HLA-E

Chr 6

major histocompatibility complex, class I, E

Also known as: HLA-6.2, QA1

HLA-E 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. HLA-E binds a restricted subset of peptides derived from the leader peptides of other class I molecules. 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 domains, 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. [provided by RefSeq, Jul 2008]

7
ClinVar variants
6
Pathogenic / LP
0.04
pLI score
11
Active trials
Clinical SummaryHLA-E
Population Constraint (gnomAD)
Constrained for loss-of-function variants (OE-LoF 0.31) despite low pLI — interpret in context.
📋
ClinVar Variants
6 Pathogenic / Likely Pathogenic of 7 total submissions
💊
Clinical Trials
11 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.
0.61LOEUF
pLI 0.037
Z-score 2.80
OE 0.31 (0.170.61)
Tolerant

Typical tolerance to LoF variation

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.
1.98Z-score
OE missense 0.62 (0.540.71)
132 obs / 213.3 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.0.31 (0.170.61)
00.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.62 (0.540.71)
00.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.79
01.21.6
LoF obs/exp: 6 / 19.3Missense obs/exp: 132 / 213.3Syn Z: 1.58

ClinVar Variant Classifications

7 submitted variants in ClinVar

Classification Summary

Pathogenic5
Likely Pathogenic1
Likely Benign1
5
Pathogenic
1
Likely Pathogenic
1
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
5
0
5
Likely Pathogenic
0
0
1
0
1
VUS
0
0
0
0
0
Likely Benign
0
1
0
0
1
Benign
0
0
0
0
0
Total01607

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

View in ClinVar →

Protein Context — Lollipop Plot

HLA-E · 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

Clinical Literature
Landmark / reviewRecent case evidence

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

PSC

Colangioids to Define the Genetic Factors Involved in Atypical Primary Sclerosing Cholangitis

ACTIVE NOT RECRUITING
NCT06865924Phase NAFondazione IRCCS Ca' Granda, Ospedale Maggiore PoliclinicoStarted 2024-12-01
Use of assembloids as in vitro models to test new pharmacological approaches
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
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
Solid Tumor, AdultColorectal CancerNon-Small Cell Lung

A Study to Evaluate the Safety and Efficacy of A2B395, an Allogeneic Logic-gated CAR T, in Participants With Solid Tumors That Express EGFR and Have Lost HLA-A*02 Expression

RECRUITING
NCT06682793Phase PHASE1, PHASE2A2 Biotherapeutics Inc.Started 2025-05-22
A2B395xT CDx with HLA-LOH assay
Sickle Cell Disease

Efficacy Safety Study of Gene Therapy for Sickle Cell DiseaseSCD Using Autologous CD34+ Cells Transduced ex Vivo, Carrying a Corrected Globin Gene and a Silencing RNA.

RECRUITING
NCT07432867Phase PHASE1, PHASE2Assistance Publique - Hôpitaux de ParisStarted 2026-02-25
DREAM01 drug productanti-inflammatory therapy
HivHIV I Infection

Multi Interventional Approaches to Mitigate HIV Reservoirs Aiming the Sustained HIV Remission Without Antiretrovirals

NOT YET RECRUITING
NCT06805656Phase PHASE2Federal University of São PauloStarted 2025-09-01
MaravirocDolutegravirDendritic Cell Vaccine
Epilepsy

Precision Medicine in the Treatment of Epilepsy

RECRUITING
NCT05450822Gitte Moos KnudsenStarted 2022-02-18
LevetiracetamLevetiracetam TabletsLamotrigine tablet
Kidney Cancer

HERV-E TCR Transduced Autologous T Cells in People With Metastatic Clear Cell Renal Cell Carcinoma

ACTIVE NOT RECRUITING
NCT03354390Phase PHASE1National Heart, Lung, and Blood Institute (NHLBI)Started 2018-07-20
cell infusion
GATA2ImmunodeficiencyMDS

Allogeneic Hematopoietic Stem Cell Transplant for GATA2 Mutations

RECRUITING
NCT01861106Phase PHASE2National Cancer Institute (NCI)Started 2013-07-24
Allogeneic HSCTBusulfan Test doseFludarabine (Fludara, Berlex Laboratories)
Hepatitis C Virus Infection

Characterization of Immune Genotypes and Antibody Profiles to Foster the discoVERY of diagnosticbioMARKERS of Liver Cancer Development

RECRUITING
NCT06718530Centro di Riferimento Oncologico - AvianoStarted 2024-05-13