Is FGF23 p.Pro30Ser (c.88C>T) pathogenic?

FGF23 p.Pro30Ser (c.88C>T) is classified Conflicting classifications of pathogenicity in FGF23 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-07-07). AlphaMissense: ambiguous (0.3455); Ultra-rare (popmax 0.0164%, mid); Associated with autosomal dominant hypophosphatemic rickets.

What condition is associated with FGF23 p.Pro30Ser (c.88C>T)?

FGF23 p.Pro30Ser (c.88C>T) is associated with autosomal dominant hypophosphatemic rickets, tumoral calcinosis, hyperphosphatemic, familial, 2 (ClinVar).

How common is FGF23 p.Pro30Ser (c.88C>T) in the general population?

FGF23 p.Pro30Ser (c.88C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

How is Autosomal dominant hypophosphatemic rickets inherited?

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

What do computational predictors say about FGF23 p.Pro30Ser (c.88C>T)?

AlphaMissense predicts ambiguous (score 0.3455) — an in-silico prediction, not a clinical call.

FGF23 p.Pro30Ser

c.88C>T · rs758725402 · VCV930793

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

ambiguous

0.3455 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

autosomal dominant hypophosphatemic rickets

Computational evidence

Protein change
AlphaMissense	0.3455	ambiguous
REVEL	0.478	indeterminate
SaProt	LLR -5.75	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.7	GERP 1.7, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 6,927 bp · p 0.55 · regional, not allelic
Overall
CADD	26.1	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

Grpmax group 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.00596% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00549%

Overall 0.00614% 99/1,612,962 alleles · ultra-rare exomes 91/1,460,752 · genomes 8/152,210 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0128%	7,810
Admixed American	0.00833%	12,001
European (non-Finnish)	0.0072%	13,883

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.Pro30Ser
Coding: c.88C>T
MANE Select: NM_020638
dbSNP: rs758725402
Type: single nucleotide variant
Location: chr12:4379495 (GRCh38)
Gene constraint: LOEUF 1.608 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.94 · 6 PDB

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

Disease context

autosomal dominant hypophosphatemic rickets — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: tumoral calcinosis, hyperphosphatemic, familial, 2

For Autosomal dominant hypophosphatemic rickets (Orphanet):

Inheritance: Autosomal dominant
Onset: Adolescent, Adult, Childhood, Infancy

Similar variants

FGF23 p.Arg179Gln Pathogenic ★★ ⚠ same condition
FGF23 p.Arg179Trp Pathogenic/Likely pathogenic ★★ same condition
FGF23 p.Gln54His Likely pathogenic ★★ ⚠ same condition
FGF23 p.Ser129Pro 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

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-pro30ser (accessed [today's date]).

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