Is FGFR2 p.Pro708= (c.2124C>T) pathogenic?

FGFR2 p.Pro708= (c.2124C>T) is classified Conflicting classifications of pathogenicity in FGFR2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-12-01). Ultra-rare (popmax 0.01%, amr); Associated with FGFR2-related craniosynostosis.

What condition is associated with FGFR2 p.Pro708= (c.2124C>T)?

FGFR2 p.Pro708= (c.2124C>T) is associated with FGFR2-related craniosynostosis (ClinVar).

How common is FGFR2 p.Pro708= (c.2124C>T) in the general population?

FGFR2 p.Pro708= (c.2124C>T) is ultra-rare (popmax 0.01%, amr) (gnomAD).

FGFR2 p.Pro708=

c.2124C>T · rs140813163 · VCV501920

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, amr)

Conditions

FGFR2-related craniosynostosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -3.2	GERP -5.2
Overall
CADD	8.139	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% Admixed American · 6/60,000 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00295%

Overall 0.00372% 60/1,614,044 alleles · ultra-rare exomes 49/1,461,884 · genomes 11/152,160 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.01%	10,000
East Asian	0.00669%	14,954
South Asian	0.00549%	18,214
African / African-American	0.00533%	18,751
Remaining individualsnot grpmax-eligible	0.0048%	20,836
European (non-Finnish)	0.00331%	30,257

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: FGFR2
Protein: p.Pro708=
Coding: c.2124C>T
MANE Select: NM_000141
dbSNP: rs140813163
Type: single nucleotide variant
Location: chr10:121485466 (GRCh38)
Gene constraint: LOEUF 0.278 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.33 · 65 PDB
Residue 708: the protein kinase domain

Full FGFR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

FGFR2-related craniosynostosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FGFR2 p.Pro708Leu Uncertain significance ★ ⚠ same residue
FGFR2 p.Pro708Thr Uncertain significance ★ ⚠ same residue
FGFR2 c.1084+1G>A Pathogenic ★★ same condition
FGFR2 c.1084+2T>C Pathogenic ★★ same condition
FGFR2 c.1084+3A>G Pathogenic ★★ same condition
FGFR2 c.940-1G>T Pathogenic ★★ same condition
FGFR2 p.Ala648Thr Pathogenic ★★ same condition
FGFR2 p.Asp321Ala 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/fgfr2-p-pro708 (accessed [today's date]).

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