# NM_006206.6(PDGFRA):c.2293C>T (p.Pro765Ser)

https://sugi.bio/variant/pdgfra-p-pro765ser

## Summary

**PDGFRA p.Pro765Ser (c.2293C>T)** is classified **Uncertain significance** in PDGFRA (ClinVar, Single submitter, 1 submitter; last evaluated 2020-03-02). AlphaMissense: likely pathogenic (0.6913); Absent from gnomAD v4.1; Associated with gastrointestinal stromal tumor.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs1325295795 · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the PDGFRA gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, and is linked to gastrointestinal stromal tumor.

*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, Not applicable |
| Age of onset (of this condition) | Adolescent, Adult, Childhood |
| Prevalence | 1-5 / 10 000 (Europe) |
| Clinical trials | 310 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | PDGFRA is a diagnostic-grade gene on 3 Genomics England panels |

**Commonly reported features of Gastrointestinal stromal tumor** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Neoplasm of the stomach — Very frequent (99-80%)
- Sarcoma — Very frequent (99-80%)
- Gastrointestinal stroma tumor — Very frequent (99-80%)
- Dysphagia — Frequent (79-30%)
- Nausea and vomiting — Frequent (79-30%)
- Constipation — Frequent (79-30%)
- Gastrointestinal hemorrhage — Frequent (79-30%)
- Intestinal obstruction — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0008598/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PDGFRA](https://sugi.bio/atlas/gene/PDGFRA/) |
| Protein change (HGVS p.) | p.Pro765Ser |
| Coding change (HGVS c.) | c.2293C>T |
| MANE Select transcript | [NM_006206](https://www.ncbi.nlm.nih.gov/nuccore/NM_006206) |
| dbSNP | [rs1325295795](https://www.ncbi.nlm.nih.gov/snp/rs1325295795/) |
| Variant type | single nucleotide variant |
| Location | chr4:54280452-54280452 (GRCh38) |
| ClinVar | [VCV1044774](https://www.ncbi.nlm.nih.gov/clinvar/variation/1044774/) |

**All HGVS expressions:** `LRG_309:g.56356C>T`, `NC_000004.11:g.55146619C>T`, `NC_000004.12:g.54280452C>T`, `NG_009250.1:g.56356C>T`, `NM_001347827.2:c.2293C>T`, `NM_001347828.2:c.2368C>T`, `NM_001347829.2:c.2293C>T`, `NM_001347830.2:c.2332C>T`, `NM_006206.6:c.2293C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.6913)
- REVEL 0.594 (indeterminate)
- SaProt LLR -6.846 (tolerated) — differs from AlphaMissense
- → **In-silico consensus:** AlphaMissense calls this damaging; SaProt does not; REVEL makes no call
- Conservation: phyloP 7.658, GERP 2.14, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 26.2**. 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.*
- Regional missense constraint: **o/e 0.87** across the covering region of the MANE Select transcript (54,278,379–54,285,444), spanning 7,065 bp. Chi-square p 0.11. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**PDGFRA** population constraint: LOEUF 0.264, pLI 1, missense-Z 3.4194; ClinGen dosage — haploinsufficiency 0, 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):

- **gastrointestinal stromal tumor** — Definitive (AD)
- **congenital heart disease** — Limited (AD)

## Protein context {#protein}

Residue **765** lies in the protein kinase domain.

AlphaFold model confidence (whole protein): pLDDT 72.91, 25% of residues very-high.

**19 experimental structure(s)** (PDB): [5GRN](https://www.rcsb.org/structure/5GRN), [5K5X](https://www.rcsb.org/structure/5K5X), [6A32](https://www.rcsb.org/structure/6A32), [6JOI](https://www.rcsb.org/structure/6JOI), [6JOJ](https://www.rcsb.org/structure/6JOJ), [6JOK](https://www.rcsb.org/structure/6JOK) — incl. mutant structure 6A32.

