Is FGFR2 p.Pro582= (c.1746C>T) pathogenic?

FGFR2 p.Pro582= (c.1746C>T) is classified Likely benign in FGFR2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-08-14). Ultra-rare (popmax 0.0539%, sas); Associated with FGFR2-related craniosynostosis.

What condition is associated with FGFR2 p.Pro582= (c.1746C>T)?

FGFR2 p.Pro582= (c.1746C>T) is associated with FGFR2-related craniosynostosis, gastric cancer, Apert syndrome (ClinVar).

How common is FGFR2 p.Pro582= (c.1746C>T) in the general population?

FGFR2 p.Pro582= (c.1746C>T) is ultra-rare (popmax 0.0539%, sas) (gnomAD).

FGFR2 p.Pro582=

c.1746C>T · rs369850306 · VCV1091719

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0539%, sas)

Conditions

FGFR2-related craniosynostosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -9.9	GERP -5.2
Overall
CADD	0.689	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0539% South Asian · 49/90,978 alleles

Filtering AF 0.0418% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0375%

Overall 0.00571% 92/1,612,434 alleles · ultra-rare exomes 81/1,461,000 · genomes 11/151,434 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0539%	1,857
African / African-American	0.0201%	4,984
East Asian	0.0134%	7,459
Remaining individualsnot grpmax-eligible	0.00641%	15,602
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,600
European (non-Finnish)	0.00144%	69,406

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.Pro582=
Coding: c.1746C>T
MANE Select: NM_000141
dbSNP: rs369850306
Type: single nucleotide variant
Location: chr10:121496649 (GRCh38)
Gene constraint: LOEUF 0.278 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.33 · 65 PDB
Residue 582: an α-helix; the protein kinase domain

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

Disease context

Also linked: gastric cancer Apert syndrome Saethre-Chotzen syndrome Pfeiffer syndrome Jackson-Weiss syndrome Crouzon syndrome Beare-Stevenson cutis gyrata syndrome LADD syndrome familial scaphocephaly syndrome, McGillivray type bent bone dysplasia syndrome 1 Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis

Similar variants

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>A Pathogenic/Likely pathogenic ★★ same condition
FGFR2 c.940-1G>T Pathogenic ★★ same condition
FGFR2 c.940-2A>C Pathogenic ★★ same condition
FGFR2 p.Ala314Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
FGFR2 p.Ala337Pro Pathogenic/Likely 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-pro582 (accessed [today's date]).

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