Is BRAF p.Pro341Ala (c.1021C>G) pathogenic?

BRAF p.Pro341Ala (c.1021C>G) is classified Uncertain significance in BRAF (ClinVar, Single submitter, 1 submitter; last evaluated 2023-08-16). AlphaMissense: ambiguous (0.4086); Ultra-rare (popmax 0.045%, sas); Associated with RASopathy.

What condition is associated with BRAF p.Pro341Ala (c.1021C>G)?

BRAF p.Pro341Ala (c.1021C>G) is associated with RASopathy (ClinVar).

How common is BRAF p.Pro341Ala (c.1021C>G) in the general population?

BRAF p.Pro341Ala (c.1021C>G) is ultra-rare (popmax 0.045%, sas) (gnomAD).

What do computational predictors say about BRAF p.Pro341Ala (c.1021C>G)?

AlphaMissense predicts ambiguous (score 0.4086) — an in-silico prediction, not a clinical call.

BRAF p.Pro341Ala

c.1021C>G · rs757653653 · VCV2904050

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4086 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.045%, sas)

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.4086	ambiguous
REVEL	0.301	indeterminate
SaProt	LLR -7.26	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.32 · evaluated, not missing
Constraint at this position
Conservation	phyloP 10	GERP 3.6, phastCons 1
Overall
CADD	25.2	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 0.045% South Asian · 41/91,072 alleles

Filtering AF 0.0341% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0302%

Overall 0.00254% 41/1,613,936 alleles · ultra-rare

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.Pro341Ala
Coding: c.1021C>G
MANE Select: NM_004333
dbSNP: rs757653653
Type: single nucleotide variant
Location: chr7:140794427 (GRCh38)
Gene constraint: LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.87 · 135 PDB
Residue 341: the 'disordered' region

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.Pro341= Conflicting classifications of pathogenicity ★ same residue
BRAF p.Pro341Gln Uncertain significance ★ ⚠ same residue
BRAF p.Pro341Leu 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

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-pro341ala (accessed [today's date]).

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