Is FGFR1 p.Pro93Ser (c.277C>T) pathogenic?

FGFR1 p.Pro93Ser (c.277C>T) is classified Uncertain significance in FGFR1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-04-03). AlphaMissense: likely benign (0.1127); Very rare (popmax 0.00162%, nfe); Associated with hypogonadotropic hypogonadism 2 with or without anosmia.

What condition is associated with FGFR1 p.Pro93Ser (c.277C>T)?

FGFR1 p.Pro93Ser (c.277C>T) is associated with hypogonadotropic hypogonadism 2 with or without anosmia, Pfeiffer syndrome (ClinVar).

How common is FGFR1 p.Pro93Ser (c.277C>T) in the general population?

FGFR1 p.Pro93Ser (c.277C>T) is very rare (popmax 0.00162%, nfe) (gnomAD).

What do computational predictors say about FGFR1 p.Pro93Ser (c.277C>T)?

AlphaMissense predicts likely benign (score 0.1127) — an in-silico prediction, not a clinical call.

FGFR1 p.Pro93Ser

c.277C>T · rs372511659 · VCV1315343

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.1127 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00162%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hypogonadotropic hypogonadism 2 with or without anosmia

Computational evidence

Protein change
AlphaMissense	0.1127	likely benign
REVEL	0.251	benign-leaning
SaProt	LLR -7.58	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 29 kb · p 0.67 · regional, not allelic
Overall
CADD	24.6	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 0.00162% European (non-Finnish) · 19/1,175,440 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000833%

Overall 0.00125% 20/1,603,984 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00162%	61,865
Remaining individualsnot grpmax-eligible	0.00161%	62,036

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.Pro93Ser
Coding: c.277C>T
MANE Select: NM_023110
dbSNP: rs372511659
Type: single nucleotide variant
Location: chr8:38429763 (GRCh38)
Gene constraint: LOEUF 0.274 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.30 · 86 PDB
Residue 93: a turn; a disulfide bond; the ig-like c2-type 1 domain

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.Pro93= Likely benign ★ same residue
FGFR1 p.Pro93Leu 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-pro93ser (accessed [today's date]).

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