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

*Describes the biological roles of PDGFRA (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:** PDGFRA's established molecular role includes protein kinase activity. p.Pro765Ser falls in the protein kinase domain. In Reactome, PDGFRA is annotated in disease pathway(s) including **Constitutive Signaling by Aberrant PI3K in Cancer**, **Imatinib-resistant PDGFR mutants**.

**Disease mechanism (Reactome):** PDGFRA loss or alteration is curated in [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530), [Imatinib-resistant PDGFR mutants](https://reactome.org/content/detail/R-HSA-9674396), [PDGFR mutants bind TKIs](https://reactome.org/content/detail/R-HSA-9674428).

### Pathways affected {#pathways}

PDGFRA participates in **13 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530) | curated |
| ⚕ [Imatinib-resistant PDGFR mutants](https://reactome.org/content/detail/R-HSA-9674396) | curated |
| ⚕ [PDGFR mutants bind TKIs](https://reactome.org/content/detail/R-HSA-9674428) | curated |
| ⚕ [Regorafenib-resistant PDGFR mutants](https://reactome.org/content/detail/R-HSA-9674403) | curated |
| ⚕ [Signaling by PDGFRA extracellular domain mutants](https://reactome.org/content/detail/R-HSA-9673770) | curated |
| ⚕ [Signaling by PDGFRA transmembrane, juxtamembrane and kinase domain mutants](https://reactome.org/content/detail/R-HSA-9673767) | curated |
| ⚕ [Sorafenib-resistant PDGFR mutants](https://reactome.org/content/detail/R-HSA-9674404) | curated |
| ⚕ [Sunitinib-resistant PDGFR mutants](https://reactome.org/content/detail/R-HSA-9674401) | curated |
| [Downstream signal transduction](https://reactome.org/content/detail/R-HSA-186763) | curated |
| [PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling](https://reactome.org/content/detail/R-HSA-6811558) | curated |
| [PIP3 activates AKT signaling](https://reactome.org/content/detail/R-HSA-1257604) | curated |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [Signaling by PDGF](https://reactome.org/content/detail/R-HSA-186797) | curated |

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

**Molecular function:** protein kinase activity, transmembrane receptor protein tyrosine kinase activity, platelet-derived growth factor alpha-receptor activity, vascular endothelial growth factor receptor activity, platelet-derived growth factor receptor binding, vascular endothelial growth factor binding.

**Biological process:** positive regulation of cell population proliferation, negative regulation of platelet activation, peptidyl-tyrosine phosphorylation, positive regulation of cell migration, cellular response to reactive oxygen species, platelet-derived growth factor receptor-alpha signaling pathway.

## Clinical significance {#significance}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2020-03-02.

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

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-03-02 |

## Associated conditions {#conditions}

[gastrointestinal stromal tumor](https://sugi.bio/atlas/disease/gastrointestinal-stromal-tumor/).

**Reported phenotype names (ClinVar):** Gastrointestinal stromal tumor, Gastrointestinal stromal tumor, somatic, Gastrointestinal stroma tumor.

## Similar variants {#similar}

Related PDGFRA variant pages (same residue, condition, or type): [PDGFRA p.Pro765=](/variant/pdgfra-p-pro765), [PDGFRA p.Pro765Gln](/variant/pdgfra-p-pro765gln), [PDGFRA p.Pro765Thr](/variant/pdgfra-p-pro765thr), [PDGFRA c.1364+3A>G](/variant/pdgfra-c-1364-plus-3a-g), [PDGFRA c.1364+4T>C](/variant/pdgfra-c-1364-plus-4t-c), [PDGFRA c.1787-5C>G](/variant/pdgfra-c-1787-minus-5c-g), [PDGFRA c.2002+2T>C](/variant/pdgfra-c-2002-plus-2t-c), [PDGFRA c.2002+4G>A](/variant/pdgfra-c-2002-plus-4g-a).

### 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 2026-07-14); 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 1044774). 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.*