Is BRAF p.Arg682Trp (c.2044C>T) pathogenic?

BRAF p.Arg682Trp (c.2044C>T) is classified Uncertain significance in BRAF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-09). AlphaMissense: likely pathogenic (0.8033); Very rare (popmax 0.0011%, sas); Associated with RASopathy.

What condition is associated with BRAF p.Arg682Trp (c.2044C>T)?

BRAF p.Arg682Trp (c.2044C>T) is associated with RASopathy (ClinVar).

How common is BRAF p.Arg682Trp (c.2044C>T) in the general population?

BRAF p.Arg682Trp (c.2044C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about BRAF p.Arg682Trp (c.2044C>T)?

AlphaMissense predicts likely pathogenic (score 0.8033) — an in-silico prediction, not a clinical call.

BRAF p.Arg682Trp

c.2044C>T · rs776664982 · VCV2499058

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8033 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.8033	likely pathogenic
REVEL	0.614	indeterminate
SaProt	LLR -14.07	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.63 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.9	GERP 1.4, phastCons 1
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,050 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000496% 8/1,613,392 alleles · very rare exomes 8/1,461,350 · genomes 0/152,042 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,050
European (non-Finnish)	0.000593%	168,535

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.Arg682Trp
Coding: c.2044C>T
MANE Select: NM_004333
dbSNP: rs776664982
Type: single nucleotide variant
Location: chr7:140739895 (GRCh38)
Gene constraint: LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.87 · 135 PDB
Residue 682: 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

Similar variants

BRAF p.Arg682= Uncertain significance ★ same residue
BRAF p.Arg682Gln 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

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-arg682trp (accessed [today's date]).

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