Is BRAF p.Gln461Lys (c.1381C>A) pathogenic?

BRAF p.Gln461Lys (c.1381C>A) is classified Uncertain significance in BRAF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-22). AlphaMissense: ambiguous (0.3824); Very rare (popmax 0.00267%, afr); Associated with Cardiovascular phenotype.

What condition is associated with BRAF p.Gln461Lys (c.1381C>A)?

BRAF p.Gln461Lys (c.1381C>A) is associated with Cardiovascular phenotype (ClinVar).

How common is BRAF p.Gln461Lys (c.1381C>A) in the general population?

BRAF p.Gln461Lys (c.1381C>A) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about BRAF p.Gln461Lys (c.1381C>A)?

AlphaMissense predicts ambiguous (score 0.3824) — an in-silico prediction, not a clinical call.

BRAF p.Gln461Lys

c.1381C>A · VCV4613756

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3824 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.3824	ambiguous
REVEL	0.536	indeterminate
SaProt	LLR -5.51	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 3.8, phastCons 1
Overall
CADD	25.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,852 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.00132% 2/151,982 alleles · very rare

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.Gln461Lys
Coding: c.1381C>A
MANE Select: NM_004333
Type: single nucleotide variant
Location: chr7:140781627 (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

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

Similar variants

BRAF p.Gln461= Benign ★★★ same residue
BRAF p.Gln461Arg Uncertain significance ★ ⚠ same residue
BRAF p.Asn236Lys Likely pathogenic ★★ same condition
BRAF p.Gln262Arg Pathogenic/Likely pathogenic ★★ same condition
BRAF p.Glu501Lys Pathogenic/Likely pathogenic ★★ same condition
BRAF c.2127+4A>G Uncertain significance ★★ same condition
BRAF p.Ala27Gly Uncertain significance ★★ ⚠ same condition
BRAF p.Ala42Ser 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-gln461lys (accessed [today's date]).

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