# NM_002609.4(PDGFRB):c.2208C>T (p.Ser736=)

https://sugi.bio/variant/pdgfrb-p-ser736

## Summary

**PDGFRB p.Ser736= (c.2208C>T)** is classified **Likely benign** in PDGFRB (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-11-01). Ultra-rare (popmax 0.0174%, mid); Associated with infantile myofibromatosis.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs776488990 · 2 submitters · 4 linked conditions · ultra-rare (popmax 0.0174%, mid)

## For patients & families {#patients}

This is a change in the PDGFRB gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to infantile myofibromatosis.

*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, Autosomal recessive, Not applicable |
| Age of onset (of this condition) | Antenatal, Infancy, Neonatal |
| Prevalence | 1-9 / 1 000 000 (Europe) |
| Clinical trials | 1 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | PDGFRB is a diagnostic-grade gene on 15 Genomics England panels |

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

- Abnormal metaphysis morphology — Very frequent (99-80%)
- Subcutaneous nodule — Very frequent (99-80%)
- Abnormality of the musculature — Very frequent (99-80%)
- Neoplasm of the skin — Very frequent (99-80%)
- Fibroma — Very frequent (99-80%)
- Bone cyst — Very frequent (99-80%)
- Sarcoma — Very frequent (99-80%)
- Gingival fibromatosis — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0002998/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [PDGFRB](https://sugi.bio/atlas/gene/PDGFRB/) |
| Protein change (HGVS p.) | p.Ser736= |
| Coding change (HGVS c.) | c.2208C>T |
| MANE Select transcript | [NM_002609](https://www.ncbi.nlm.nih.gov/nuccore/NM_002609) |
| dbSNP | [rs776488990](https://www.ncbi.nlm.nih.gov/snp/rs776488990/) |
| Variant type | single nucleotide variant |
| Location | chr5:150122016-150122016 (GRCh38) |
| ClinVar | [VCV2418520](https://www.ncbi.nlm.nih.gov/clinvar/variation/2418520/) |

**All HGVS expressions:** `NC_000005.10:g.150122016G>A`, `NC_000005.9:g.149501579G>A`, `NG_023367.1:g.38844C>T`, `NG_023367.2:g.38829C>T`, `NM_001355016.2:c.2016C>T`, `NM_001355017.2:c.1725C>T`, `NM_002609.4:c.2208C>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 -6.022, GERP -4.77 — fast-evolving / accelerated position
- CADD: **PHRED 0.531**. 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 **0.0174%** (mid) · FAF95 0.000542% · FAF99 0.000428% · 1/5,738 in the highest group · 16/1,613,346 alleles overall — ultra-rare (popmax 0.0174%, mid).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Middle Eastern (grpmax) | 0.0174% | 5,738 |
| Admixed American | 0.00167% | 59,998 |
| African / African-American | 0.00134% | 74,880 |
| South Asian | 0.0011% | 91,064 |
| European (non-Finnish) | 0.00102% | 98,325 |

*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}

**PDGFRB** population constraint: LOEUF 0.504, pLI 0.93843, missense-Z 2.8591. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

## Protein context {#protein}

Residue **736** lies in the protein kinase domain.

AlphaFold model confidence (whole protein): pLDDT 72.96, 30% of residues very-high.

**9 experimental structure(s)** (PDB): [11UE](https://www.rcsb.org/structure/11UE), [1H9O](https://www.rcsb.org/structure/1H9O), [1SHA](https://www.rcsb.org/structure/1SHA), [2IUI](https://www.rcsb.org/structure/2IUI), [2L6W](https://www.rcsb.org/structure/2L6W), [2PLD](https://www.rcsb.org/structure/2PLD).

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

*Describes the biological roles of PDGFRB (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:** PDGFRB's established molecular role includes protein kinase activity. p.Ser736= falls in the protein kinase domain. In Reactome, PDGFRB is annotated in disease pathway(s) including **Constitutive Signaling by Aberrant PI3K in Cancer**.

**Disease mechanism (Reactome):** PDGFRB loss or alteration is curated in [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530).

### Pathways affected {#pathways}

PDGFRB participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530) | 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, protein tyrosine kinase activity, platelet-derived growth factor beta-receptor activity, GTPase activator activity, signaling receptor binding, platelet-derived growth factor receptor binding.

**Biological process:** signal transduction, positive regulation of cell population proliferation, positive regulation of smooth muscle cell migration, peptidyl-tyrosine phosphorylation, positive regulation of cell migration, platelet-derived growth factor receptor-beta signaling pathway.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2022-11-01.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2022); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2022-07-21 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2022-11-01 |

## Associated conditions {#conditions}

[infantile myofibromatosis](https://sugi.bio/atlas/disease/infantile-myofibromatosis/), [acroosteolysis-keloid-like lesions-premature aging syndrome](https://sugi.bio/atlas/disease/acroosteolysis-keloid-like-lesions-premature-aging-syndrome/), [basal ganglia calcification, idiopathic, 4](https://sugi.bio/atlas/disease/basal-ganglia-calcification-idiopathic-4/), [skeletal overgrowth-craniofacial dysmorphism-hyperelastic skin-white matter lesions syndrome](https://sugi.bio/atlas/disease/skeletal-overgrowth-craniofacial-dysmorphism-hyperelastic-skin-white-matter-lesions-syndrome/).

**Reported phenotype names (ClinVar):** Infantile myofibromatosis, Acroosteolysis-keloid-like lesions-premature aging syndrome, Basal ganglia calcification, idiopathic, 4, Skeletal overgrowth-craniofacial dysmorphism-hyperelastic skin-white matter lesions syndrome, not provided, Congenital generalized fibromatosis, SKELETAL OVERGROWTH WITH FACIAL DYSMORPHISM, HYPERELASTIC SKIN, WHITE MATTER LESIONS, AND NEUROLOGIC DETERIORATION, Kosaki overgrowth syndrome, Familial Idiopathic Basal Ganglia Calcification 4, Progeroid syndrome, Penttinen type.

## Similar variants {#similar}

Related PDGFRB variant pages (same residue, condition, or type): [PDGFRB p.Arg561Cys](/variant/pdgfrb-p-arg561cys), [PDGFRB p.Asn666His](/variant/pdgfrb-p-asn666his), [PDGFRB p.Asn666Lys](/variant/pdgfrb-p-asn666lys), [PDGFRB p.Asn666Ser](/variant/pdgfrb-p-asn666ser), [PDGFRB p.Pro560Leu](/variant/pdgfrb-p-pro560leu), [PDGFRB p.Pro584Arg](/variant/pdgfrb-p-pro584arg), [PDGFRB p.Trp566Arg](/variant/pdgfrb-p-trp566arg), [PDGFRB p.Ala513Thr](/variant/pdgfrb-p-ala513thr).

### 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 2418520). 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.*