Is FGFR1 p.Pro150Ser (c.448C>T) pathogenic?

FGFR1 p.Pro150Ser (c.448C>T) is classified Uncertain significance in FGFR1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-21). AlphaMissense: likely benign (0.1703); Very rare (popmax 0.00267%, afr); Associated with Pfeiffer syndrome.

What condition is associated with FGFR1 p.Pro150Ser (c.448C>T)?

FGFR1 p.Pro150Ser (c.448C>T) is associated with Pfeiffer syndrome, hypogonadotropic hypogonadism 2 with or without anosmia (ClinVar).

How common is FGFR1 p.Pro150Ser (c.448C>T) in the general population?

FGFR1 p.Pro150Ser (c.448C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about FGFR1 p.Pro150Ser (c.448C>T)?

AlphaMissense predicts likely benign (score 0.1703) — an in-silico prediction, not a clinical call.

FGFR1 p.Pro150Ser

c.448C>T · rs746094709 · VCV1311567

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1703 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Pfeiffer syndrome

Computational evidence

Protein change
AlphaMissense	0.1703	likely benign
REVEL	0.221	benign-leaning
SaProt	LLR -7.59	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.20	donor loss at this position · masked 0 · deltas
Pangolin	Δ0.39	loss · gain 0.33 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 12	GERP 1.3, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 29 kb · p 0.67 · regional, not allelic
Overall
CADD	25.1	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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

Grpmax group 0.00267% African / African-American · 2/75,044 alleles

Filtering AF 0.000442% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000411% 6/1,460,718 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,522
South Asian	0.0022%	45,527
European (non-Finnish)	0.00017%	589,498

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.Pro150Ser
Coding: c.448C>T
MANE Select: NM_023110
dbSNP: rs746094709
Type: single nucleotide variant
Location: chr8:38428346 (GRCh38)
Gene constraint: LOEUF 0.274 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.30 · 86 PDB
Residue 150: the 'disordered' region

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.Pro150= Likely benign ★ same residue
FGFR1 p.Pro150His 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

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-pro150ser (accessed [today's date]).

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