Is BRAF p.Val600Leu (c.1798G>C) pathogenic?

BRAF p.Val600Leu (c.1798G>C) is classified Pathogenic/Likely pathogenic in BRAF (ClinVar, Multiple submitters, 2 submitters). AlphaMissense: likely pathogenic (0.9555); Absent from gnomAD v4.1; Associated with cardiofaciocutaneous syndrome 1.

What condition is associated with BRAF p.Val600Leu (c.1798G>C)?

BRAF p.Val600Leu (c.1798G>C) is associated with cardiofaciocutaneous syndrome 1 (ClinVar).

How common is BRAF p.Val600Leu (c.1798G>C) in the general population?

BRAF p.Val600Leu (c.1798G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRAF p.Val600Leu (c.1798G>C)?

AlphaMissense predicts likely pathogenic (score 0.9555) — an in-silico prediction, not a clinical call.

BRAF p.Val600Leu

c.1798G>C · rs121913378 · VCV376289

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9555 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

cardiofaciocutaneous syndrome 1

Computational evidence

Protein change
AlphaMissense	0.9555	likely pathogenic ✓ concordant with ClinVar
REVEL	0.592	indeterminate
SaProt	LLR -9.05	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 6.8, phastCons 1
Overall
CADD	25.1	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.

Cancer therapy — CIViC

Disease	Therapies	Level	Significance
Melanoma	Refametinib	C	Resistance
Erdheim-Chester Disease	Vemurafenib	A	Sensitivity/Response
Melanoma	Vemurafenib,Atezolizumab,Cobimetinib	A	Sensitivity/Response
Langerhans-cell Histiocytosis	Vemurafenib	B	Sensitivity/Response
Childhood Low-grade Glioma	Tovorafenib	A	Sensitivity/Response
Histiocytic Sarcoma	Dabrafenib/Trametinib Regimen	C	Sensitivity/Response
Anaplastic Thyroid Carcinoma	Dabrafenib/Trametinib Regimen	C	Sensitivity/Response
Melanoma	Encorafenib,Binimetinib	B	Sensitivity/Response

Variant & gene context

Gene: BRAF
Protein: p.Val600Leu
Coding: c.1798G>C
MANE Select: NM_004333
dbSNP: rs121913378
Type: single nucleotide variant
Location: chr7:140753337 (GRCh38)
Gene constraint: LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.87 · 135 PDB
Residue 600: an α-helix; the protein kinase domain; a UniProt-annotated variant site (in a melanoma cell line; requires 2 nucleotide substitutions); a UniProt-annotated variant site (in crc; also found in sarcoma, metastatic melanoma, ovarian serous carcinoma, pilocytic astrocytoma; somatic mutation; most common mutation; constitutive and elevated kinase activity; efficiently induces cell transformation; suppression of mutation in melanoma causes growth arrest and promotes apoptosis; loss of regulation by pmrt5)

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

Disease context

cardiofaciocutaneous syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BRAF p.Val600Gly Pathogenic ★★★ same residue
BRAF p.Val600Met Likely pathogenic ★ same residue
BRAF p.Val600Glu Conflicting classifications of pathogenicity ★ ⚠ same residue
BRAF p.Val600= Likely benign ★ same residue
BRAF p.Ala246Pro Pathogenic ★★★ same condition
BRAF p.Asn581Asp Pathogenic ★★★ same condition
BRAF p.Gln257Arg 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-val600leu (accessed [today's date]).

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