Is BRAF p.Gln257Arg (c.770A>G) pathogenic?

BRAF p.Gln257Arg (c.770A>G) is classified Pathogenic in BRAF (ClinVar, Expert panel, 35 submitters; last evaluated 2017-04-03). AlphaMissense: likely pathogenic (0.9831); Very rare (popmax 8.48e-05%, nfe); Associated with cardiofaciocutaneous syndrome.

What condition is associated with BRAF p.Gln257Arg (c.770A>G)?

BRAF p.Gln257Arg (c.770A>G) is associated with cardiofaciocutaneous syndrome, colorectal cancer, cardiofaciocutaneous syndrome 1 (ClinVar).

How common is BRAF p.Gln257Arg (c.770A>G) in the general population?

BRAF p.Gln257Arg (c.770A>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about BRAF p.Gln257Arg (c.770A>G)?

AlphaMissense predicts likely pathogenic (score 0.9831) — an in-silico prediction, not a clinical call.

BRAF p.Gln257Arg

c.770A>G · rs180177035 · VCV13973

Pathogenic Expert panel

Classification

Pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 35 submitters

AlphaMissense

likely pathogenic

0.9831 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cardiofaciocutaneous syndrome

ClinGen expert panel — RASopathy VCEP

Pathogenic for cardiofaciocutaneous syndrome. Applied ACMG criteria (verbatim):

PM2 PS2_VeryStrong PS3 PM1 PP2 PP3

Curation rationale (ClinGen, verbatim)

The c.770A>G (p.Gln257Arg) variant in BRAF has been reported in the literature as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID:18042262, PMID:17551924, PMID:16474404). In vitro functional studies provide some evidence that the p.Q257R variant may impact protein function (PS3; PMID:18413255; PMID:19376813). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the BRAF gene, 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). Furthermore, this variant is located in exon 6, which has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID:29493581). Computational prediction tools and conservation analysis suggest that the p.Q257R variant may impact the protein (PP3). In summary, this variant meets criteria to be classified as pathogenic for cardio-facio-cutaneous syndrome in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PP2, PP3, PM1, PM2, PS3, PS2_VeryStrong.

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

Computational evidence

Protein change
AlphaMissense	0.9831	likely pathogenic ✓ concordant with ClinVar
REVEL	0.838	moderately pathogenic-leaning
SaProt	LLR -8.50	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	Δ0.21	acceptor loss, 10 bp away · masked 0 · deltas
Constraint at this position
Conservation	phyloP 7.8	GERP 3.8, phastCons 1
Overall
CADD	27.9	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 8.48e-05% European (non-Finnish) · 1/1,179,918 alleles

Overall 6.84e-05% 1/1,461,672 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.Gln257Arg
Coding: c.770A>G
MANE Select: NM_004333
dbSNP: rs180177035
Type: single nucleotide variant
Location: chr7:140801502 (GRCh38)
Gene constraint: LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.87 · 135 PDB
Residue 257: a β-strand; a UniProt-annotated variant site (in cfc1)

Full BRAF gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

cardiofaciocutaneous syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: colorectal cancer cardiofaciocutaneous syndrome 1 melanoma, cutaneous malignant, susceptibility to, 1 Noonan syndrome 1 lung cancer Noonan syndrome 7 LEOPARD syndrome 3 Noonan syndrome and Noonan-related syndrome RASopathy

Similar variants

BRAF p.Gln257Lys Pathogenic/Likely pathogenic ★★ same residue
BRAF p.Gln257His 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.Gly265Arg Likely pathogenic ★★★ same condition
BRAF p.Gly464Glu 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-gln257arg (accessed [today's date]).

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