Is FGF23 p.Ser129Pro (c.385T>C) pathogenic?

FGF23 p.Ser129Pro (c.385T>C) is classified Pathogenic/Likely pathogenic in FGF23 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-12-13). AlphaMissense: likely pathogenic (0.9571); Absent from gnomAD v4.1; Associated with tumoral calcinosis, hyperphosphatemic, familial, 2.

What condition is associated with FGF23 p.Ser129Pro (c.385T>C)?

FGF23 p.Ser129Pro (c.385T>C) is associated with tumoral calcinosis, hyperphosphatemic, familial, 2, tumoral calcinosis, hyperphosphatemic, familial, 1 (ClinVar).

How common is FGF23 p.Ser129Pro (c.385T>C) in the general population?

FGF23 p.Ser129Pro (c.385T>C) is absent from gnomAD v4.1 (gnomAD).

How is Familial tumoral calcinosis inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about FGF23 p.Ser129Pro (c.385T>C)?

AlphaMissense predicts likely pathogenic (score 0.9571) — an in-silico prediction, not a clinical call.

FGF23 p.Ser129Pro

c.385T>C · rs1555096583 · VCV444061

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9571 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

tumoral calcinosis, hyperphosphatemic, familial, 2

Computational evidence

Protein change
AlphaMissense	0.9571	likely pathogenic ✓ concordant with ClinVar · top 6% in FGF23
REVEL	0.701	pathogenic-leaning
SaProt	LLR -10.12	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9	GERP 0.74, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 2,268 bp · p 0.37 · regional, not allelic
Overall
CADD	23.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FGF23
Protein: p.Ser129Pro
Coding: c.385T>C
MANE Select: NM_020638
dbSNP: rs1555096583
Type: single nucleotide variant
Location: chr12:4370714 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.94 · 6 PDB
Residue 129: a UniProt-annotated variant site (in hftc2; full-length and n-terminal fragments are barely detectable, whereas a c-terminal fragment with the same molecular weight as that from wild-type can be detected)

Full FGF23 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

tumoral calcinosis, hyperphosphatemic, familial, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: tumoral calcinosis, hyperphosphatemic, familial, 1

For Familial tumoral calcinosis (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

FGF23 p.Ser129Phe Pathogenic same residue
FGF23 p.Arg179Gln Pathogenic ★★ ⚠ same condition
FGF23 p.Gly123Trp Pathogenic/Likely pathogenic ★★ same condition
FGF23 p.Ala213Thr Uncertain significance ★★ ⚠ same condition
FGF23 p.Ala236Pro Uncertain significance ★★ ⚠ same condition
FGF23 p.Ala45Thr Uncertain significance ★★ ⚠ same condition
FGF23 p.Arg187Trp Uncertain significance ★★ ⚠ same condition
FGF23 p.Arg5Cys Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/fgf23-p-ser129pro (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown