HLA-C

Chr 6Multi

major histocompatibility complex, class I, C

Also known as: D6S204, HLA-JY3, HLAC, HLC-C, MHC, PSORS1

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]

Primary Disease Associations & Inheritance

{HIV-1 viremia, susceptibility to}MIM #609423
{Psoriasis susceptibility 1}MIM #177900
Multi
UniProtPsoriasis 1
20
ClinVar variants
7
Pathogenic / LP
0.00
pLI score
12
Active trials
Clinical SummaryHLA-C
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
7 Pathogenic / Likely Pathogenic· 4 VUS of 20 total submissions
💊
Clinical Trials
12 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.02LOEUF
pLI 0.000
Z-score 1.51
OE 0.63 (0.401.02)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.13Z-score
OE missense 0.97 (0.861.10)
193 obs / 198.3 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.63 (0.401.02)
00.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.97 (0.861.10)
00.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.98
01.21.6
LoF obs/exp: 12 / 19.1Missense obs/exp: 193 / 198.3Syn Z: 0.16

ClinVar Variant Classifications

20 submitted variants in ClinVar

Classification Summary

Pathogenic4
Likely Pathogenic3
VUS4
Likely Benign8
Benign1
4
Pathogenic
3
Likely Pathogenic
4
VUS
8
Likely Benign
1
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
4
0
4
Likely Pathogenic
0
0
3
0
3
VUS
0
0
4
0
4
Likely Benign
0
2
1
5
8
Benign
0
1
0
0
1
Total0312520

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

HLA-C · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

{HIV-1 viremia, susceptibility to}

MIM #609423

Molecular basis of disorder known

{Psoriasis susceptibility 1}

MIM #177900

Molecular basis of disorder known

Multifactorial
📖
GeneReview available — HLA-C
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
HLA-Cw1 and Psoriasis.
Huang YW et al.·Am J Clin Dermatol
2021Review
Immunology of implantation.
Loke YW et al.·Baillieres Best Pract Res Clin Obstet Gynaecol
2000Review
Human uterine lymphocytes.
King A et al.·Hum Reprod Update
1998Review
Immunology of pre-eclampsia.
Redman CW et al.·Am J Reprod Immunol
2010Review
Immunogenetics.
van Rood JJ·Curr Opin Hematol
1994Review
HLA-C and guttate psoriasis.
Mallon E et al.·Br J Dermatol
2000
Top 10 resultsSearch PubMed ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

Type1 Diabetes Mellitus

EXtremely Early-onset Type 1 Diabetes EXtremely Early-onset Type 1 Diabetes (A Musketeers' Memorandum Study)

RECRUITING
NCT03369821University of ExeterStarted 2017-09-19
Beta Cell Loss and Immune FunctionImmune Function with RNAseq
Diffuse Hemispheric Glioma, H3 G34-Mutant

A Vaccine (Neoantigen-Targeted ppDC) for the Treatment of H3 G34-mutant Diffuse Hemispheric Glioma

ACTIVE NOT RECRUITING
NCT06342908Phase PHASE1Jonsson Comprehensive Cancer CenterStarted 2024-06-14
Biospecimen CollectionDendritic Cell TherapyLeukapheresis
Humoral Primary Immunodeficiencies (PIDs)Secondary Form of Humoral ImmunodeficienciesCombined Immunodeficiency (CID)

Study of Populations at Risk of Developing Chronic Hepatitis Linked to Chronic Enteric Virus Infection in Patients With Primary Immunodeficiency and Secondary Humoral Deficiency

RECRUITING
NCT06659588Assistance Publique - Hôpitaux de ParisStarted 2024-10-10
Plasma, urine and stool collection
EndometriosisImmunityMicrobiota

Innate Immunity, MIcrobiota and Inovative Treatments in Endometriosis

NOT YET RECRUITING
NCT07078435Phase NAUniversity Hospital, GrenobleStarted 2025-09-09
surgery (any volume) and / or pharmaceuticals treatment initiated or planned or only dynamic observation, in accordance with current clinical guidelinesBlood testStool samples
NY-ESO-1 Expressing Solid Tumors in HLA-A2 Positive PatientsSynovial SarcomaMelanoma

Study of TBI-1301 (NY-ESO-1 Specific TCR Gene Transduced Autologous T Lymphocytes) in Patients With Solid Tumors

ACTIVE NOT RECRUITING
NCT02869217Phase PHASE1University Health Network, TorontoStarted 2016-09
CyclophosphamideTBI-1301Fludarabine
AutophagyGalectinsHIV Infections

Study of Autophagy and the Effects of GALIG Gene Products in HIV-1 Infected Patients Who Are Under Antiretroviral Therapy Since Primary-infection, Chronic Phase, or Never Treated.

RECRUITING
NCT04160455Centre Hospitalier Régional d'OrléansStarted 2019-11-07
expression of a panel
Gastrointestinal CancerPancreatic CancerGastric Cancer

Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12D Variant of Mutated RAS in HLA-A*11:01 Patients

RECRUITING
NCT03745326Phase PHASE1, PHASE2National Cancer Institute (NCI)Started 2019-05-16
CyclophosphamideFludarabineAldesleukin
Non Hodgkin's Lymphoma

Allogenic CD19-targeting CAR-γδT Cell Therapy in R/R NHL

RECRUITING
NCT05554939Phase PHASE1, PHASE2Chinese PLA General HospitalStarted 2022-12-11
Allogenic CD19 CAR-γδT cellFludarabineCyclophosphamide
Diabetic Foot Ulcer (DFU)Venous Leg Ulcer (VLU)

Safety and Preliminary Efficacy of TrophiPatch, an Adipose-Derived Stromal Cell Patch for Chronic Leg Ulcers

RECRUITING
NCT07048054Phase PHASE1, PHASE2Nicolò BrembillaStarted 2025-07
TrophiPatch: allogeneic adipose-derived stromal cell patch
Desmoid FibromatosisRecurrent Desmoid FibromatosisUnresectable Desmoid Fibromatosis

A Study of a New Drug, Nirogacestat, for Treating Desmoid Tumors That Cannot be Removed by Surgery

ACTIVE NOT RECRUITING
NCT04195399Phase PHASE2Children's Oncology GroupStarted 2020-10-07
Biospecimen CollectionComputed TomographyEchocardiography Test
Acute Myeloid LeukemiaMinimal Residual DiseaseNatural Killer Cell

Infusion of Alloreactive nk Cells for Mrd-positive Aml Patients

RECRUITING
NCT06885476Phase NAIRCCS Azienda Ospedaliero-Universitaria di BolognaStarted 2021-01-22
Infusion of alloreactive NK cells
Non-hodgkin Lymphoma,B Cell

Allogeneic TRAC Locus-inserted CD19-targeting STAR T Cell Therapy in r/r B-NHL

RECRUITING
NCT06321289Phase PHASE1, PHASE2Chinese PLA General HospitalStarted 2024-03-20
Allogeneic CD19-STAR T cellFludarabineCyclophosphamide