Is FGFR1 p.Ser451Cys (c.1352C>G) pathogenic?

FGFR1 p.Ser451Cys (c.1352C>G) is classified Uncertain significance in FGFR1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-17). AlphaMissense: likely benign (0.2673); Very rare (popmax 0.000508%, nfe); Associated with Pfeiffer syndrome.

What condition is associated with FGFR1 p.Ser451Cys (c.1352C>G)?

FGFR1 p.Ser451Cys (c.1352C>G) is associated with Pfeiffer syndrome, hypogonadotropic hypogonadism 2 with or without anosmia (ClinVar).

How common is FGFR1 p.Ser451Cys (c.1352C>G) in the general population?

FGFR1 p.Ser451Cys (c.1352C>G) is very rare (popmax 0.000508%, nfe) (gnomAD).

What do computational predictors say about FGFR1 p.Ser451Cys (c.1352C>G)?

AlphaMissense predicts likely benign (score 0.2673) — an in-silico prediction, not a clinical call.

FGFR1 p.Ser451Cys

c.1352C>G · rs374672119 · VCV1906072

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2673 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000508%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Pfeiffer syndrome

Computational evidence

Protein change
AlphaMissense	0.2673	likely benign
REVEL	0.793	moderately pathogenic-leaning
SaProt	LLR -11.93	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.5, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 3,851 bp · p 0.04 · regional, not allelic
Overall
CADD	32.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000508% European (non-Finnish) · 6/1,180,040 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00012%

Overall 0.000372% 6/1,614,082 alleles · very rare

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.Ser451Cys
Coding: c.1352C>G
MANE Select: NM_023110
dbSNP: rs374672119
Type: single nucleotide variant
Location: chr8:38418306 (GRCh38)
Gene constraint: LOEUF 0.274 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.30 · 86 PDB
Residue 451: 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.Ser451Tyr 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-ser451cys (accessed [today's date]).

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