Is BRAF p.Arg146Gln (c.437G>A) pathogenic?

BRAF p.Arg146Gln (c.437G>A) is classified Conflicting classifications of pathogenicity in BRAF (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-09-24). AlphaMissense: likely benign (0.1643); Ultra-rare (popmax 0.0133%, amr); Associated with cardiofaciocutaneous syndrome 1.

What condition is associated with BRAF p.Arg146Gln (c.437G>A)?

BRAF p.Arg146Gln (c.437G>A) is associated with cardiofaciocutaneous syndrome 1, lung carcinoma, Noonan syndrome 1 (ClinVar).

How common is BRAF p.Arg146Gln (c.437G>A) in the general population?

BRAF p.Arg146Gln (c.437G>A) is ultra-rare (popmax 0.0133%, amr) (gnomAD).

What do computational predictors say about BRAF p.Arg146Gln (c.437G>A)?

AlphaMissense predicts likely benign (score 0.1643) — an in-silico prediction, not a clinical call.

BRAF p.Arg146Gln

c.437G>A · rs557241012 · VCV372564

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1643 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0133%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

cardiofaciocutaneous syndrome 1

Computational evidence

Protein change
AlphaMissense	0.1643	likely benign
REVEL	0.277	benign-leaning
SaProt	LLR -5.12	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 3.6, phastCons 1
Overall
CADD	27.4	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 0.0133% Admixed American · 8/60,012 alleles

Filtering AF 0.00661% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00482%

Overall 0.000929% 15/1,614,116 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0133%	7,501
South Asian	0.00329%	30,359
African / African-American	0.00133%	75,052
European (non-Finnish)	0.000254%	393,334

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.Arg146Gln
Coding: c.437G>A
MANE Select: NM_004333
dbSNP: rs557241012
Type: single nucleotide variant
Location: chr7:140834676 (GRCh38)
Gene constraint: LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.87 · 135 PDB

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

Also linked: lung carcinoma Noonan syndrome 1 Noonan syndrome 7 LEOPARD syndrome 3 RASopathy

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-arg146gln (accessed [today's date]).

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