# NM_004333.6(BRAF):c.1227A>G (p.Ser409=)

https://sugi.bio/variant/braf-p-ser409

## Summary

**BRAF p.Ser409= (c.1227A>G)** is classified **Benign** in BRAF (ClinVar, Expert panel, 15 submitters; last evaluated 2017-04-03). Rare (popmax 0.352%, nfe); Associated with RASopathy.

**At a glance:** Benign · review: Expert panel · rsID rs145035762 · 15 submitters · 4 linked conditions · rare (popmax 0.352%, nfe)

## For patients & families {#patients}

This is a change in the BRAF gene that is classified as benign — not considered disease-causing, submitted by 15 submitters, and is linked to RASopathy.

*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 | 9 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0022213/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BRAF](https://sugi.bio/atlas/gene/BRAF/) |
| Protein change (HGVS p.) | p.Ser409= |
| Coding change (HGVS c.) | c.1227A>G |
| MANE Select transcript | [NM_004333](https://www.ncbi.nlm.nih.gov/nuccore/NM_004333) |
| dbSNP | [rs145035762](https://www.ncbi.nlm.nih.gov/snp/rs145035762/) |
| Variant type | single nucleotide variant |
| Location | chr7:140783108-140783108 (GRCh38) |
| ClinVar | [VCV40360](https://www.ncbi.nlm.nih.gov/clinvar/variation/40360/) |

**All HGVS expressions:** `LRG_299:g.146657A>G`, `LRG_299t1:c.1227A>G`, `NC_000007.13:g.140482908T>C`, `NC_000007.14:g.140783108T>C`, `NG_007873.3:g.146657A>G`, `NM_001354609.2:c.1227A>G`, `NM_001374244.1:c.1347A>G`, `NM_001374258.1:c.1347A>G`, `NM_001378467.1:c.1236A>G`, `NM_001378468.1:c.1227A>G`, `NM_001378469.1:c.1178-17A>G`, `NM_001378470.1:c.1125A>G`, `NM_001378471.1:c.1141-25A>G`, `NM_001378472.1:c.1071A>G`, `NM_001378473.1:c.1071A>G`, `NM_001378474.1:c.1227A>G`, `NM_001378475.1:c.963A>G`, `NM_004333.6:c.1227A>G`

## 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 -0.431, GERP 0.734, phastCons 0.16 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 7.611**. 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 **0.352%** (nfe) · FAF95 0.343% · FAF99 0.34% · 4,157/1,180,000 in the highest group · 5,414/1,614,086 alleles overall — rare (popmax 0.352%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 1.62% | 62 |
| European (non-Finnish) (grpmax) | 0.352% | 284 |
| Remaining individuals (not grpmax-eligible) | 0.248% | 403 |
| African / African-American | 0.0653% | 1,531 |
| Admixed American | 0.0233% | 4,287 |
| Middle Eastern | 0.0165% | 6,058 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.00338% | 29,604 |
| South Asian | 0.0022% | 45,541 |

Finnish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**BRAF** population constraint: LOEUF 0.237, pLI 1, missense-Z 4.9103; 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):

- **Noonan syndrome** — Moderate (AD)
- **Noonan syndrome with multiple lentigines** — Limited (AD)
- **cardiofaciocutaneous syndrome** — Definitive (AD)
- **Costello syndrome** — Disputed (AD)

## Protein context {#protein}

Residue **409** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 67.87, 31% of residues very-high.

**135 experimental structure(s)** (PDB): [1UWH](https://www.rcsb.org/structure/1UWH), [1UWJ](https://www.rcsb.org/structure/1UWJ), [2FB8](https://www.rcsb.org/structure/2FB8), [2L05](https://www.rcsb.org/structure/2L05), [3C4C](https://www.rcsb.org/structure/3C4C), [3D4Q](https://www.rcsb.org/structure/3D4Q) — incl. mutant structure 1UWJ.

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

*Describes the biological roles of BRAF (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:** BRAF's established molecular role includes protein kinase activity. p.Ser409= falls in the disordered region. In Reactome, BRAF is annotated in disease pathway(s) including **Gain-of-function MRAS complexes activate RAF signaling**, **Paradoxical activation of RAF signaling by kinase inactive BRAF**.

**Disease mechanism (Reactome):** BRAF loss or alteration is curated in [Gain-of-function MRAS complexes activate RAF signaling](https://reactome.org/content/detail/R-HSA-9726842), [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955), [SHOC2 M1731 mutant abolishes MRAS complex function](https://reactome.org/content/detail/R-HSA-9726840).

