HHLA2

Chr 3

HHLA2 member of B7 family

Also known as: B7-H5, B7-H7, B7H7, B7y

NCBI Gene: 11148ENSG00000114455UniProt: Q9UM44OMIM: 604371

The protein is a surface ligand on monocytes that regulates T-cell mediated immunity by binding to receptors on T lymphocytes, with evidence suggesting it can both inhibit and costimulate T-cell proliferation and cytokine production. This gene is not well-established as a cause of human disease, as it shows no constraint against loss-of-function variants in population databases. Clinical significance of variants in this gene remains uncertain.

OMIMResearchSummary from RefSeq, UniProt
MultiplemechanismLOEUF 1.00
Clinical Summary— HHLA2
⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
16 unique Pathogenic / Likely Pathogenic· 58 VUS of 87 total submissions
Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint
1.00LOEUF
pLI 0.000
Z-score 1.55
OE 0.62 (0.40–1.00)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint
0.57Z-score
OE missense 0.89 (0.79–1.00)
194 obs / 217.8 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios
LoF OE0.62 (0.40–1.00)
0≤0.351.4
Missense OE0.89 (0.79–1.00)
0≤0.61.4
Synonymous OE0.75
0≤1.21.6
LoF obs/exp: 12 / 19.3Missense obs/exp: 194 / 217.8Syn Z: 1.77
DN
0.76top 25%
GOF
0.75top 25%
LOF
0.2092th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median
GOFprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

87 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic16
VUS58
Likely Benign5
16
Pathogenic
58
VUS
5
Likely Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
16
0
16
Likely Pathogenic
0
0
0
0
0
VUS
0
52
6
0
58
Likely Benign
0
5
0
0
5
Benign
0
0
0
0
0
Total05722079

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

View in ClinVar →

Protein Context — Lollipop Plot

HHLA2 · protein map & ClinVar variants

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

3D Protein StructureAlphaFold

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →
Clinical Literature
Open Research Assistant →
Full-Text Mentions
NLP-detected gene mentions in article bodies · via PubTator3
PubTator3
Top 5 full-text resultsSearch PubTator3 ↗
Key Publications
Landmark & review papers · by relevance
PubMed
Top 5 results · since 2015Search PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients