FGF23
Chr 12ADARfibroblast growth factor 23
Also known as: ADHR, FGFN, HFTC2, HPDR2, HYPF, PHPTC
FGF23 encodes a hormone that regulates phosphate homeostasis by inhibiting renal phosphate reabsorption and controlling vitamin D metabolism. Mutations cause autosomal dominant hypophosphatemic rickets or autosomal recessive hyperphosphatemic familial tumoral calcinosis, representing opposite ends of the phosphate regulation spectrum. The gene shows low constraint to loss-of-function variants (pLI 0.03, LOEUF 1.28), consistent with both loss-of-function and gain-of-function alleles causing distinct phosphate disorders.
Primary Disease Associations & 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 (gain-of-function and dominant-negative). The Badonyi & Marsh model scores dominant-negative highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports gain-of-function. 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.
Literature Evidence
Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.
ClinVar Variant Classifications
319 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 | 6 | 55 | 0 | 61 |
Likely Pathogenic | 1 | 5 | 6 | 0 | 12 |
VUS | 3 | 106 | 41 | 5 | 155 |
Likely Benign | 0 | 2 | 19 | 37 | 58 |
Benign | 0 | 1 | 17 | 0 | 18 |
Conflicting | — | 14 | |||
| Total | 4 | 120 | 138 | 42 | 318 |
LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly
View in ClinVar →Protein Context — Lollipop Plot
FGF23 · 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
Safety and Efficacy of Klotho and Follistatin Gene Therapy
RECRUITINGSafety and Efficacy of Injectable Klotho Plasmid Gene Therapy in Humans
RECRUITINGEffect of Burosumab on the Inflammatory Profile of Patients With X-linked Hypophosphatemic Rickets FLAM-XLH
NOT YET RECRUITINGThe Bone-parathyroid Crosstalk in Primary Hyperparathyroidism
NOT YET RECRUITINGDifferent Limb Lengths in Gastric Bypass Surgery (SLIM) - Part 3: Metabolism and Inflammation
RECRUITINGPhysical Exercise and Biomolecular Analysis to Reduce Uremic Toxins in Chronic Kidney Disease: An Exploratory Study
ENROLLING BY INVITATIONPAINDYS_Characterizing Pain in Fibrous Dysplasia of Bone/McCune-Albright Syndrome: an Exploratory Pilot Study
NOT YET RECRUITINGEvaluating the Role of IGF-1 and S-Klotho In Plaque Phenotype and Vulnerability: the VISION Study.
ACTIVE NOT RECRUITINGEffect of Intravenous Iron on Quality of Life in Older Patients With Acute Coronary Syndrome
RECRUITINGPhosphorus-31 Spectroscopy in Phosphate Diabetes
NOT YET RECRUITINGAcute Reno-Cardiac Action of Dapagliflozin In Advanced Heart Failure Patients on Heart Transplant Waiting List
RECRUITINGA Study of Lirafugratinib in Non-CCA Solid Tumors With FGFR2 Fusion or Rearrangement
NOT YET RECRUITINGExternal Resources
Links to major genomics databases and tools