Is FGFR3 p.Arg421Gln (c.1262G>A) pathogenic?

FGFR3 p.Arg421Gln (c.1262G>A) is classified Uncertain significance in FGFR3 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-06-23). AlphaMissense: ambiguous (0.3722); Very rare (popmax 0.00339%, nfe); Associated with FGFR3-related chondrodysplasia.

What condition is associated with FGFR3 p.Arg421Gln (c.1262G>A)?

FGFR3 p.Arg421Gln (c.1262G>A) is associated with FGFR3-related chondrodysplasia (ClinVar).

How common is FGFR3 p.Arg421Gln (c.1262G>A) in the general population?

FGFR3 p.Arg421Gln (c.1262G>A) is very rare (popmax 0.00339%, nfe) (gnomAD).

What do computational predictors say about FGFR3 p.Arg421Gln (c.1262G>A)?

AlphaMissense predicts ambiguous (score 0.3722) — an in-silico prediction, not a clinical call.

FGFR3 p.Arg421Gln

c.1262G>A · rs587778355 · VCV134403

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3722 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00339%, nfe)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

FGFR3-related chondrodysplasia

Computational evidence

Protein change
AlphaMissense	0.3722	ambiguous
REVEL	0.855	moderately pathogenic-leaning
SaProt	LLR -10.55	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 1.18	unconstrained · MANE · 2,931 bp · p 0.0092 · regional, not allelic
Overall
CADD	33.0	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

Grpmax group 0.00339% European (non-Finnish) · 40/1,179,908 alleles

Filtering AF 0.00255% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00225%

Overall 0.00316% 51/1,612,196 alleles · very rare exomes 50/1,460,090 · genomes 1/152,106 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.0128%	7,796
European (non-Finnish)grpmax	0.00339%	29,498
South Asian	0.00329%	30,359

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg421Gln
Coding: c.1262G>A
MANE Select: NM_000142
dbSNP: rs587778355
Type: single nucleotide variant
Location: chr4:1804516 (GRCh38)
Gene constraint: LOEUF 0.458 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 75.25 · 16 PDB

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

Disease context

FGFR3-related chondrodysplasia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FGFR3 p.Arg421= Conflicting classifications of pathogenicity ★ same residue
FGFR3 p.Arg248Cys Pathogenic ★★ same condition
FGFR3 p.Arg621His Pathogenic/Likely pathogenic ★★ same condition
FGFR3 p.Asn540Asp Pathogenic/Likely pathogenic ★★ same condition
FGFR3 p.Asn540Lys Pathogenic ★★ same condition
FGFR3 p.Asn540Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
FGFR3 p.Asn540Thr Pathogenic/Likely pathogenic ★★ same condition
FGFR3 p.Gly370Cys Pathogenic ★★ ⚠ 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/fgfr3-p-arg421gln (accessed [today's date]).

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