Is BRAF p.Ser446= (c.1338G>A) pathogenic?

BRAF p.Ser446= (c.1338G>A) is classified Likely benign in BRAF (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-14). Very rare (popmax 0.005%, amr); Associated with RASopathy.

What condition is associated with BRAF p.Ser446= (c.1338G>A)?

BRAF p.Ser446= (c.1338G>A) is associated with RASopathy, colorectal cancer, cardiofaciocutaneous syndrome 1 (ClinVar).

How common is BRAF p.Ser446= (c.1338G>A) in the general population?

BRAF p.Ser446= (c.1338G>A) is very rare (popmax 0.005%, amr) (gnomAD).

BRAF p.Ser446=

c.1338G>A · rs765215499 · VCV1624632

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.005%, amr)

Conditions

RASopathy

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.061	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.46	GERP -3.7, phastCons 1
Overall
CADD	6.759	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.005% Admixed American · 3/59,976 alleles

Filtering AF 0.00133% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000668%

Overall 0.000929% 15/1,613,850 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.005%	19,992
Finnishnot grpmax-eligible	0.00469%	21,332
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,602
South Asian	0.0022%	45,531
Remaining individualsnot grpmax-eligible	0.0016%	62,478
African / African-American	0.00134%	74,898
European (non-Finnish)	0.000339%	294,994

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.Ser446=
Coding: c.1338G>A
MANE Select: NM_004333
dbSNP: rs765215499
Type: single nucleotide variant
Location: chr7:140781670 (GRCh38)
Gene constraint: LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.87 · 135 PDB
Residue 446: a modified residue (phosphoserine); 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: colorectal cancer cardiofaciocutaneous syndrome 1 melanoma, cutaneous malignant, susceptibility to, 1 Noonan syndrome 1 lung cancer Noonan syndrome 7 LEOPARD syndrome 3

Similar variants

BRAF p.Ser446Ter 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-ser446 (accessed [today's date]).

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