Is BRAF p.Arg347Pro (c.1040G>C) pathogenic?

BRAF p.Arg347Pro (c.1040G>C) is classified Uncertain significance in BRAF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-16). AlphaMissense: likely pathogenic (0.6015); Very rare (popmax 0.000169%, nfe); Associated with RASopathy.

What condition is associated with BRAF p.Arg347Pro (c.1040G>C)?

BRAF p.Arg347Pro (c.1040G>C) is associated with RASopathy (ClinVar).

How common is BRAF p.Arg347Pro (c.1040G>C) in the general population?

BRAF p.Arg347Pro (c.1040G>C) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about BRAF p.Arg347Pro (c.1040G>C)?

AlphaMissense predicts likely pathogenic (score 0.6015) — an in-silico prediction, not a clinical call.

BRAF p.Arg347Pro

c.1040G>C · rs397516884 · VCV44793

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.6015 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.6015	likely pathogenic
REVEL	0.446	indeterminate
SaProt	LLR -5.64	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 3.6, phastCons 1
Overall
CADD	29.0	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 0.000169% European (non-Finnish) · 2/1,179,958 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,836 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.Arg347Pro
Coding: c.1040G>C
MANE Select: NM_004333
dbSNP: rs397516884
Type: single nucleotide variant
Location: chr7:140794408 (GRCh38)
Gene constraint: LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.87 · 135 PDB
Residue 347: 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

Similar variants

BRAF p.Arg347Ter Uncertain significance ★★ same residue
BRAF p.Arg347Gln 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-arg347pro (accessed [today's date]).

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