Is FGFR3 p.Pro63Arg (c.188C>G) pathogenic?

FGFR3 p.Pro63Arg (c.188C>G) is classified Conflicting classifications of pathogenicity in FGFR3 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2024-11-22). AlphaMissense: likely benign (0.0756); Very rare (popmax 0.00576%, nfe).

How common is FGFR3 p.Pro63Arg (c.188C>G) in the general population?

FGFR3 p.Pro63Arg (c.188C>G) is very rare (popmax 0.00576%, nfe) (gnomAD).

What do computational predictors say about FGFR3 p.Pro63Arg (c.188C>G)?

AlphaMissense predicts likely benign (score 0.0756) — an in-silico prediction, not a clinical call.

FGFR3 p.Pro63Arg

c.188C>G · rs371729802 · VCV465348

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0756 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00576%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0756	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -6.31	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -2.8	GERP -1.6
Regional constraint	o/e 1.02	unconstrained · MANE · 7,434 bp · p 0.79 · regional, not allelic
Overall
CADD	0.652	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 0.00576% European (non-Finnish) · 68/1,179,906 alleles

Filtering AF 0.00462% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00423%

Overall 0.0044% 71/1,612,470 alleles · very rare exomes 69/1,460,240 · genomes 2/152,230 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00576%	17,352
Admixed American	0.00333%	29,996
African / African-American	0.00133%	74,938

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: FGFR3
Protein: p.Pro63Arg
Coding: c.188C>G
MANE Select: NM_000142
dbSNP: rs371729802
Type: single nucleotide variant
Location: chr4:1799332 (GRCh38)
Gene constraint: LOEUF 0.458 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 75.25 · 16 PDB
Residue 63: the ig-like c2-type 1 domain

Full FGFR3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FGFR3 p.Pro63= Likely benign ★★ same residue
FGFR3 p.Pro63Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
FGFR3 p.Ala391Glu Pathogenic ★★ same type
FGFR3 p.Arg248Cys Pathogenic ★★ same type
FGFR3 p.Arg621His Pathogenic/Likely pathogenic ★★ same type
FGFR3 p.Asn540Asp Pathogenic/Likely pathogenic ★★ same type
FGFR3 p.Asn540Lys Pathogenic ★★ same type
FGFR3 p.Asn540Ser Pathogenic/Likely pathogenic ★★ ⚠ 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/fgfr3-p-pro63arg (accessed [today's date]).

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