Is BRAF p.Pro14Arg (c.41C>G) pathogenic?

BRAF p.Pro14Arg (c.41C>G) is classified Uncertain significance in BRAF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-06). AlphaMissense: likely benign (0.1316); Very rare (popmax 0.00231%, nfe); Associated with RASopathy.

What condition is associated with BRAF p.Pro14Arg (c.41C>G)?

BRAF p.Pro14Arg (c.41C>G) is associated with RASopathy (ClinVar).

How common is BRAF p.Pro14Arg (c.41C>G) in the general population?

BRAF p.Pro14Arg (c.41C>G) is very rare (popmax 0.00231%, nfe) (gnomAD).

What do computational predictors say about BRAF p.Pro14Arg (c.41C>G)?

AlphaMissense predicts likely benign (score 0.1316) — an in-silico prediction, not a clinical call.

BRAF p.Pro14Arg

c.41C>G · rs397507455 · VCV40334

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1316 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00231%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.1316	likely benign
REVEL	0.093	moderately benign-leaning
SaProt	LLR -6.77	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.3	GERP 0.47, phastCons 1
Overall
CADD	17.08	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — 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 0.00231% European (non-Finnish) · 23/994,514 alleles

Filtering AF 0.00154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00129%

Overall 0.0017% 23/1,354,156 alleles · very rare exomes 22/1,203,410 · genomes 1/150,746 · 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.Pro14Arg
Coding: c.41C>G
MANE Select: NM_004333
dbSNP: rs397507455
Type: single nucleotide variant
Location: chr7:140924663 (GRCh38)
Gene constraint: LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.87 · 135 PDB
Residue 14: 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.Pro14Leu Uncertain significance ★★ ⚠ same residue
BRAF p.Pro14= Likely benign ★ 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-pro14arg (accessed [today's date]).

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