# NM_000142.5(FGFR3):c.1227C>T (p.Pro409=)

https://sugi.bio/variant/fgfr3-p-pro409

## Summary

**FGFR3 p.Pro409= (c.1227C>T)** is classified **Benign/Likely benign** in FGFR3 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2026-01-02). Rare (popmax 0.14%, eas).

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs533316478 · 4 submitters · rare (popmax 0.14%, eas)

## For patients & families {#patients}

This is a change in the FGFR3 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 4 submitters.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [FGFR3](https://sugi.bio/atlas/gene/FGFR3/) |
| Protein change (HGVS p.) | p.Pro409= |
| Coding change (HGVS c.) | c.1227C>T |
| MANE Select transcript | [NM_000142](https://www.ncbi.nlm.nih.gov/nuccore/NM_000142) |
| dbSNP | [rs533316478](https://www.ncbi.nlm.nih.gov/snp/rs533316478/) |
| Variant type | single nucleotide variant |
| Location | chr4:1804481-1804481 (GRCh38) |
| ClinVar | [VCV255327](https://www.ncbi.nlm.nih.gov/clinvar/variation/255327/) |

**All HGVS expressions:** `LRG_1021:g.16170C>T`, `LRG_1021t1:c.1227C>T`, `NC_000004.11:g.1806208C>T`, `NC_000004.12:g.1804481C>T`, `NG_012632.1:g.16170C>T`, `NM_000142.5:c.1227C>T`, `NM_001163213.2:c.1233C>T`, `NM_001354809.2:c.1227C>T`, `NM_001354810.2:c.1227C>T`, `NM_022965.4:c.931-343C>T`, `NR_148971.2:n.1653C>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 -1.955, GERP -2.64 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 8.479**. 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 **0.14%** (eas) · FAF95 0.113% · FAF99 0.103% · 63/44,870 in the highest group · 85/1,613,136 alleles overall — rare (popmax 0.14%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.14% | 712 |
| Remaining individuals (not grpmax-eligible) | 0.0336% | 2,976 |
| European (non-Finnish) | 8.47e-05% | 1,179,948 |

*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}

**FGFR3** population constraint: LOEUF 0.458, pLI 0.99865, missense-Z 1.1956; ClinGen dosage — haploinsufficiency 0/3, triplosensitivity 0/3. *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):

- **achondroplasia** — Definitive (AD)
- **hypochondroplasia** — Definitive (AD)
- **thanatophoric dysplasia** — Definitive (AD)
- **camptodactyly-tall stature-scoliosis-hearing loss syndrome** — Moderate (SD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 75.25, 38% of residues very-high.

**16 experimental structure(s)** (PDB): [1RY7](https://www.rcsb.org/structure/1RY7), [2LZL](https://www.rcsb.org/structure/2LZL), [4K33](https://www.rcsb.org/structure/4K33), [6LVM](https://www.rcsb.org/structure/6LVM), [6PNX](https://www.rcsb.org/structure/6PNX), [7DHL](https://www.rcsb.org/structure/7DHL).

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

*Describes the biological roles of FGFR3 (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:** FGFR3's established molecular role includes protein tyrosine kinase activity. In Reactome, FGFR3 is annotated in disease pathway(s) including **Signaling by FGFR3 fusions in cancer**, **Signaling by FGFR3 in disease**.

**Disease mechanism (Reactome):** FGFR3 loss or alteration is curated in [Signaling by FGFR3 fusions in cancer](https://reactome.org/content/detail/R-HSA-8853334), [Signaling by FGFR3 in disease](https://reactome.org/content/detail/R-HSA-5655332), [Signaling by activated point mutants of FGFR3](https://reactome.org/content/detail/R-HSA-1839130).

### Pathways affected {#pathways}

FGFR3 participates in **16 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Signaling by FGFR3 fusions in cancer](https://reactome.org/content/detail/R-HSA-8853334) | curated |
| ⚕ [Signaling by FGFR3 in disease](https://reactome.org/content/detail/R-HSA-5655332) | curated |
| ⚕ [Signaling by activated point mutants of FGFR3](https://reactome.org/content/detail/R-HSA-1839130) | curated |
| ⚕ [t(4;14) translocations of FGFR3](https://reactome.org/content/detail/R-HSA-2033515) | curated |
| ⚕ [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530) | other |
| [FGFR3b ligand binding and activation](https://reactome.org/content/detail/R-HSA-190371) | other |
| [FGFR3c ligand binding and activation](https://reactome.org/content/detail/R-HSA-190372) | other |
| [FRS-mediated FGFR3 signaling](https://reactome.org/content/detail/R-HSA-5654706) | other |
| [Negative regulation of FGFR3 signaling](https://reactome.org/content/detail/R-HSA-5654732) | other |
| [PI-3K cascade:FGFR3](https://reactome.org/content/detail/R-HSA-5654710) | 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; FGFR3](https://reactome.org/content/detail/R-HSA-5654227) | other |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | other |
| [SHC-mediated cascade:FGFR3](https://reactome.org/content/detail/R-HSA-5654704) | other |

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

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

**Biological process:** cell surface receptor signaling pathway via JAK-STAT, positive regulation of cell population proliferation, fibroblast growth factor receptor signaling pathway, positive regulation of phospholipase activity, positive regulation of tyrosine phosphorylation of STAT protein, positive regulation of MAPK cascade.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-02.

**Submitter consensus:** conflicting (3 Likely benign, 1 Benign).

**Submission history:** 4 submissions (2021–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Likely benign | criteria provided, single submitter | clinical testing |  |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-02 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2021-02-04 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-21 |

**Reported phenotype names (ClinVar):** not specified, not provided, AllHighlyPenetrant, none provided.

## Similar variants {#similar}

Related FGFR3 variant pages (same residue, condition, or type): [FGFR3 p.Ala391Glu](/variant/fgfr3-p-ala391glu), [FGFR3 p.Arg248Cys](/variant/fgfr3-p-arg248cys), [FGFR3 p.Arg621His](/variant/fgfr3-p-arg621his), [FGFR3 p.Asn540Asp](/variant/fgfr3-p-asn540asp), [FGFR3 p.Asn540Lys](/variant/fgfr3-p-asn540lys), [FGFR3 p.Asn540Ser](/variant/fgfr3-p-asn540ser), [FGFR3 p.Asn540Thr](/variant/fgfr3-p-asn540thr), [FGFR3 p.Gly268Cys](/variant/fgfr3-p-gly268cys).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 255327). 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.*