Is FGF23 p.Arg231Ter (c.691C>T) pathogenic?

FGF23 p.Arg231Ter (c.691C>T) is classified Uncertain significance in FGF23 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-03-22). Very rare (popmax 0.000339%, nfe).

How common is FGF23 p.Arg231Ter (c.691C>T) in the general population?

FGF23 p.Arg231Ter (c.691C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

FGF23 p.Arg231Ter

c.691C>T · rs764061118 · VCV1383032

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (3 of 3) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.59	GERP -3.9
Overall
CADD	26.5	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,988 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,613,620 alleles · very rare exomes 4/1,461,462 · genomes 0/152,158 · 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.Arg231Ter
Coding: c.691C>T
MANE Select: NM_020638
dbSNP: rs764061118
Type: single nucleotide variant
Location: chr12:4370408 (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

Similar variants

FGF23 p.Arg231Gln Uncertain significance ★ ⚠ same residue
FGF23 p.Arg231= Likely benign ★ 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-arg231ter (accessed [today's date]).

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