Is BRAF p.Pro345Arg (c.1034C>G) pathogenic?

BRAF p.Pro345Arg (c.1034C>G) is classified Uncertain significance in BRAF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-15). AlphaMissense: ambiguous (0.5488); Very rare (popmax 0.000678%, nfe); Associated with RASopathy.

What condition is associated with BRAF p.Pro345Arg (c.1034C>G)?

BRAF p.Pro345Arg (c.1034C>G) is associated with RASopathy (ClinVar).

How common is BRAF p.Pro345Arg (c.1034C>G) in the general population?

BRAF p.Pro345Arg (c.1034C>G) is very rare (popmax 0.000678%, nfe) (gnomAD).

What do computational predictors say about BRAF p.Pro345Arg (c.1034C>G)?

AlphaMissense predicts ambiguous (score 0.5488) — an in-silico prediction, not a clinical call.

BRAF p.Pro345Arg

c.1034C>G · VCV4740152

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5488 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000678%, nfe)

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.5488	ambiguous
REVEL	0.337	indeterminate
SaProt	LLR -7.11	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 3.6, phastCons 1
Overall
CADD	26.6	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 0.000678% European (non-Finnish) · 8/1,180,000 alleles

Filtering AF 0.000292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000211%

Overall 0.000496% 8/1,614,062 alleles · very rare exomes 8/1,461,858 · genomes 0/152,204 · joint denominator

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.Pro345Arg
Coding: c.1034C>G
MANE Select: NM_004333
Type: single nucleotide variant
Location: chr7:140794414 (GRCh38)
Gene constraint: LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.87 · 135 PDB
Residue 345: 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.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
BRAF p.Gly469Glu 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-pro345arg (accessed [today's date]).

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