### Pathways affected {#pathways}

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

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Gain-of-function MRAS complexes activate RAF signaling](https://reactome.org/content/detail/R-HSA-9726842) | curated |
| ⚕ [Paradoxical activation of RAF signaling by kinase inactive BRAF](https://reactome.org/content/detail/R-HSA-6802955) | curated |
| ⚕ [SHOC2 M1731 mutant abolishes MRAS complex function](https://reactome.org/content/detail/R-HSA-9726840) | curated |
| ⚕ [Signaling by BRAF and RAF1 fusions](https://reactome.org/content/detail/R-HSA-6802952) | curated |
| ⚕ [Signaling by RAF1 mutants](https://reactome.org/content/detail/R-HSA-9656223) | curated |
| ⚕ [Signaling by high-kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802948) | curated |
| ⚕ [Signaling by moderate kinase activity BRAF mutants](https://reactome.org/content/detail/R-HSA-6802946) | curated |
| ⚕ [Signaling downstream of RAS mutants](https://reactome.org/content/detail/R-HSA-9649948) | curated |
| [MAP2K and MAPK activation](https://reactome.org/content/detail/R-HSA-5674135) | curated |
| [Negative feedback regulation of MAPK pathway](https://reactome.org/content/detail/R-HSA-5674499) | curated |
| [Negative regulation of MAPK pathway](https://reactome.org/content/detail/R-HSA-5675221) | curated |
| [RAF activation](https://reactome.org/content/detail/R-HSA-5673000) | curated |
| [Spry regulation of FGF signaling](https://reactome.org/content/detail/R-HSA-1295596) | curated |
| [ARMS-mediated activation](https://reactome.org/content/detail/R-HSA-170984) | electronic |
| [Frs2-mediated activation](https://reactome.org/content/detail/R-HSA-170968) | electronic |
| [Signalling to p38 via RIT and RIN](https://reactome.org/content/detail/R-HSA-187706) | electronic |

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

**Molecular function:** protein kinase activity, protein serine/threonine kinase activity, MAP kinase kinase activity, calcium ion binding, identical protein binding, scaffold protein binding.

**Biological process:** MAPK cascade, epidermal growth factor receptor signaling pathway, positive regulation of gene expression, positive regulation of D-glucose transmembrane transport, positive regulation of peptidyl-serine phosphorylation, negative regulation of apoptotic process.

## Clinical significance {#significance}

**Benign** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2017-04-03.

**Submitter consensus:** conflicting (11 Benign, 5 Likely benign).

**Submission history:** 16 submissions (2012–2026); classifications have differed over time.

**ClinGen expert panel:** Benign — RASopathy VCEP (RASopathy). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `BP5`, `BP7`, `BP4`, `BA1`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The filtering allele frequency of the c.1227A>G (p.Ser409=) variant in the BRAF gene is 0.313% for European (Non-Finnish) chromosomes by the Exome Aggregation Consortium (233/66620 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1). Additionally, this variant is a synonymous (silent) variant at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP7). The p.Ser409= variant has been identified in a patient with an alternate molecular basis for disease (BP5; GeneDx, Partners LMM, EGL Genetics internal data; GTR ID's: 21766, 26957, 500060; SCV000057203.8; SCV000061570.5; SCV000112807.7). Computational prediction tools and conservation analysis suggest that the p.Ser409= variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied: BA1, BP7, BP5, BP4.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50021 · approved 2017-04-03 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/dd0b96ec-49ad-4f28-801a-b7b31c5fe734).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2017-04-27 |
| ClinGen RASopathy Variant Curation Expert Panel | Benign | reviewed by expert panel | curation | 2017-04-03 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-01 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2016-05-31 |
| Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Benign | criteria provided, single submitter | clinical testing | 2012-01-30 |
| Clinical Genetics, Academic Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, The Hospital for Sick Children | Benign | criteria provided, single submitter | clinical testing | 2020-04-01 |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2019-02-16 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | criteria provided, single submitter | clinical testing | 2016-03-18 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2025-01-13 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-06-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-27 |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2015-04-07 |

## Associated conditions {#conditions}

[RASopathy](https://sugi.bio/atlas/disease/rasopathy/), [Noonan syndrome 7](https://sugi.bio/atlas/disease/noonan-syndrome-7/), [LEOPARD syndrome 3](https://sugi.bio/atlas/disease/leopard-syndrome-3/), [Noonan syndrome and Noonan-related syndrome](https://sugi.bio/atlas/disease/noonan-syndrome-and-noonan-related-syndrome/).

**Reported phenotype names (ClinVar):** RASopathy, not specified, Noonan syndrome 7, LEOPARD syndrome 3, not provided, Cardiovascular phenotype, Noonan syndrome and Noonan-related syndrome, AllHighlyPenetrant, none provided, rasopathies.

## Similar variants {#similar}

Related BRAF variant pages (same residue, condition, or type): [BRAF p.Ser409Leu](/variant/braf-p-ser409leu), [BRAF p.Ala246Pro](/variant/braf-p-ala246pro), [BRAF p.Asn581Asp](/variant/braf-p-asn581asp), [BRAF p.Asp594Val](/variant/braf-p-asp594val), [BRAF p.Cys532Tyr](/variant/braf-p-cys532tyr), [BRAF p.Gln257Arg](/variant/braf-p-gln257arg), [BRAF p.Gly265Arg](/variant/braf-p-gly265arg), [BRAF p.Gly464Glu](/variant/braf-p-gly464glu).

### 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 40360). 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.*