# NM_000141.5(FGFR2):c.1800C>T (p.Phe600=)

https://sugi.bio/variant/fgfr2-p-phe600

## Summary

**FGFR2 p.Phe600= (c.1800C>T)** is classified **Uncertain significance** in FGFR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-07). Very rare (popmax 0.00136%, nfe); Associated with bent bone dysplasia syndrome 1.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 11 linked conditions · very rare (popmax 0.00136%, nfe)

## For patients & families {#patients}

This is a change in the FGFR2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to bent bone dysplasia syndrome 1.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Antenatal, Neonatal |
| Diagnostic panels | FGFR2 is a diagnostic-grade gene on 16 Genomics England panels |

**Commonly reported features of FGFR2-related bent bone dysplasia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Gingival overgrowth — Very frequent (99-80%)
- Hypertelorism — Very frequent (99-80%)
- Micrognathia — Very frequent (99-80%)
- Abnormality of the outer ear — Very frequent (99-80%)
- Low-set ears — Very frequent (99-80%)
- Megalocornea — Very frequent (99-80%)
- Natal tooth — Very frequent (99-80%)
- Short clavicles — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010965/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [FGFR2](https://sugi.bio/atlas/gene/FGFR2/) |
| Protein change (HGVS p.) | p.Phe600= |
| Coding change (HGVS c.) | c.1800C>T |
| MANE Select transcript | [NM_000141](https://www.ncbi.nlm.nih.gov/nuccore/NM_000141) |
| Variant type | single nucleotide variant |
| Location | chr10:121496595-121496595 (GRCh38) |
| ClinVar | [VCV3590823](https://www.ncbi.nlm.nih.gov/clinvar/variation/3590823/) |

**All HGVS expressions:** `LRG_994:g.106864C>T`, `LRG_994t1:c.1800C>T`, `LRG_994t2:c.1803C>T`, `NC_000010.10:g.123256109G>A`, `NC_000010.11:g.121496595G>A`, `NG_012449.2:g.106864C>T`, `NM_000141.5:c.1800C>T`, `NM_001144913.1:c.1803C>T`, `NM_001144914.1:c.1464C>T`, `NM_001144915.2:c.1533C>T`, `NM_001144916.2:c.1455C>T`, `NM_001144917.2:c.1452C>T`, `NM_001144918.2:c.1449C>T`, `NM_001144919.2:c.1536C>T`, `NM_001320654.2:c.1116C>T`, `NM_001320658.2:c.1794C>T`, `NM_022970.4:c.1803C>T`, `NM_023029.3:c.1533C>T`, `NR_073009.2:n.2236C>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 3.441, GERP -1.31, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 9.268**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00136%** (nfe) · FAF95 0.000803% · FAF99 0.00065% · 16/1,180,014 in the highest group · 17/1,613,646 alleles overall — very rare (popmax 0.00136%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00136% | 73,751 |
| African / African-American | 0.00134% | 74,814 |

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**FGFR2** population constraint: LOEUF 0.278, pLI 1, missense-Z 4.4473. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **Apert syndrome** — Definitive (AD)
- **bent bone dysplasia syndrome 1** — Definitive (AD)
- **Beare-Stevenson cutis gyrata syndrome** — Definitive (AD)
- **Crouzon syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **600** lies in an α-helix; the protein kinase domain.

AlphaFold model confidence (whole protein): pLDDT 74.33, 37% of residues very-high.

**65 experimental structure(s)** (PDB): [10OO](https://www.rcsb.org/structure/10OO), [10OQ](https://www.rcsb.org/structure/10OQ), [10OU](https://www.rcsb.org/structure/10OU), [1DJS](https://www.rcsb.org/structure/1DJS), [1E0O](https://www.rcsb.org/structure/1E0O), [1EV2](https://www.rcsb.org/structure/1EV2) — incl. mutant structure 10OO.

## What this gene does {#gene-function}

*Describes the biological roles of FGFR2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** FGFR2's established molecular role includes fibroblast growth factor receptor activity. p.Phe600= falls in the protein kinase domain. In Reactome, FGFR2 is annotated in disease pathway(s) including **Activated point mutants of FGFR2**, **Signaling by FGFR2 amplification mutants**.

**Disease mechanism (Reactome):** FGFR2 loss or alteration is curated in [Activated point mutants of FGFR2](https://reactome.org/content/detail/R-HSA-2033519), [Signaling by FGFR2 amplification mutants](https://reactome.org/content/detail/R-HSA-2023837), [Signaling by FGFR2 fusions](https://reactome.org/content/detail/R-HSA-8853333).

