HLA-F

Chr 6

major histocompatibility complex, class I, F

Also known as: CDA12, HLA-5.4, HLA-CDA12, HLAF

NCBI Gene: 3134ENSG00000204642UniProt: P30511

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. [provided by RefSeq, Jul 2008]

11
ClinVar variants
6
Pathogenic / LP
0.00
pLI score
7
Active trials
Clinical Summary— HLA-F
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
6 Pathogenic / Likely Pathogenic· 2 VUS of 11 total submissions
💊
Clinical Trials
7 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
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.
0.93LOEUF
pLI 0.000
Z-score 1.78
OE 0.55 (0.34–0.93)
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.
1.10Z-score
OE missense 0.81 (0.72–0.91)
207 obs / 256.7 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.0.55 (0.34–0.93)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.81 (0.72–0.91)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.95
0≤1.21.6
LoF obs/exp: 10 / 18.2Missense obs/exp: 207 / 256.7Syn Z: 0.37

ClinVar Variant Classifications

11 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic5
Likely Pathogenic1
VUS2
Likely Benign3
5
Pathogenic
1
Likely Pathogenic
2
VUS
3
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
2
0
2
Likely Benign
0
0
1
2
3
Benign
0
0
0
0
0
Total009211

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

View in ClinVar →

Protein Context — Lollipop Plot

HLA-F · 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

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Current research status of HLA in immune-related diseases.
Liu B et al.·Immun Inflamm Dis
2021Review
HLA Class Ib-receptor interactions during embryo implantation and early pregnancy.
Nilsson LL et al.·Hum Reprod Update
2022Review
HLA-F and LILRB1 Genetic Polymorphisms Associated with Alloimmunisation in Sickle Cell Disease.
Bernit E et al.·Int J Mol Sci
2023
HLA-F transcriptional and protein differential expression according to its genetic polymorphisms.
Paganini J et al.·HLA
2023
Evolution and molecular interactions of major histocompatibility complex (MHC)-G, -E and -F genes.
Arnaiz-Villena A et al.·Cell Mol Life Sci
2022Review
Advances in the study of HLA class Ib in maternal-fetal immune tolerance.
Yang Y et al.·Front Immunol
2022Review
Association of HLA-A and Non-Classical HLA Class I Alleles.
Carlini F et al.·PLoS One
2016
Extended loci histocompatibility matching in HSCT-Going beyond classical HLA.
Neuchel C et al.·Int J Immunogenet
2021Review
Correlation of alteration of HLA-F expression and clinical characterization in 593 brain glioma samples.
Feng E et al.·J Neuroinflammation
2019
Maternal HLA Ib Polymorphisms in Pregnancy Allo-Immunization.
Persson G et al.·Front Immunol
2021
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Type 1 Diabetes Mellitus

Clinical Phase II/III Trial of Ustekinumab to Treat Type 1 Diabetes (UST1D2)

ACTIVE NOT RECRUITING
NCT03941132Phase PHASE2, PHASE3University of British ColumbiaStarted 2021-01-04
UstekinumabPlacebo
Lung Transplantation

Trifecta-Lung cfDNA-MMDx Study

RECRUITING
NCT05837663University of AlbertaStarted 2023-11-01
Transfusion-dependent Thalassemia

Efficacy of Combination of Hdroxyurea and Thalidomide Over Either Hydroxyurea or Thalidomide Alone in the Treatment of Transfusion Dependent Thalassemia in Children: A Quasi-Randomised Clinical Trial

RECRUITING
NCT06299670Phase PHASE4Bangabandhu Sheikh Mujib Medical University, Dhaka, BangladeshStarted 2023-11-01
ThalidomideHydroxy UreaCombinations
Accelerated Phase Chronic Myelogenous Leukemia, BCR-ABL1 PositiveAcute Biphenotypic LeukemiaAcute Lymphoblastic Leukemia

Personalized NK Cell Therapy in CBT

RECRUITING
NCT02727803Phase PHASE2M.D. Anderson Cancer CenterStarted 2016-05-19
Allogeneic Natural Killer Cell Line NK-92Anti-Thymocyte GlobulinBusulfan
Heart Transplant Rejection

Trifecta-Heart cfDNA-MMDx Study

RECRUITING
NCT04707872University of AlbertaStarted 2021-06-01
MMDx diagnostic testProsperaHLA antibody
VEXAS Syndrome

Multicenter, Interdisciplinary National VEXAS Registry With Accompanying Biomaterial Collection

RECRUITING
NCT06377462Technische Universität DresdenStarted 2024-03-13
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

External Resources

Links to major genomics databases and tools