Is BRAF p.Leu646Val (c.1936C>G) pathogenic?

BRAF p.Leu646Val (c.1936C>G) is classified Uncertain significance in BRAF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-08-07). AlphaMissense: ambiguous (0.4356); Very rare (popmax 0.00267%, afr); Associated with RASopathy.

What condition is associated with BRAF p.Leu646Val (c.1936C>G)?

BRAF p.Leu646Val (c.1936C>G) is associated with RASopathy (ClinVar).

How common is BRAF p.Leu646Val (c.1936C>G) in the general population?

BRAF p.Leu646Val (c.1936C>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about BRAF p.Leu646Val (c.1936C>G)?

AlphaMissense predicts ambiguous (score 0.4356) — an in-silico prediction, not a clinical call.

BRAF p.Leu646Val

c.1936C>G · rs758803218 · VCV2866122

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4356 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

2/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.4356	ambiguous
REVEL	0.751	pathogenic-leaning
SaProt	LLR -11.95	damaging
⇒ REVEL and SaProt both call this damaging; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.3, phastCons 1
Overall
CADD	23.8	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 0.00267% African / African-American · 2/74,858 alleles

Filtering AF 0.000443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000186% 3/1,612,648 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,429
European (non-Finnish)	8.48e-05%	1,179,496

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.Leu646Val
Coding: c.1936C>G
MANE Select: NM_004333
dbSNP: rs758803218
Type: single nucleotide variant
Location: chr7:140749343 (GRCh38)
Gene constraint: LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.87 · 135 PDB
Residue 646: an α-helix; 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.Leu646= 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
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-leu646val (accessed [today's date]).

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