FGF23

Chr 12ADAR

fibroblast growth factor 23

Also known as: ADHR, FGFN, HFTC2, HPDR2, HYPF, PHPTC

NCBI Gene: 8074 ENSG00000118972 UniProt: Q9GZV9 OMIM: 605380

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.

OMIM ResearchSummary from RefSeq, OMIM, UniProt

This gene encodes a member of the fibroblast growth factor family of proteins, which possess broad mitogenic and cell survival activities and are involved in a variety of biological processes. The product of this gene regulates phosphate homeostasis and transport in the kidney. The full-length, functional protein may be deactivated via cleavage into N-terminal and C-terminal chains. Mutation of this cleavage site causes autosomal dominant hypophosphatemic rickets (ADHR). Mutations in this gene are also associated with hyperphosphatemic familial tumoral calcinosis (HFTC). [provided by RefSeq, Feb 2013]

OMIM ResearchGenerating clinical summary…

Primary Disease Associations & Inheritance

Hypophosphatemic rickets, autosomal dominantMIM #193100

Tumoral calcinosis, hyperphosphatemic, familial, 2MIM #617993

Clinical highlights

Gene–disease validity

Not independently assessedOMIM lists Hypophosphatemic rickets, autosomal dominant; Tumoral calcinosis, hyperphosphatemic, familial; no ClinGen or GenCC tier

Active trials

537

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.28

LOEUF

Multiple*

Mechanism· predicted

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.28LOEUF

pLI 0.031

Z-score 1.14

OE 0.50 (0.23–1.28)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.40Z-score

OE missense 0.91 (0.80–1.04)

150 obs / 164.3 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.50 (0.23–1.28)

0≤0.351.4

Missense OE?0.91 (0.80–1.04)

0≤0.61.4

Synonymous OE?0.78

0≤1.21.6

LoF obs/exp: 3 / 6.0Missense obs/exp: 150 / 164.3Syn Z: 1.49

Background carrier burden — how many people carry a rare variant somewhere in FGF23?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 220

333 rare PASS variants

Rare truncating (LoF)

1 in 6,200

33 rare PASS variants

Rare synonymous (reference)

1 in 300

132 rare PASS variants

Truncating variants are far rarer here than missense — that gap, in human units, is what constraint means for FGF23. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 270	1 in 4,900
South Asian	~43k	1 in 200	1 in 2,000
Remaining (unassigned)	~30k	1 in 180	1 in 6,000
European (Finnish)	~27k	1 in 380	1 in 4,400
Admixed American	~22k	1 in 220	none seen
African / African American	~21k	1 in 180	≈ 1 in 17,000
East Asian	~20k	1 in 170	none seen
Ashkenazi Jewish	~13k	1 in 1,000	none seen
Middle Eastern	~2,884	1 in 170	none seen

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): All 3 coding exons well covered in gnomAD exomes and genomes.? see exons ↓