Is FGFR1 p.Leu165Ser (c.494T>C) pathogenic?

FGFR1 p.Leu165Ser (c.494T>C) is classified Pathogenic in FGFR1 (ClinVar, No assertion criteria, 2 submitters; last evaluated 2013-09-01). AlphaMissense: likely pathogenic (0.9979); Absent from gnomAD v4.1; Associated with Hartsfield-Bixler-Demyer syndrome.

What condition is associated with FGFR1 p.Leu165Ser (c.494T>C)?

FGFR1 p.Leu165Ser (c.494T>C) is associated with Hartsfield-Bixler-Demyer syndrome (ClinVar).

How common is FGFR1 p.Leu165Ser (c.494T>C) in the general population?

FGFR1 p.Leu165Ser (c.494T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about FGFR1 p.Leu165Ser (c.494T>C)?

AlphaMissense predicts likely pathogenic (score 0.9979) — an in-silico prediction, not a clinical call.

FGFR1 p.Leu165Ser

c.494T>C · rs397515481 · VCV66079

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9979 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Hartsfield-Bixler-Demyer syndrome

Computational evidence

Protein change
AlphaMissense	0.9979	likely pathogenic ✓ concordant with ClinVar · top 8% in FGFR1
REVEL	0.834	moderately pathogenic-leaning
SaProt	LLR -16.07	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 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.44	unconstrained · MANE · 6,243 bp · p 6.1e-19 · regional, not allelic
Overall
CADD	27.8	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

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.Leu165Ser
Coding: c.494T>C
MANE Select: NM_023110
dbSNP: rs397515481
Type: single nucleotide variant
Location: chr8:38428048 (GRCh38)
Gene constraint: LOEUF 0.274 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.30 · 86 PDB
Residue 165: the 'heparin-binding' region; a β-strand; the ig-like c2-type 2 domain; a UniProt-annotated variant site (in hrtfds)

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

Disease context

Hartsfield-Bixler-Demyer syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FGFR1 c.1977+1G>A Pathogenic/Likely pathogenic ★★ same condition
FGFR1 c.448+1G>A Likely pathogenic ★★ same condition
FGFR1 p.Gln72Ter Pathogenic/Likely pathogenic ★★ same condition
FGFR1 p.Gly237Asp Pathogenic/Likely pathogenic ★★ same condition
FGFR1 p.Gly270Asp Likely pathogenic ★★ same condition
FGFR1 p.Pro252Arg Pathogenic ★★ same condition
FGFR1 c.91+6G>T Uncertain significance ★★ same condition
FGFR1 c.*112C>T 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-leu165ser (accessed [today's date]).

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