# NM_023110.3(FGFR1):c.507G>A (p.Pro169=)

https://sugi.bio/variant/fgfr1-p-pro169

## Summary

**FGFR1 p.Pro169= (c.507G>A)** is classified **Likely benign** in FGFR1 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-12-26). Ultra-rare (popmax 0.0176%, sas); Associated with Pfeiffer syndrome.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs374145904 · 3 submitters · 2 linked conditions · ultra-rare (popmax 0.0176%, sas)

## For patients & families {#patients}

This is a change in the FGFR1 gene that is classified as likely benign — not considered disease-causing, submitted by 3 submitters, and is linked to Pfeiffer syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0007380/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [FGFR1](https://sugi.bio/atlas/gene/FGFR1/) |
| Protein change (HGVS p.) | p.Pro169= |
| Coding change (HGVS c.) | c.507G>A |
| MANE Select transcript | [NM_023110](https://www.ncbi.nlm.nih.gov/nuccore/NM_023110) |
| dbSNP | [rs374145904](https://www.ncbi.nlm.nih.gov/snp/rs374145904/) |
| Variant type | single nucleotide variant |
| Location | chr8:38428035-38428035 (GRCh38) |
| ClinVar | [VCV1194500](https://www.ncbi.nlm.nih.gov/clinvar/variation/1194500/) |

**All HGVS expressions:** `LRG_993:g.45800G>A`, `LRG_993t1:c.507G>A`, `NC_000008.10:g.38285553C>T`, `NC_000008.11:g.38428035C>T`, `NG_007729.1:g.45800G>A`, `NM_001174063.2:c.507G>A`, `NM_001174064.2:c.483G>A`, `NM_001174065.2:c.501G>A`, `NM_001174066.2:c.240G>A`, `NM_001174067.2:c.600G>A`, `NM_001354367.2:c.501G>A`, `NM_001354368.2:c.234G>A`, `NM_001354369.2:c.501G>A`, `NM_001354370.2:c.234G>A`, `NM_015850.4:c.501G>A`, `NM_023105.3:c.240G>A`, `NM_023106.3:c.234G>A`, `NM_023110.3:c.507G>A`

## 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 -4.712, GERP -4.28 — fast-evolving / accelerated position
- CADD: **PHRED 7.663**. 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 **0.0176%** (sas) · FAF95 0.011% · FAF99 0.00888% · 16/91,088 in the highest group · 34/1,614,230 alleles overall — ultra-rare (popmax 0.0176%, sas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| South Asian (grpmax) | 0.0176% | 5,693 |
| African / African-American | 0.00666% | 15,012 |
| East Asian | 0.00223% | 44,884 |
| European (non-Finnish) | 0.00102% | 98,337 |

*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}

**FGFR1** population constraint: LOEUF 0.274, pLI 1, missense-Z 4.2752; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *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):

- **Pfeiffer syndrome type 1** — Definitive (AD)
- **osteoglophonic dysplasia** — Limited (AD)
- **Hartsfield-Bixler-Demyer syndrome** — Moderate (AD)

## Protein context {#protein}

Residue **169** lies in the 'heparin-binding' region; a β-strand; the ig-like c2-type 2 domain.

AlphaFold model confidence (whole protein): pLDDT 74.30, 34% of residues very-high.

**86 experimental structure(s)** (PDB): [1AGW](https://www.rcsb.org/structure/1AGW), [1CVS](https://www.rcsb.org/structure/1CVS), [1EVT](https://www.rcsb.org/structure/1EVT), [1FGI](https://www.rcsb.org/structure/1FGI), [1FGK](https://www.rcsb.org/structure/1FGK), [1FQ9](https://www.rcsb.org/structure/1FQ9) — incl. mutant structure 3KXX.

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

*Describes the biological roles of FGFR1 (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:** FGFR1's established molecular role includes protein tyrosine kinase activity. p.Pro169= falls in the heparin-binding region. In Reactome, FGFR1 is annotated in disease pathway(s) including **Signaling by FGFR1 in disease**, **Signaling by activated point mutants of FGFR1**.

**Disease mechanism (Reactome):** FGFR1 loss or alteration is curated in [Signaling by FGFR1 in disease](https://reactome.org/content/detail/R-HSA-5655302), [Signaling by activated point mutants of FGFR1](https://reactome.org/content/detail/R-HSA-1839122), [Signaling by plasma membrane FGFR1 fusions](https://reactome.org/content/detail/R-HSA-8853336).

