Is FGFR2 p.Val667= (c.2001C>G) pathogenic?

FGFR2 p.Val667= (c.2001C>G) is classified Benign/Likely benign in FGFR2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-24). Rare (popmax 0.612%, afr); Associated with FGFR2-related craniosynostosis.

What condition is associated with FGFR2 p.Val667= (c.2001C>G)?

FGFR2 p.Val667= (c.2001C>G) is associated with FGFR2-related craniosynostosis, Saethre-Chotzen syndrome, Crouzon syndrome (ClinVar).

How common is FGFR2 p.Val667= (c.2001C>G) in the general population?

FGFR2 p.Val667= (c.2001C>G) is rare (popmax 0.612%, afr) (gnomAD).

FGFR2 p.Val667=

c.2001C>G · rs61731218 · VCV298997

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

rare (popmax 0.612%, afr)

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 2.8	GERP -4, phastCons 1
Overall
CADD	7.128	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.612% African / African-American · 459/75,058 alleles

Filtering AF 0.565% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.547%

Overall 0.0308% 497/1,614,060 alleles · rare exomes 237/1,461,704 · genomes 260/152,356 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.612%	164
Middle Eastern	0.033%	3,030
Remaining individualsnot grpmax-eligible	0.0304%	3,289
Admixed American	0.0183%	5,456
South Asian	0.00439%	22,761
European (non-Finnish)	0.000169%	589,974

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.Val667=
Coding: c.2001C>G
MANE Select: NM_000141
dbSNP: rs61731218
Type: single nucleotide variant
Location: chr10:121487410 (GRCh38)
Gene constraint: LOEUF 0.278 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 74.33 · 65 PDB
Residue 667: 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: Saethre-Chotzen syndrome Crouzon syndrome Beare-Stevenson cutis gyrata syndrome craniosynostosis

Similar variants

FGFR2 p.Val667Ala 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.Ala314Ser Pathogenic/Likely pathogenic ★★ ⚠ same condition
FGFR2 p.Ala337Pro Pathogenic/Likely pathogenic ★★ same condition
FGFR2 p.Ala344= 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-val667 (accessed [today's date]).

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