Is BRAF p.Met186Ile (c.558G>A) pathogenic?

BRAF p.Met186Ile (c.558G>A) is classified Uncertain significance in BRAF (ClinVar, Single submitter, 1 submitter; last evaluated 2021-02-21). AlphaMissense: ambiguous (0.4969); Absent from gnomAD v4.1; Associated with RASopathy.

What condition is associated with BRAF p.Met186Ile (c.558G>A)?

BRAF p.Met186Ile (c.558G>A) is associated with RASopathy (ClinVar).

How common is BRAF p.Met186Ile (c.558G>A) in the general population?

BRAF p.Met186Ile (c.558G>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRAF p.Met186Ile (c.558G>A)?

AlphaMissense predicts ambiguous (score 0.4969) — an in-silico prediction, not a clinical call.

BRAF p.Met186Ile

c.558G>A · rs2129048397 · VCV1411217

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4969 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.4969	ambiguous
REVEL	0.313	indeterminate
SaProt	LLR -7.58	tolerated
Splicing
SpliceAI	Δ0.20	donor loss, 50 bp away · masked 0 · deltas
Pangolin	Δ0.21	loss · gain 0.00 · agrees with SpliceAI · independent
Constraint at this position
Conservation	phyloP 5.9	GERP 3.6, phastCons 1
Overall
CADD	24.5	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.Met186Ile
Coding: c.558G>A
MANE Select: NM_004333
dbSNP: rs2129048397
Type: single nucleotide variant
Location: chr7:140808942 (GRCh38)
Gene constraint: LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.87 · 135 PDB
Residue 186: the rbd domain; an α-helix

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.Met186Lys 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
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-met186ile (accessed [today's date]).

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