# NM_006206.6(PDGFRA):c.474T>C (p.Pro158=)

https://sugi.bio/variant/pdgfra-p-pro158

## Summary

**PDGFRA p.Pro158= (c.474T>C)** is classified **Benign/Likely benign** in PDGFRA (ClinVar, Multiple submitters, 3 submitters; last evaluated 2026-06-16). Very rare (popmax 0.00167%, amr); Associated with polyps, multiple and recurrent inflammatory fibroid, gastrointestinal.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs1722881178 · 3 submitters · 3 linked conditions · very rare (popmax 0.00167%, amr)

## For patients & families {#patients}

This is a change in the PDGFRA gene that is classified as benign/likely benign — not considered disease-causing, submitted by 3 submitters, and is linked to polyps, multiple and recurrent inflammatory fibroid, gastrointestinal.

*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:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015106/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.Pro158= |
| Coding change (HGVS c.) | c.474T>C |
| MANE Select transcript | [NM_006206](https://www.ncbi.nlm.nih.gov/nuccore/NM_006206) |
| dbSNP | [rs1722881178](https://www.ncbi.nlm.nih.gov/snp/rs1722881178/) |
| Variant type | single nucleotide variant |
| Location | chr4:54263773-54263773 (GRCh38) |
| ClinVar | [VCV1742841](https://www.ncbi.nlm.nih.gov/clinvar/variation/1742841/) |

**All HGVS expressions:** `LRG_309:g.39677T>C`, `LRG_309t1:c.474T>C`, `NC_000004.11:g.55129940T>C`, `NC_000004.12:g.54263773T>C`, `NG_009250.1:g.39677T>C`, `NM_001347827.2:c.474T>C`, `NM_001347828.2:c.549T>C`, `NM_001347829.2:c.474T>C`, `NM_001347830.2:c.513T>C`, `NM_006206.6:c.474T>C`

## 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 -9.607, GERP -3.65 — fast-evolving / accelerated position
- CADD: **PHRED 0.065**. 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: **below the reporting threshold**. This position is scored for a different substitution (T>G, Δ0.45 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00167%** (amr) · 1/59,986 in the highest group · 1/152,162 alleles overall — very rare (popmax 0.00167%, amr).

*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 **158** lies in a disulfide bond; the ig-like c2-type 2 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.Pro158= falls in the ig-like c2-type 2 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}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-06-16.

**Submitter consensus:** conflicting (2 Likely benign, 1 Benign).

**Submission history:** 3 submissions (2022–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2022-09-30 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-04-27 |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2026-06-16 |

## Associated conditions {#conditions}

[polyps, multiple and recurrent inflammatory fibroid, gastrointestinal](https://sugi.bio/atlas/disease/polyps-multiple-and-recurrent-inflammatory-fibroid-gastrointestinal/), [gastrointestinal stromal tumor](https://sugi.bio/atlas/disease/gastrointestinal-stromal-tumor/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Polyps, multiple and recurrent inflammatory fibroid, gastrointestinal, Hereditary cancer-predisposing syndrome, Gastrointestinal stromal tumor, Neoplastic Syndromes, Hereditary, Tumor predisposition, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome, Gastrointestinal stromal tumor, somatic, Gastrointestinal stroma tumor.

## Similar variants {#similar}

Related PDGFRA variant pages (same residue, condition, or type): [PDGFRA p.Pro158Ala](/variant/pdgfra-p-pro158ala), [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), [PDGFRA c.2002+4G>T](/variant/pdgfra-c-2002-plus-4g-t), [PDGFRA c.2002+5G>C](/variant/pdgfra-c-2002-plus-5g-c).

### 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 1742841). 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.*