Is BRAF p.Gln461= (c.1383A>G) pathogenic?

BRAF p.Gln461= (c.1383A>G) is classified Benign in BRAF (ClinVar, Expert panel, 14 submitters; last evaluated 2017-04-18). Low-frequency (popmax 1.34%, afr); Associated with RASopathy.

What condition is associated with BRAF p.Gln461= (c.1383A>G)?

BRAF p.Gln461= (c.1383A>G) is associated with RASopathy, Noonan syndrome 7, LEOPARD syndrome 3 (ClinVar).

How common is BRAF p.Gln461= (c.1383A>G) in the general population?

BRAF p.Gln461= (c.1383A>G) is low-frequency (popmax 1.34%, afr) (gnomAD).

BRAF p.Gln461=

c.1383A>G · rs56216404 · VCV40363

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 14 submitters

gnomAD v4.1

Rare

low-frequency (popmax 1.34%, afr)

Conditions

RASopathy

ClinGen expert panel — RASopathy VCEP

Benign for RASopathy. Applied ACMG criteria (verbatim):

BA1

Curation rationale (ClinGen, verbatim)

The filtering allele frequency of the c.1383A>G (p.Gln461=) variant in the BRAF gene is 0.986% (120/10404) of African chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581)

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	0.084	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.7	GERP -2.9
Overall
CADD	5.854	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 1.34% African / African-American · 1,007/75,040 alleles

Filtering AF 1.27% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.25%

Overall 0.0747% 1,206/1,614,110 alleles · low-frequency

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.34%	75
Remaining individualsnot grpmax-eligible	0.0992%	1,008
Middle Eastern	0.099%	1,010
Admixed American	0.065%	1,539
South Asian	0.0143%	7,006
European (non-Finnish)	0.00669%	14,937

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.Gln461=
Coding: c.1383A>G
MANE Select: NM_004333
dbSNP: rs56216404
Type: single nucleotide variant
Location: chr7:140781625 (GRCh38)
Gene constraint: LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.87 · 135 PDB
Residue 461: a β-strand; the protein kinase domain

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.Gln461Arg Uncertain significance ★ ⚠ same residue
BRAF p.Gln461Lys 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

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-gln461 (accessed [today's date]).

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