-3 Nef downregulates HLA-A/B/C, which moderately requires the CPG-motif in Nef	PubMed
	nef	Four glutamic acids from position 62 to 65 in the SH3 domain of HIV-1 Nef bind to the cytoplasmic tail at position 320Y of MHC-I, and are required for the Nef-mediated downregulation of MHC-I from the cell surface	PubMed
	nef	HIV-1 Nef downregulates the expression of MHC-I at the surface of lymphoid, monocytic and epithelial cells, causing MHC-I molecules to be rapidly internalized, accumulated in endosomal vesicles and degraded	PubMed
	nef	HIV-1 Nef clones from acute controllers display a lesser ability to downregulate CD4 and HLA class I from the cell surface, and a reduced ability to enhance virion infectivity compared to those from acute progressors	PubMed
	nef	HIV-1 Nef clones obtained from chronic patients infected with HIV-1 subtypes A, B, C or D show a functional hierarchy of subtype B > A/D > C for Nef-mediated HLA class I downregulation	PubMed
	nef	HIV-1 Nef clones, isolated from plasma of elite controllers (EC) and chronic progressors (CP), show significantly lower HLA class I downregulation activity in EC than that in CP	PubMed
	nef	Protective HLA alleles have a true preference for HIV-1 Gag protein, while non-protective HLA alleles preferentially interact with HIV-1 Nef	PubMed
	nef	The HIV-1 Nef highly conserved valine-glycine-phenylalanine amino acid triplet (VGF) motif, which links the acidic cluster and the proline-rich motif, is important for downregulation of CXCR4 and MHC-I	PubMed
	nef	HLA-A2 molecules with HLA-A cytoplasmic domains are more downregulated by HIV-1 Nef than those with HLA-B domains. There is no downregulation of HLA-A2 with HLA-C cytoplasmic domains by Nef	PubMed
	nef	Asp327 and Tyr320 of MHC-I, Asp123 of Nef, and Arg225, Arg393, Lys396, Arg211, and Arg246 of mu 1 are involved in a crucial three-way electrostatic network, which results in the Nef-MHC-I CD-mu 1 complex formation	PubMed
	nef	HIV-1 Nef with A84D, Y135F, and G140R mutation impairs to its ability to downregulate MHC-I	PubMed
	nef	Double (W13A/V16R) and triple (W13A/V16R/M20A) substitution mutants of HIV-1 Nef fail to downregulate MHC-I	PubMed
	nef	HIV-1 Nef-mediated downregulation of MHC-I requires Nef motif EEEE(65)-dependent binding to the sorting protein PACS-2, which targets Nef to the paranuclear region and enables Nef PXXP(75) to bind and activate a trans-Golgi network localized Src kinase	PubMed
	nef	HIV-1 Nef-induced downregulation of MHC-I expression and MHC-I targeting to the trans-Golgi network (TGN) require the binding of Nef to PACS-1, a molecule that controls the TGN localization of the cellular protein furin	PubMed
	nef	HIV-1 Nef downregulates expression of MHC-I by blocking transport of MHC-I molecules to the cell surface through a mechanism that requires phosphoinositide 3-kinase (PI 3-kinase) activity	PubMed
	nef	Interaction of HIV-1 Nef with the mu subunit of AP adaptor complexes requires the recognition of tyrosine-based sorting signals, which likely facilitates the connection between MHC I and the clathrin-dependent sorting machinery	PubMed
	nef	A methionine residue at amino acid 20 in the alpha-helix domain is required for the ability of HIV-1 Nef to downregulate MHC-I expression but not for the downregulation of CD4	PubMed
	nef	Amino acid residue Y320 in the MHC-I cytoplasmic domain and residues E62-65 and P78 in HIV-1 Nef are required for interaction with the mu subunit of AP-1	PubMed
	nef	In promonocytic cells, Nef/Hck recruits the ZAP-70 homolog Syk to downregulate MHC-I	PubMed
	nef	Nef/Hck complex recruits and phosphorylates the tyrosine kinase ZAP-70, which binds class I PI3K to trigger MHC-I downregulation in primary CD4+ T cells	PubMed
	nef	MHC-I is found in the Rab7(+) vesicles and is targeted for degradation via the activity of the Nef-interacting protein, beta-COP	PubMed
	nef	Deletion of the 19 N-terminal amino acids including the myristoylation signal from HIV-1 Nef inhibits both MHC-I and CD4 downregulation while preserving most CTL, T-helper and B-cell epitopes	PubMed
Pr55(Gag)	gag	Protective HLA alleles have a true preference for HIV-1 Gag protein, while non-protective HLA alleles preferentially interact with HIV-1 Nef	PubMed
	gag	HIV-1 Gag peptides (Gag144-152, Gag163-171 and Gag295-304) enhance binding of KIR2DL2 to HLA-C03:04 and result in inhibition of KIR2DL2+ primary NK cells	PubMed
	gag	HIV-1 Gag virus-like particles efficiently activate human monocyte-derived dendritic cells (MDDC) and induce MDDC maturation with an associated increase in the surface expression of CD80, CD86 and MHC classes I and II	PubMed
	gag	The PTAP L-domains in the p6 domain of HIV-1 Gag regulates ubiquitination of Gag which controls MHC-I presentation and gag processing in the DRiP pathway.	PubMed
	gag	HLA-C/HIV-1 Gag209-218 peptide complexes bind KIR2DL2, which results in functional inhibition of primary NK cells	PubMed
	gag	Specific HIV-1 residues in Vpr, Gag, and Rev and HLA alleles (particularly B and C) confer susceptibility to the CTL response in HIV-1 infected patients	PubMed
	gag	Targeting HIV-1 Gag into the defective ribosomal product pathway enhances MHC class I antigen presentation and CD8+ T cell activation	PubMed
Rev	rev	Specific HIV-1 residues in Vpr, Gag, and Rev and HLA alleles (particularly B and C) confer susceptibility to the CTL response in HIV-1 infected patients	PubMed
Tat	tat	Four mutations (C27S, K51T, R55L, and G79A) on HIV-1 Tat result in the loss of the deleterious effects of Tat on the expression of MHC I, IL-2, and CD25 genes compared with wild-type Tat in Jurkat cells	PubMed
	tat	HIV-1 Tat upregulates MHC class I in monocyte-derived dendritic cells and CD8(+) T cells, thereby driving T cell-mediated immune responses	PubMed
	tat	HIV-1 Tat represses the MHC class I gene promoter by binding to and repressing TAFII250, a component of the general transcription factor TFIID, suggesting a mechanism for HIV-1 to downregulate MHC class I expression and avoid immune surveillance	PubMed
Vpr	vpr	Specific HIV-1 residues in Vpr, Gag, and Rev and HLA alleles (particularly B and C) confer susceptibility to the CTL response in HIV-1 infected patients	PubMed
Vpu	vpu	Using antibodies specific to MHC class I A, B, and C molecules (clone W6/32), HIV-1 Vpu protein has been shown to downregulate the expression of MHC class I molecules on the surface of HIV-1 infected cells	PubMed
	vpu	HLA class I-associated immune responses have minor effects on Vpu variability, suggesting that Vpu conformation and function are preserved through many possible combinations of primary and secondary polymorphisms	PubMed

