Is FGFR3 p.Ala559Pro (c.1675G>C) pathogenic?

FGFR3 p.Ala559Pro (c.1675G>C) is classified Uncertain significance in FGFR3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-11-06). AlphaMissense: ambiguous (0.4008); Very rare (popmax 0.00424%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FGFR3 p.Ala559Pro (c.1675G>C)?

FGFR3 p.Ala559Pro (c.1675G>C) is associated with Inborn genetic diseases (ClinVar).

How common is FGFR3 p.Ala559Pro (c.1675G>C) in the general population?

FGFR3 p.Ala559Pro (c.1675G>C) is very rare (popmax 0.00424%, nfe) (gnomAD).

What do computational predictors say about FGFR3 p.Ala559Pro (c.1675G>C)?

AlphaMissense predicts ambiguous (score 0.4008) — an in-silico prediction, not a clinical call.

FGFR3 p.Ala559Pro

c.1675G>C · rs768385286 · VCV432751

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.4008 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00424%, nfe)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4008	ambiguous
REVEL	0.53	indeterminate
SaProt	LLR -7.22	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.2	GERP -1, phastCons 0.99
Regional constraint	o/e 0.98	unconstrained · MANE · 627 bp · p 0.79 · regional, not allelic
Overall
CADD	24.6	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 0.00424% European (non-Finnish) · 50/1,179,860 alleles

Filtering AF 0.00326% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00294%

Overall 0.00391% 63/1,612,502 alleles · very rare exomes 60/1,460,290 · genomes 3/152,212 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0176%	5,676
European (non-Finnish)grpmax	0.00424%	23,597
Finnishnot grpmax-eligible	0.00159%	62,834
African / African-American	0.00133%	74,920

Remaining individuals 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.Ala559Pro
Coding: c.1675G>C
MANE Select: NM_000142
dbSNP: rs768385286
Type: single nucleotide variant
Location: chr4:1805779 (GRCh38)
Gene constraint: LOEUF 0.458 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 75.25 · 16 PDB
Residue 559: the protein kinase domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FGFR3 p.Ala559Thr Uncertain significance ★★ ⚠ same residue
FGFR3 p.Ala559Val Uncertain significance ★★ ⚠ same residue
FGFR3 p.Ala128Thr Uncertain significance ★★ ⚠ same condition
FGFR3 p.Ala141Thr Uncertain significance ★★ ⚠ same condition
FGFR3 p.Arg439Cys Uncertain significance ★★ ⚠ same condition
FGFR3 p.Arg439His Uncertain significance ★★ ⚠ same condition
FGFR3 p.Arg471Trp Uncertain significance ★★ ⚠ same condition
FGFR3 p.Arg728Gln 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/fgfr3-p-ala559pro (accessed [today's date]).

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