Is FGFR1 p.Ser565Phe (c.1694C>T) pathogenic?

FGFR1 p.Ser565Phe (c.1694C>T) is classified Uncertain significance in FGFR1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-12-03). AlphaMissense: ambiguous (0.5163); Very rare (popmax 0.00167%, amr); Associated with encephalocraniocutaneous lipomatosis.

What condition is associated with FGFR1 p.Ser565Phe (c.1694C>T)?

FGFR1 p.Ser565Phe (c.1694C>T) is associated with encephalocraniocutaneous lipomatosis, Pfeiffer syndrome, hypogonadotropic hypogonadism 2 with or without anosmia (ClinVar).

How common is FGFR1 p.Ser565Phe (c.1694C>T) in the general population?

FGFR1 p.Ser565Phe (c.1694C>T) is very rare (popmax 0.00167%, amr) (gnomAD).

How is Encephalocraniocutaneous lipomatosis inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about FGFR1 p.Ser565Phe (c.1694C>T)?

AlphaMissense predicts ambiguous (score 0.5163) — an in-silico prediction, not a clinical call.

FGFR1 p.Ser565Phe

c.1694C>T · rs768223019 · VCV811993

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.5163 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

encephalocraniocutaneous lipomatosis

Computational evidence

Protein change
AlphaMissense	0.5163	ambiguous
REVEL	0.802	moderately pathogenic-leaning
SaProt	LLR -10.95	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.4, phastCons 1
Regional constraint	o/e 0.62	unconstrained · MANE · 1,923 bp · p 0.00017 · regional, not allelic
Overall
CADD	31.0	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 0.00167% Admixed American · 1/59,992 alleles

Overall 6.84e-05% 1/1,461,288 alleles · very rare

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.Ser565Phe
Coding: c.1694C>T
MANE Select: NM_023110
dbSNP: rs768223019
Type: single nucleotide variant
Location: chr8:38416030 (GRCh38)
Gene constraint: LOEUF 0.274 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.30 · 86 PDB
Residue 565: the protein kinase domain; a UniProt-annotated variant site (in hh2)

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

Disease context

encephalocraniocutaneous lipomatosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Pfeiffer syndrome hypogonadotropic hypogonadism 2 with or without anosmia

For Encephalocraniocutaneous lipomatosis (Orphanet):

Inheritance: Not applicable
Onset: Antenatal, Neonatal

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-ser565phe (accessed [today's date]).

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