Is BRAF p.Met689Val (c.2065A>G) pathogenic?

BRAF p.Met689Val (c.2065A>G) is classified Uncertain significance in BRAF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-11-27). AlphaMissense: ambiguous (0.4637); Very rare (popmax 0.00267%, afr); Associated with RASopathy.

What condition is associated with BRAF p.Met689Val (c.2065A>G)?

BRAF p.Met689Val (c.2065A>G) is associated with RASopathy, cardiofaciocutaneous syndrome 1 (ClinVar).

How common is BRAF p.Met689Val (c.2065A>G) in the general population?

BRAF p.Met689Val (c.2065A>G) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about BRAF p.Met689Val (c.2065A>G)?

AlphaMissense predicts ambiguous (score 0.4637) — an in-silico prediction, not a clinical call.

BRAF p.Met689Val

c.2065A>G · rs1028549781 · VCV2098351

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4637 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.4637	ambiguous
REVEL	0.604	indeterminate
SaProt	LLR -10.76	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 4, phastCons 1
Overall
CADD	24.3	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 · 2/74,926 alleles

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

Overall 0.000186% 3/1,613,520 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00267%	37,463
European (non-Finnish)	8.47e-05%	1,179,954

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.Met689Val
Coding: c.2065A>G
MANE Select: NM_004333
dbSNP: rs1028549781
Type: single nucleotide variant
Location: chr7:140739874 (GRCh38)
Gene constraint: LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.87 · 135 PDB
Residue 689: 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

Also linked: cardiofaciocutaneous syndrome 1

Similar variants

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
BRAF p.Gly469Glu 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-met689val (accessed [today's date]).

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