### Pathways affected {#pathways}

FGFR2 participates in **17 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Activated point mutants of FGFR2](https://reactome.org/content/detail/R-HSA-2033519) | curated |
| ⚕ [Signaling by FGFR2 amplification mutants](https://reactome.org/content/detail/R-HSA-2023837) | curated |
| ⚕ [Signaling by FGFR2 fusions](https://reactome.org/content/detail/R-HSA-8853333) | curated |
| ⚕ [Signaling by FGFR2 in disease](https://reactome.org/content/detail/R-HSA-5655253) | curated |
| ⚕ [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530) | other |
| ⚕ [Signaling by FGFR2 IIIa TM](https://reactome.org/content/detail/R-HSA-8851708) | electronic |
| [FGFR2b ligand binding and activation](https://reactome.org/content/detail/R-HSA-190377) | other |
| [FGFR2c ligand binding and activation](https://reactome.org/content/detail/R-HSA-190375) | other |
| [FRS-mediated FGFR2 signaling](https://reactome.org/content/detail/R-HSA-5654700) | other |
| [Negative regulation of FGFR2 signaling](https://reactome.org/content/detail/R-HSA-5654727) | other |
| [PI-3K cascade:FGFR2](https://reactome.org/content/detail/R-HSA-5654695) | other |
| [PI3K Cascade](https://reactome.org/content/detail/R-HSA-109704) | other |
| [PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling](https://reactome.org/content/detail/R-HSA-6811558) | other |
| [PIP3 activates AKT signaling](https://reactome.org/content/detail/R-HSA-1257604) | other |
| [Phospholipase C-mediated cascade; FGFR2](https://reactome.org/content/detail/R-HSA-5654221) | other |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | other |
| [SHC-mediated cascade:FGFR2](https://reactome.org/content/detail/R-HSA-5654699) | other |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** fibroblast growth factor receptor activity, fibroblast growth factor binding, identical protein binding, protein homodimerization activity.

**Biological process:** positive regulation of cell population proliferation, fibroblast growth factor receptor signaling pathway, positive regulation of phospholipase activity, negative regulation of keratinocyte proliferation, peptidyl-tyrosine phosphorylation, positive regulation of MAPK cascade.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2024-06-07.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-06-07 |

## Associated conditions {#conditions}

[bent bone dysplasia syndrome 1](https://sugi.bio/atlas/disease/bent-bone-dysplasia-syndrome-1/), [gastric cancer](https://sugi.bio/atlas/disease/gastric-cancer/), [Apert syndrome](https://sugi.bio/atlas/disease/apert-syndrome/), [Saethre-Chotzen syndrome](https://sugi.bio/atlas/disease/saethre-chotzen-syndrome/), [Pfeiffer syndrome](https://sugi.bio/atlas/disease/pfeiffer-syndrome/), [Jackson-Weiss syndrome](https://sugi.bio/atlas/disease/jackson-weiss-syndrome/), [Crouzon syndrome](https://sugi.bio/atlas/disease/crouzon-syndrome/), [Beare-Stevenson cutis gyrata syndrome](https://sugi.bio/atlas/disease/beare-stevenson-cutis-gyrata-syndrome/), [familial scaphocephaly syndrome, McGillivray type](https://sugi.bio/atlas/disease/familial-scaphocephaly-syndrome-mcgillivray-type/), [Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis](https://sugi.bio/atlas/disease/antley-bixler-syndrome-without-genital-anomalies-or-disordered-steroidogenesis/), [LADD syndrome 1](https://sugi.bio/atlas/disease/ladd-syndrome-1/).

**Reported phenotype names (ClinVar):** Bent bone dysplasia syndrome 1, Acrocephalosyndactyly type I, Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis, Beare-Stevenson cutis gyrata syndrome, Crouzon syndrome, Familial scaphocephaly syndrome, McGillivray type, Gastric cancer, Jackson-Weiss syndrome, LADD syndrome 1, Pfeiffer syndrome.

## Similar variants {#similar}

Related FGFR2 variant pages (same residue, condition, or type): [FGFR2 c.1084+2T>C](/variant/fgfr2-c-1084-plus-2t-c), [FGFR2 c.1084+3A>G](/variant/fgfr2-c-1084-plus-3a-g), [FGFR2 c.940-1G>A](/variant/fgfr2-c-940-minus-1g-a), [FGFR2 c.940-2A>C](/variant/fgfr2-c-940-minus-2a-c), [FGFR2 p.Ala314Ser](/variant/fgfr2-p-ala314ser), [FGFR2 p.Ala337Pro](/variant/fgfr2-p-ala337pro), [FGFR2 p.Ala344=](/variant/fgfr2-p-ala344), [FGFR2 p.Ala344Gly](/variant/fgfr2-p-ala344gly).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 3590823). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*