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Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

D6S1019 (e-PCR)
- UniSTS:65555

stD6S1124E.1 (e-PCR)
- UniSTS:151085

HUM000C210 (e-PCR)
- UniSTS:59187

HUM00TB019 (e-PCR)
- UniSTS:57411

STS-M80468 (e-PCR)
- UniSTS:19295

D6S1281 (e-PCR)
- UniSTS:45995

PMC165225P2 (e-PCR)
- UniSTS:271534

RH70531 (e-PCR)
- UniSTS:75451

WIAF-1551 (e-PCR)
- UniSTS:11475

D6S2071 (e-PCR)
- UniSTS:12506

D6S1053 (e-PCR)
- UniSTS:63715

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enables TAP binding	IDA Inferred from Direct Assay more info	PubMed
enables peptide antigen binding	IBA Inferred from Biological aspect of Ancestor more info
enables peptide antigen binding	IDA Inferred from Direct Assay more info	PubMed
enables protein binding	IPI Inferred from Physical Interaction more info	PubMed
enables signaling receptor binding	IBA Inferred from Biological aspect of Ancestor more info

Process	Evidence Code	Pubs
involved_in adaptive immune response	IEA Inferred from Electronic Annotation more info
involved_in antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-independent	IBA Inferred from Biological aspect of Ancestor more info
involved_in antigen processing and presentation of endogenous peptide antigen via MHC class I via ER pathway, TAP-independent	IDA Inferred from Direct Assay more info	PubMed
involved_in antigen processing and presentation of endogenous peptide antigen via MHC class Ib	IBA Inferred from Biological aspect of Ancestor more info
involved_in immune response	IBA Inferred from Biological aspect of Ancestor more info
involved_in immune response	NAS Non-traceable Author Statement more info	PubMed
involved_in innate immune response	IEA Inferred from Electronic Annotation more info
involved_in positive regulation of T cell mediated cytotoxicity	IBA Inferred from Biological aspect of Ancestor more info

Component	Evidence Code	Pubs
located_in ER to Golgi transport vesicle membrane	TAS Traceable Author Statement more info
located_in Golgi apparatus	IDA Inferred from Direct Assay more info	PubMed
located_in Golgi membrane	TAS Traceable Author Statement more info
part_of MHC class I protein complex	IDA Inferred from Direct Assay more info	PubMed
located_in cell surface	IDA Inferred from Direct Assay more info	PubMed
located_in early endosome membrane	TAS Traceable Author Statement more info
located_in endoplasmic reticulum	IDA Inferred from Direct Assay more info	PubMed
is_active_in external side of plasma membrane	IBA Inferred from Biological aspect of Ancestor more info
located_in extracellular exosome	HDA more info	PubMed
is_active_in extracellular space	IBA Inferred from Biological aspect of Ancestor more info
located_in lumenal side of endoplasmic reticulum membrane	TAS Traceable Author Statement more info
located_in membrane	HDA more info	PubMed
located_in phagocytic vesicle membrane	TAS Traceable Author Statement more info
located_in plasma membrane	NAS Non-traceable Author Statement more info	PubMed
located_in plasma membrane	TAS Traceable Author Statement more info
located_in recycling endosome membrane	TAS Traceable Author Statement more info
located_in secretory granule membrane	TAS Traceable Author Statement more info

General protein information

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Preferred Names: HLA class I histocompatibility antigen, C alpha chain

Names: HLA-C antigen; MHC class I antigen heavy chain HLA-C; human leukocyte antigen-C alpha chain; major histocompatibility antigen HLA-C

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.