Is BRAF p.Val471Phe (c.1411G>T) pathogenic?

BRAF p.Val471Phe (c.1411G>T) is classified Pathogenic/Likely pathogenic in BRAF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-05-17). AlphaMissense: likely pathogenic (0.9991); Absent from gnomAD v4.1; Associated with RASopathy.

What condition is associated with BRAF p.Val471Phe (c.1411G>T)?

BRAF p.Val471Phe (c.1411G>T) is associated with RASopathy (ClinVar).

How common is BRAF p.Val471Phe (c.1411G>T) in the general population?

BRAF p.Val471Phe (c.1411G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRAF p.Val471Phe (c.1411G>T)?

AlphaMissense predicts likely pathogenic (score 0.9991) — an in-silico prediction, not a clinical call.

BRAF p.Val471Phe

c.1411G>T · rs121913376 · VCV40367

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9991 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

ClinGen expert panel — RASopathy VCEP

Pathogenic for RASopathy. Applied ACMG criteria (verbatim):

PM6 PM2 PS4_Supporting PS3 PM1 PP2 PP3

Curation rationale (ClinGen, verbatim)

The c.1411G>T (p.Val471Phe) variant in BRAF was absent from large population studies (PM2; gnomAD.broadinstitute.org). It has been identified in at least 2 individuals diagnosed with RASopathies (PS4_Supporting; PMID: 22495831, 30937965). One of these cases was shown to be a de novo occurrence without maternity or paternity confirmed (PM6). In vitro functional studies provide some evidence that the p.Val471Phe variant may impact protein function (PS3; PMID: 25348715). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; 29493581). Computational prediction tools and conservation analysis suggest that the p.Val471Phe variant in BRAF may impact the protein (PP3). This variant is located in BRAF, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies. RASopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PS3, PS4_Supporting, PM1, PM2, PM6, PP2, PP3.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.9991	likely pathogenic ✓ concordant with ClinVar · top 7% in BRAF
REVEL	0.975	strongly pathogenic-leaning
SaProt	LLR -14.53	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 3.8, phastCons 1
Overall
CADD	31.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: BRAF
Protein: p.Val471Phe
Coding: c.1411G>T
MANE Select: NM_004333
dbSNP: rs121913376
Type: single nucleotide variant
Location: chr7:140781597 (GRCh38)
Gene constraint: LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.87 · 135 PDB
Residue 471: a β-strand; a binding site; 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.Val471Ile Likely pathogenic ★★ same residue
BRAF p.Val471= 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-val471phe (accessed [today's date]).

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