Is BRAF p.Ser732= (c.2196C>G) pathogenic?

BRAF p.Ser732= (c.2196C>G) is classified Conflicting classifications of pathogenicity in BRAF (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-01-27). Ultra-rare (popmax 0.0163%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with BRAF p.Ser732= (c.2196C>G)?

BRAF p.Ser732= (c.2196C>G) is associated with Cardiovascular phenotype, Noonan syndrome 7, LEOPARD syndrome 3 (ClinVar).

How common is BRAF p.Ser732= (c.2196C>G) in the general population?

BRAF p.Ser732= (c.2196C>G) is ultra-rare (popmax 0.0163%, nfe) (gnomAD).

BRAF p.Ser732=

c.2196C>G · rs142592480 · VCV417227

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0163%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.06	moderately benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.8	GERP 2.3, phastCons 1
Overall
CADD	10.75	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0163% European (non-Finnish) · 192/1,179,784 alleles

Filtering AF 0.0144% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0136%

Overall 0.0124% 200/1,612,072 alleles · ultra-rare exomes 194/1,461,864 · genomes 6/150,208 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0163%	6,145
Remaining individualsnot grpmax-eligible	0.00801%	12,485
African / African-American	0.00404%	24,727

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.Ser732=
Coding: c.2196C>G
MANE Select: NM_004333
dbSNP: rs142592480
Type: single nucleotide variant
Location: chr7:140734702 (GRCh38)
Gene constraint: LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.87 · 135 PDB
Residue 732: an α-helix

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

Disease context

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

Also linked: Noonan syndrome 7 LEOPARD syndrome 3 RASopathy

Similar variants

BRAF p.Ser732Phe 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-ser732 (accessed [today's date]).

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