Is FGF23 p.Pro153Arg (c.458C>G) pathogenic?

FGF23 p.Pro153Arg (c.458C>G) is classified Uncertain significance in FGF23 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-06-13). AlphaMissense: likely benign (0.2813); Very rare (popmax 8.47e-05%, nfe).

How common is FGF23 p.Pro153Arg (c.458C>G) in the general population?

FGF23 p.Pro153Arg (c.458C>G) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about FGF23 p.Pro153Arg (c.458C>G)?

AlphaMissense predicts likely benign (score 0.2813) — an in-silico prediction, not a clinical call.

FGF23 p.Pro153Arg

c.458C>G · rs1865053647 · VCV1463219

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2813 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.2813	likely benign
REVEL	0.628	indeterminate
SaProt	LLR -6.77	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.9, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 2,268 bp · p 0.37 · regional, not allelic
Overall
CADD	25.4	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,179,978 alleles

Overall 6.2e-05% 1/1,614,136 alleles · very rare exomes 1/1,461,834 · genomes 0/152,302 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: FGF23
Protein: p.Pro153Arg
Coding: c.458C>G
MANE Select: NM_020638
dbSNP: rs1865053647
Type: single nucleotide variant
Location: chr12:4370641 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.94 · 6 PDB
Residue 153: an α-helix

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

Similar variants

FGF23 p.Pro153Ala Uncertain significance ★★ ⚠ same residue
FGF23 p.Pro153Leu Uncertain significance ★ ⚠ same residue
FGF23 p.Arg179Gln Pathogenic ★★ ⚠ same type
FGF23 p.Arg179Trp Pathogenic/Likely pathogenic ★★ same type
FGF23 p.Gln54His Likely pathogenic ★★ ⚠ same type
FGF23 p.Gly123Trp Pathogenic/Likely pathogenic ★★ same type
FGF23 p.Ser129Pro Pathogenic/Likely pathogenic ★★ same type
FGF23 p.Ala202Val Uncertain significance ★★ ⚠ same type

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-pro153arg (accessed [today's date]).

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