### Pathways affected {#pathways}

FGFR1 participates in **22 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Signaling by FGFR1 in disease](https://reactome.org/content/detail/R-HSA-5655302) | curated |
| ⚕ [Signaling by activated point mutants of FGFR1](https://reactome.org/content/detail/R-HSA-1839122) | curated |
| ⚕ [Signaling by plasma membrane FGFR1 fusions](https://reactome.org/content/detail/R-HSA-8853336) | curated |
| ⚕ [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530) | other |
| ⚕ [Signaling by FGFR1 amplification mutants](https://reactome.org/content/detail/R-HSA-1839120) | other |
| [Downstream signaling of activated FGFR1](https://reactome.org/content/detail/R-HSA-5654687) | other |
| [Epithelial-Mesenchymal Transition (EMT) during gastrulation](https://reactome.org/content/detail/R-HSA-9758919) | electronic |
| [FGFR1b ligand binding and activation](https://reactome.org/content/detail/R-HSA-190370) | other |
| [FGFR1c and Klotho ligand binding and activation](https://reactome.org/content/detail/R-HSA-190374) | other |
| [FGFR1c ligand binding and activation](https://reactome.org/content/detail/R-HSA-190373) | other |
| [FRS-mediated FGFR1 signaling](https://reactome.org/content/detail/R-HSA-5654693) | other |
| [Formation of paraxial mesoderm](https://reactome.org/content/detail/R-HSA-9793380) | electronic |
| [NCAM signaling for neurite out-growth](https://reactome.org/content/detail/R-HSA-375165) | other |
| [Negative regulation of FGFR1 signaling](https://reactome.org/content/detail/R-HSA-5654726) | other |
| [PI-3K cascade:FGFR1](https://reactome.org/content/detail/R-HSA-5654689) | 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: FGFR1](https://reactome.org/content/detail/R-HSA-5654219) | other |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | other |
| [SHC-mediated cascade:FGFR1](https://reactome.org/content/detail/R-HSA-5654688) | other |
| [Signal transduction by L1](https://reactome.org/content/detail/R-HSA-445144) | other |

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

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

**Biological process:** epithelial to mesenchymal transition, positive regulation of cell population proliferation, fibroblast growth factor receptor signaling pathway, peptidyl-tyrosine phosphorylation, positive regulation of MAP kinase activity, positive regulation of MAPK cascade.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-12-26.

**Submitter consensus:** unanimous (3/3 Likely benign).

**Submission history:** 3 submissions (2020–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2020-07-24 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-12-26 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-25 |

## Associated conditions {#conditions}

[Pfeiffer syndrome](https://sugi.bio/atlas/disease/pfeiffer-syndrome/), [hypogonadotropic hypogonadism 2 with or without anosmia](https://sugi.bio/atlas/disease/hypogonadotropic-hypogonadism-2-with-or-without-anosmia/).

**Reported phenotype names (ClinVar):** Pfeiffer syndrome, not provided, Hypogonadotropic hypogonadism 2 with or without anosmia, not specified, none provided, ACS V, HYPOGONADOTROPIC HYPOGONADISM 2 WITHOUT ANOSMIA, FGFR1-Related GnRH Deficiency (Kallmann Syndrome 2), HYPOGONADOTROPIC HYPOGONADISM 2 WITH OR WITHOUT ANOSMIA, SUSCEPTIBILITY TO, HYPOGONADOTROPIC HYPOGONADISM 2 WITHOUT ANOSMIA, SUSCEPTIBILITY TO.

## Similar variants {#similar}

Related FGFR1 variant pages (same residue, condition, or type): [FGFR1 p.Pro169Leu](/variant/fgfr1-p-pro169leu), [FGFR1 p.Pro169Ala](/variant/fgfr1-p-pro169ala), [FGFR1 p.Pro169Arg](/variant/fgfr1-p-pro169arg), [FGFR1 p.Pro169Ser](/variant/fgfr1-p-pro169ser), [FGFR1 c.1977+1G>A](/variant/fgfr1-c-1977-plus-1g-a), [FGFR1 c.1977+1G>T](/variant/fgfr1-c-1977-plus-1g-t), [FGFR1 c.448+1G>A](/variant/fgfr1-c-448-plus-1g-a), [FGFR1 c.449-6G>A](/variant/fgfr1-c-449-minus-6g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 1194500). 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.*