Is FGFR1 p.Pro366= (c.1098G>A) pathogenic?

FGFR1 p.Pro366= (c.1098G>A) is classified Conflicting classifications of pathogenicity in FGFR1 (ClinVar, Conflicting submitters, 7 submitters; last evaluated 2026-01-06). Rare (popmax 0.347%, mid); Associated with hypogonadotropic hypogonadism 2 with or without anosmia.

What condition is associated with FGFR1 p.Pro366= (c.1098G>A)?

FGFR1 p.Pro366= (c.1098G>A) is associated with hypogonadotropic hypogonadism 2 with or without anosmia, Pfeiffer syndrome (ClinVar).

How common is FGFR1 p.Pro366= (c.1098G>A) in the general population?

FGFR1 p.Pro366= (c.1098G>A) is rare (popmax 0.347%, mid) (gnomAD).

FGFR1 p.Pro366=

c.1098G>A · rs56174879 · VCV498519

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

rare (popmax 0.347%, mid)

Conditions

hypogonadotropic hypogonadism 2 with or without anosmia

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 -15	GERP -4.6
Overall
CADD	0.195	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.347% Middle Eastern · 21/6,056 alleles

Filtering AF 0.232% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.217%

Overall 0.0209% 337/1,614,100 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.347%	288
African / African-American	0.259%	387
East Asian	0.109%	916
Remaining individualsnot grpmax-eligible	0.0304%	3,290
Admixed American	0.0217%	4,617
Finnishnot grpmax-eligible	0.00625%	16,007
European (non-Finnish)	0.00314%	31,892

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.Pro366=
Coding: c.1098G>A
MANE Select: NM_023110
dbSNP: rs56174879
Type: single nucleotide variant
Location: chr8:38419719 (GRCh38)
Gene constraint: LOEUF 0.274 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.30 · 86 PDB
Residue 366: a UniProt-annotated variant site (in hh2; with or without anosmia); a UniProt-annotated variant site (in hh2)

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

Disease context

hypogonadotropic hypogonadism 2 with or without anosmia — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Pfeiffer syndrome

Similar variants

FGFR1 p.Pro366Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
FGFR1 p.Pro366Ser Likely benign ★ ⚠ 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
FGFR1 p.Arg209Cys 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-pro366 (accessed [today's date]).

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