Is FGFR1 p.Ser393= (c.1179G>A) pathogenic?

FGFR1 p.Ser393= (c.1179G>A) is classified Conflicting classifications of pathogenicity in FGFR1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-07-21). Very rare (popmax 0.00203%, nfe); Associated with hypogonadotropic hypogonadism 2 with or without anosmia.

How common is FGFR1 p.Ser393= (c.1179G>A) in the general population?

FGFR1 p.Ser393= (c.1179G>A) is very rare (popmax 0.00203%, nfe) (gnomAD).

FGFR1 p.Ser393=

Q: What condition is associated with FGFR1 p.Ser393= (c.1179G>A)?

FGFR1 p.Ser393= (c.1179G>A) is associated with hypogonadotropic hypogonadism 2 with or without anosmia, Pfeiffer syndrome, Jackson-Weiss syndrome (ClinVar).

c.1179G>A · rs374674165 · VCV1431252

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00203%, nfe)

Conditions

hypogonadotropic hypogonadism 2 with or without anosmia

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2	GERP -4.9
Overall
CADD	2.946	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00203% European (non-Finnish) · 24/1,179,994 alleles

Filtering AF 0.00138% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00116%

Overall 0.00161% 26/1,613,938 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00203%	49,166
Finnishnot grpmax-eligible	0.00156%	64,020
African / African-American	0.00134%	74,886

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.Ser393=
Coding: c.1179G>A
MANE Select: NM_023110
dbSNP: rs374674165
Type: single nucleotide variant
Location: chr8:38419638 (GRCh38)
Gene constraint: LOEUF 0.274 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.30 · 86 PDB
Residue 393: a UniProt-annotated variant site (in hh2)

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 Jackson-Weiss syndrome osteoglophonic dysplasia trigonocephaly 1 encephalocraniocutaneous lipomatosis Hartsfield-Bixler-Demyer syndrome

Similar variants

FGFR1 p.Ser393Leu Likely benign ★★ 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-ser393 (accessed [today's date]).

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