Is FGFR1 p.Ala550Pro (c.1648G>C) pathogenic?

FGFR1 p.Ala550Pro (c.1648G>C) is classified Uncertain significance in FGFR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-22). AlphaMissense: likely pathogenic (0.9925); Absent from gnomAD v4.1; Associated with Pfeiffer syndrome.

What condition is associated with FGFR1 p.Ala550Pro (c.1648G>C)?

FGFR1 p.Ala550Pro (c.1648G>C) is associated with Pfeiffer syndrome, hypogonadotropic hypogonadism 2 with or without anosmia (ClinVar).

How common is FGFR1 p.Ala550Pro (c.1648G>C) in the general population?

FGFR1 p.Ala550Pro (c.1648G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FGFR1 p.Ala550Pro (c.1648G>C)?

AlphaMissense predicts likely pathogenic (score 0.9925) — an in-silico prediction, not a clinical call.

FGFR1 p.Ala550Pro

c.1648G>C · VCV3758635

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9925 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Pfeiffer syndrome

Computational evidence

Protein change
AlphaMissense	0.9925	likely pathogenic
REVEL	0.926	moderately pathogenic-leaning
SaProt	LLR -13.43	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 1,923 bp · p 0.00017 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: FGFR1
Protein: p.Ala550Pro
Coding: c.1648G>C
MANE Select: NM_023110
Type: single nucleotide variant
Location: chr8:38417321 (GRCh38)
Gene constraint: LOEUF 0.274 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.30 · 86 PDB
Residue 550: a β-strand; the protein kinase domain; a UniProt-annotated variant site (in hh2)

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.Ala550Val 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
FGFR1 p.Arg209Cys Likely pathogenic ★★ same condition
FGFR1 p.Arg250Gln 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-ala550pro (accessed [today's date]).

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