Is FGFR1 p.Arg675Pro (c.2024G>C) pathogenic?

FGFR1 p.Arg675Pro (c.2024G>C) is classified Conflicting classifications of pathogenicity in FGFR1 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-02-16). AlphaMissense: likely pathogenic (0.9988); Very rare (popmax 9.22e-05%, nfe); Associated with trigonocephaly 1.

What condition is associated with FGFR1 p.Arg675Pro (c.2024G>C)?

FGFR1 p.Arg675Pro (c.2024G>C) is associated with trigonocephaly 1, Pfeiffer syndrome, hypogonadotropic hypogonadism 2 with or without anosmia (ClinVar).

How common is FGFR1 p.Arg675Pro (c.2024G>C) in the general population?

FGFR1 p.Arg675Pro (c.2024G>C) is very rare (popmax 9.22e-05%, nfe) (gnomAD).

What do computational predictors say about FGFR1 p.Arg675Pro (c.2024G>C)?

AlphaMissense predicts likely pathogenic (score 0.9988) — an in-silico prediction, not a clinical call.

FGFR1 p.Arg675Pro

c.2024G>C · rs771078736 · VCV909924

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9988 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 9.22e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

trigonocephaly 1

Computational evidence

Protein change
AlphaMissense	0.9988	likely pathogenic · top 6% in FGFR1
REVEL	0.799	moderately pathogenic-leaning
SaProt	LLR -15.44	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 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.44	unconstrained · MANE · 1,341 bp · p 2.2e-08 · regional, not allelic
Overall
CADD	34.0	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 9.22e-05% European (non-Finnish) · 1/1,084,432 alleles

Overall 0.000493% 7/1,419,112 alleles · very rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0158%	6,321
Remaining individualsnot grpmax-eligible	0.00355%	28,138
European (non-Finnish)grpmax	9.22e-05%	1,084,432

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Arg675Pro
Coding: c.2024G>C
MANE Select: NM_023110
dbSNP: rs771078736
Type: single nucleotide variant
Location: chr8:38414583 (GRCh38)
Gene constraint: LOEUF 0.274 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 74.30 · 86 PDB
Residue 675: a UniProt-annotated variant site (in hh2); the protein kinase domain

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

Disease context

trigonocephaly 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

Similar variants

FGFR1 p.Arg675Trp Uncertain significance ★★ ⚠ same residue
FGFR1 p.Arg675Gln Uncertain significance ★ ⚠ same residue
FGFR1 p.Arg675Gly Uncertain significance ★ ⚠ 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

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-arg675pro (accessed [today's date]).

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