Is FGFR1 p.Ser91Pro (c.271T>C) pathogenic?

FGFR1 p.Ser91Pro (c.271T>C) is classified Uncertain significance in FGFR1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-02). AlphaMissense: ambiguous (0.4203); Very rare (popmax 0.00034%, nfe); Associated with Inborn genetic diseases.

What condition is associated with FGFR1 p.Ser91Pro (c.271T>C)?

FGFR1 p.Ser91Pro (c.271T>C) is associated with Inborn genetic diseases (ClinVar).

How common is FGFR1 p.Ser91Pro (c.271T>C) in the general population?

FGFR1 p.Ser91Pro (c.271T>C) is very rare (popmax 0.00034%, nfe) (gnomAD).

What do computational predictors say about FGFR1 p.Ser91Pro (c.271T>C)?

AlphaMissense predicts ambiguous (score 0.4203) — an in-silico prediction, not a clinical call.

FGFR1 p.Ser91Pro

c.271T>C · VCV4257234

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4203 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00034%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4203	ambiguous
REVEL	0.181	moderately benign-leaning
SaProt	LLR -8.89	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP -0.13, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 29 kb · p 0.67 · regional, not allelic
Overall
CADD	23.1	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 0.00034% European (non-Finnish) · 4/1,177,392 alleles

Filtering AF 8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000249% 4/1,608,080 alleles · very rare exomes 4/1,455,818 · genomes 0/152,262 · joint denominator

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.Ser91Pro
Coding: c.271T>C
MANE Select: NM_023110
Type: single nucleotide variant
Location: chr8:38429769 (GRCh38)
Gene constraint: LOEUF 0.274 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.30 · 86 PDB
Residue 91: the ig-like c2-type 1 domain

Full FGFR1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FGFR1 p.Ser91= Conflicting classifications of pathogenicity ★ same residue
FLG p.Arg1798Ter Pathogenic/Likely pathogenic ★★ same condition
FGFR1 p.Arg424Ser Uncertain significance ★★ ⚠ same condition
FGFR1 p.Leu465Phe Uncertain significance ★★ ⚠ same condition
FGFR1 p.Thr783Ile Uncertain significance ★★ same condition
FGFR1 p.Val795Ile Uncertain significance ★★ ⚠ same condition
FLG p.Gln686Pro Uncertain significance ★★ ⚠ same condition
FLG p.Gly2545Val Uncertain significance ★★ ⚠ 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-ser91pro (accessed [today's date]).

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