Is BRAF p.Arg354Gln (c.1061G>A) pathogenic?

BRAF p.Arg354Gln (c.1061G>A) is classified Uncertain significance in BRAF (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-15). AlphaMissense: ambiguous (0.3559); Very rare (popmax 0.00223%, eas); Associated with melanoma, cutaneous malignant, susceptibility to, 1.

What condition is associated with BRAF p.Arg354Gln (c.1061G>A)?

BRAF p.Arg354Gln (c.1061G>A) is associated with melanoma, cutaneous malignant, susceptibility to, 1, colorectal cancer, cardiofaciocutaneous syndrome 1 (ClinVar).

How common is BRAF p.Arg354Gln (c.1061G>A) in the general population?

BRAF p.Arg354Gln (c.1061G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about BRAF p.Arg354Gln (c.1061G>A)?

AlphaMissense predicts ambiguous (score 0.3559) — an in-silico prediction, not a clinical call.

BRAF p.Arg354Gln

c.1061G>A · rs1158980679 · VCV1320770

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3559 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

melanoma, cutaneous malignant, susceptibility to, 1

Computational evidence

Protein change
AlphaMissense	0.3559	ambiguous
REVEL	0.418	indeterminate
SaProt	LLR -7.19	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	33.0	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 0.00223% East Asian · 1/44,864 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.00031% 5/1,613,300 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,864
African / African-American	0.00134%	74,640
South Asian	0.0011%	91,060
European (non-Finnish)	0.00017%	589,957

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.Arg354Gln
Coding: c.1061G>A
MANE Select: NM_004333
dbSNP: rs1158980679
Type: single nucleotide variant
Location: chr7:140794387 (GRCh38)
Gene constraint: LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.87 · 135 PDB
Residue 354: the 'disordered' region

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

Disease context

melanoma, cutaneous malignant, susceptibility to, 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: colorectal cancer cardiofaciocutaneous syndrome 1 Noonan syndrome 1 lung cancer 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-arg354gln (accessed [today's date]).

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