Is FGFR1 p.Phe686= (c.2058C>T) pathogenic?

FGFR1 p.Phe686= (c.2058C>T) is classified Likely benign in FGFR1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-27). Ultra-rare (popmax 0.0164%, mid); Associated with Pfeiffer syndrome.

What condition is associated with FGFR1 p.Phe686= (c.2058C>T)?

FGFR1 p.Phe686= (c.2058C>T) is associated with Pfeiffer syndrome, Jackson-Weiss syndrome, hypogonadotropic hypogonadism 2 with or without anosmia (ClinVar).

How common is FGFR1 p.Phe686= (c.2058C>T) in the general population?

FGFR1 p.Phe686= (c.2058C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

FGFR1 p.Phe686=

c.2058C>T · rs1193961883 · VCV1616507

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Conditions

Pfeiffer syndrome

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 -0.53	GERP -4.9
Overall
CADD	8.133	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00145% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00123%

Overall 0.00161% 26/1,613,856 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
European (non-Finnish)	0.00212%	47,199

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: FGFR1
Protein: p.Phe686=
Coding: c.2058C>T
MANE Select: NM_023110
dbSNP: rs1193961883
Type: single nucleotide variant
Location: chr8:38414280 (GRCh38)
Gene constraint: LOEUF 0.274 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.30 · 86 PDB
Residue 686: a UniProt-annotated variant site (in hh2); an α-helix; the protein kinase domain

Full FGFR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Pfeiffer syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Jackson-Weiss syndrome hypogonadotropic hypogonadism 2 with or without anosmia osteoglophonic dysplasia trigonocephaly 1 encephalocraniocutaneous lipomatosis Hartsfield-Bixler-Demyer syndrome

Similar variants

FGFR1 p.Phe686Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
FGFR1 p.Phe686fs Pathogenic ★ same residue
FLG p.Gln686Pro Uncertain significance ★★ ⚠ same residue
FGFR1 c.1977+1G>A Pathogenic/Likely pathogenic ★★ same condition
FGFR1 c.1977+1G>T Pathogenic/Likely pathogenic ★★ same condition
FGFR1 c.448+1G>A Likely pathogenic ★★ same condition
FGFR1 c.449-6G>A Likely pathogenic ★★ same condition
FGFR1 c.91+1G>A 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/fgfr1-p-phe686 (accessed [today's date]).

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