Is BRAF p.Ser446Ter (c.1337C>A) pathogenic?

BRAF p.Ser446Ter (c.1337C>A) is classified Uncertain significance in BRAF (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-07-29). Absent from gnomAD v4.1; Associated with prostate cancer, hereditary, 1.

What condition is associated with BRAF p.Ser446Ter (c.1337C>A)?

BRAF p.Ser446Ter (c.1337C>A) is associated with prostate cancer, hereditary, 1 (ClinVar).

How common is BRAF p.Ser446Ter (c.1337C>A) in the general population?

BRAF p.Ser446Ter (c.1337C>A) is absent from gnomAD v4.1 (gnomAD).

How is Familial prostate cancer inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

BRAF p.Ser446Ter

c.1337C>A · rs2129023901 · VCV1711074

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

prostate cancer, hereditary, 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a LoF-intolerant gene
NMD	predicted	premature termination codon in exon 11 of 18
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 3.8, phastCons 1
Overall
CADD	43.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BRAF
Protein: p.Ser446Ter
Coding: c.1337C>A
MANE Select: NM_004333
dbSNP: rs2129023901
Type: single nucleotide variant
Location: chr7:140781671 (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

prostate cancer, hereditary, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial prostate cancer (Orphanet):

Inheritance: Not applicable
Onset: Adult
Prevalence: 1-9 / 100 000 (United States)

Similar variants

BRAF p.Ser446= Likely benign ★★ same residue
BRAF c.1742-13T>G Uncertain significance ★ same condition
BRAF p.Gly460Glu Uncertain significance ★ ⚠ same condition
BRAF p.Ile463Thr Uncertain significance ★ ⚠ same condition
BRAF p.Asp445= Likely benign ★ same condition
BRAF c.1315-15A>T Uncertain significance same condition
BRAF c.1315-35T>A Uncertain significance same condition
BRAF c.1432+102C>A Uncertain significance 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-ser446ter (accessed [today's date]).

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