Is FGFR1 p.Ser777= (c.2331C>G) pathogenic?

FGFR1 p.Ser777= (c.2331C>G) is classified Likely benign in FGFR1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-11-21). Ultra-rare (popmax 0.0467%, amr); Associated with hypogonadotropic hypogonadism 2 with or without anosmia.

How common is FGFR1 p.Ser777= (c.2331C>G) in the general population?

FGFR1 p.Ser777= (c.2331C>G) is ultra-rare (popmax 0.0467%, amr) (gnomAD).

FGFR1 p.Ser777=

Q: What condition is associated with FGFR1 p.Ser777= (c.2331C>G)?

FGFR1 p.Ser777= (c.2331C>G) is associated with hypogonadotropic hypogonadism 2 with or without anosmia, Pfeiffer syndrome, Jackson-Weiss syndrome (ClinVar).

c.2331C>G · rs763571736 · VCV390879

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0467%, amr)

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 -5.8	GERP -4.7
Overall
CADD	0.634	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0467% Admixed American · 28/60,010 alleles

Filtering AF 0.0331% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0286%

Overall 0.00205% 30/1,461,866 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0467%	2,143
South Asian	0.0022%	45,541

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.Ser777=
Coding: c.2331C>G
MANE Select: NM_023110
dbSNP: rs763571736
Type: single nucleotide variant
Location: chr8:38413766 (GRCh38)
Gene constraint: LOEUF 0.274 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.30 · 86 PDB
Residue 777: 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 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
FGFR1 p.Arg250Trp Pathogenic/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-ser777 (accessed [today's date]).

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