HRH4
Chr 18histamine receptor H4
Also known as: AXOR35, BG26, GPCR105, GPRv53, H4, H4R, HH4R
HRH4 encodes histamine receptor H4, a G protein-coupled receptor that mediates chemotaxis of immune cells to sites of inflammation and influences release of proinflammatory cytokines in response to histamine. Pathogenic variants in HRH4 cause autosomal recessive primary immunodeficiency with recurrent infections and allergic manifestations. The gene shows low constraint against loss-of-function variants, consistent with autosomal recessive inheritance.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
Highly tolerant — LoF variants common in population
Mild missense constraint
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.
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
102 submitted variants in ClinVar
Classification Summary
Curated Variants Distribution
Classified variants from ClinVar · 5 ACMG categories
| Classification | LoF | Missense + Inframe | Non-coding | Synonymous | Total |
|---|---|---|---|---|---|
Pathogenic | 0 | 0 | 33 | 0 | 33 |
Likely Pathogenic | 0 | 0 | 1 | 0 | 1 |
VUS | 0 | 53 | 6 | 0 | 59 |
Likely Benign | 0 | 5 | 0 | 0 | 5 |
Benign | 0 | 0 | 0 | 0 | 0 |
| Total | 0 | 58 | 40 | 0 | 98 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
HRH4 · protein map & ClinVar variants
Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.
External Resources
Links to major genomics databases and tools
Clinical Trials
Active and recruiting trials from ClinicalTrials.gov
No active trials found for this gene.
Search ClinicalTrials.gov →External Resources
Links to major genomics databases and tools