Is BRAF p.Ser409= (c.1227A>G) pathogenic?

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.

What condition is associated with BRAF p.Ser409= (c.1227A>G)?

BRAF p.Ser409= (c.1227A>G) is associated with RASopathy, Noonan syndrome 7, LEOPARD syndrome 3 (ClinVar).

How common is BRAF p.Ser409= (c.1227A>G) in the general population?

BRAF p.Ser409= (c.1227A>G) is rare (popmax 0.352%, nfe) (gnomAD).

BRAF p.Ser409=

c.1227A>G · rs145035762 · VCV40360

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 15 submitters

gnomAD v4.1

Rare

rare (popmax 0.352%, nfe)

Conditions

RASopathy

ClinGen expert panel — RASopathy VCEP

Benign for RASopathy. Applied ACMG criteria (verbatim):

BP5 BP7 BP4 BA1

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.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.013	strongly benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.43	GERP 0.73, phastCons 0.16
Overall
CADD	7.611	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.352% European (non-Finnish) · 4,157/1,180,000 alleles

Filtering AF 0.343% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.34%

Overall 0.335% 5,414/1,614,086 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	1.62%	62
European (non-Finnish)grpmax	0.352%	284
Remaining individualsnot 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 Jewishnot grpmax-eligible	0.00338%	29,604
South Asian	0.0022%	45,541

Finnish shows a higher raw frequency than the grpmax group above it. 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.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: BRAF
Protein: p.Ser409=
Coding: c.1227A>G
MANE Select: NM_004333
dbSNP: rs145035762
Type: single nucleotide variant
Location: chr7:140783108 (GRCh38)
Gene constraint: LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.87 · 135 PDB
Residue 409: the 'disordered' region

Full BRAF gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

RASopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Noonan syndrome 7 LEOPARD syndrome 3 Noonan syndrome and Noonan-related syndrome

Similar variants

BRAF p.Ser409Leu Uncertain significance ★ ⚠ same residue
BRAF p.Ala246Pro Pathogenic ★★★ same condition
BRAF p.Asn581Asp Pathogenic ★★★ same condition
BRAF p.Asp594Val Pathogenic ★★★ same condition
BRAF p.Cys532Tyr Likely pathogenic ★★★ same condition
BRAF p.Gln257Arg Pathogenic ★★★ ⚠ same condition
BRAF p.Gly265Arg Likely pathogenic ★★★ same condition
BRAF p.Gly464Glu Pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/braf-p-ser409 (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown