FKBP4
Chr 12FKBP prolyl isomerase 4
Also known as: FKBP51, FKBP52, FKBP59, HBI, Hsp56, PPIase, p52
The protein is a cis-trans prolyl isomerase and co-chaperone that associates with heat shock proteins to facilitate intracellular trafficking of steroid hormone receptors, controls neuronal growth cones through TRPC1 channel regulation, and inhibits tau-mediated microtubule assembly. Mutations cause autosomal recessive intellectual disability and developmental delay. This gene is highly constrained against loss-of-function variants, suggesting that complete protein loss is not well tolerated.
Population Genetics & Constraint
gnomAD v4 — loss-of-function & missense intolerance
More LoF-intolerant than ~75% of genes
Mild missense constraint
This gene has evidence for multiple mechanisms of pathogenicity (gain-of-function and dominant-negative). Both the Badonyi & Marsh prediction and the broader genomic evidence point to gain-of-function 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
135 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 | 60 | 0 | 60 |
Likely Pathogenic | 0 | 0 | 3 | 0 | 3 |
VUS | 0 | 41 | 5 | 0 | 46 |
Likely Benign | 0 | 3 | 1 | 0 | 4 |
Benign | 0 | 2 | 1 | 1 | 4 |
| Total | 0 | 46 | 70 | 1 | 117 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
FKBP4 · 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
Fertility And Sexual Function In CAH: CALLIOPE
RECRUITINGReality-monitoring & Stress
RECRUITINGEffect of Transcranial Alternative Current Stimulation at Alpha Frequency (α-tACS) on Stressed Healthy Subjects
RECRUITINGExternal Resources
Links to major genomics databases and tools