Is FGFR1 p.Pro169= (c.507G>A) pathogenic?

FGFR1 p.Pro169= (c.507G>A) is classified Likely benign in FGFR1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-26). Ultra-rare (popmax 0.0176%, sas); Associated with Pfeiffer syndrome.

What condition is associated with FGFR1 p.Pro169= (c.507G>A)?

FGFR1 p.Pro169= (c.507G>A) is associated with Pfeiffer syndrome, hypogonadotropic hypogonadism 2 with or without anosmia (ClinVar).

How common is FGFR1 p.Pro169= (c.507G>A) in the general population?

FGFR1 p.Pro169= (c.507G>A) is ultra-rare (popmax 0.0176%, sas) (gnomAD).

FGFR1 p.Pro169=

c.507G>A · rs374145904 · VCV1194500

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0176%, sas)

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 -4.7	GERP -4.3
Overall
CADD	7.663	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0176% South Asian · 16/91,088 alleles

Filtering AF 0.011% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00888%

Overall 0.00211% 34/1,614,230 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0176%	5,693
African / African-American	0.00666%	15,012
East Asian	0.00223%	44,884
European (non-Finnish)	0.00102%	98,337

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.Pro169=
Coding: c.507G>A
MANE Select: NM_023110
dbSNP: rs374145904
Type: single nucleotide variant
Location: chr8:38428035 (GRCh38)
Gene constraint: LOEUF 0.274 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.30 · 86 PDB
Residue 169: the 'heparin-binding' region; a β-strand; the ig-like c2-type 2 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: hypogonadotropic hypogonadism 2 with or without anosmia

Similar variants

FGFR1 p.Pro169Leu Uncertain significance ★★ ⚠ same residue
FGFR1 p.Pro169Ala Uncertain significance ★ ⚠ same residue
FGFR1 p.Pro169Arg Uncertain significance ★ same residue
FGFR1 p.Pro169Ser 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

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-pro169 (accessed [today's date]).

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