Is BRAF p.Gly643= (c.1929A>G) pathogenic?

BRAF p.Gly643= (c.1929A>G) is classified Benign in BRAF (ClinVar, Expert panel, 16 submitters; last evaluated 2017-04-18). Common (popmax 67.7%, afr) — too common for a highly-penetrant pathogenic allele; Associated with RASopathy.

What condition is associated with BRAF p.Gly643= (c.1929A>G)?

BRAF p.Gly643= (c.1929A>G) is associated with RASopathy, Noonan syndrome 7, LEOPARD syndrome 3 (ClinVar).

BRAF p.Gly643=

Q: How common is BRAF p.Gly643= (c.1929A>G) in the general population?

BRAF p.Gly643= (c.1929A>G) is common (popmax 67.7%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1929A>G · rs9648696 · VCV40391

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 16 submitters

gnomAD v4.1

Common

common (popmax 67.7%, afr) — too common for a highly-penetrant pathogenic allele

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.1929A>G (p.Gly643=) variant in the BRAF gene is 66.117% (6984/10356) 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	0.247	benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.11	GERP -2.2, phastCons 0.5
Overall
CADD	7.943	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 67.7% African / African-American · 50,668/74,860 alleles

Filtering AF 67.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 67%

Overall 17.8% 287,439/1,612,556 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	67.7%	1
Middle Eastern	31.7%	3
South Asian	31.5%	3
Ashkenazi Jewishnot grpmax-eligible	21%	5
Remaining individualsnot grpmax-eligible	20.2%	5
East Asian	15.8%	6
Finnishnot grpmax-eligible	14.4%	7
European (non-Finnish)	13.8%	7
Admixed American	13.1%	8
Amishnot grpmax-eligible	10.4%	10

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.Gly643=
Coding: c.1929A>G
MANE Select: NM_004333
dbSNP: rs9648696
Type: single nucleotide variant
Location: chr7:140749350 (GRCh38)
Gene constraint: LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.87 · 135 PDB
Residue 643: an α-helix; 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

Similar variants

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
BRAF p.Gly469Glu 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-gly643 (accessed [today's date]).

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