Is BRAF p.Pro343Ser (c.1027C>T) pathogenic?

BRAF p.Pro343Ser (c.1027C>T) is classified Conflicting classifications of pathogenicity in BRAF (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-05-19). AlphaMissense: ambiguous (0.5589); Ultra-rare (popmax 0.0329%, mid); Associated with RASopathy.

What condition is associated with BRAF p.Pro343Ser (c.1027C>T)?

BRAF p.Pro343Ser (c.1027C>T) is associated with RASopathy (ClinVar).

How common is BRAF p.Pro343Ser (c.1027C>T) in the general population?

BRAF p.Pro343Ser (c.1027C>T) is ultra-rare (popmax 0.0329%, mid) (gnomAD).

What do computational predictors say about BRAF p.Pro343Ser (c.1027C>T)?

AlphaMissense predicts ambiguous (score 0.5589) — an in-silico prediction, not a clinical call.

BRAF p.Pro343Ser

c.1027C>T · rs758935249 · VCV426721

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5589 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, mid)

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.5589	ambiguous
REVEL	0.476	indeterminate
SaProt	LLR -6.26	tolerated
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.23 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	GERP 3.6, phastCons 1
Overall
CADD	31.0	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 0.0329% Middle Eastern · 2/6,084 alleles

Filtering AF 0.0058% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00241%

Overall 0.00173% 28/1,613,932 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0329%	3,042
European (non-Finnish)	0.00203%	49,167
Admixed American	0.00167%	59,990
Remaining individualsnot grpmax-eligible	0.0016%	62,484

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.Pro343Ser
Coding: c.1027C>T
MANE Select: NM_004333
dbSNP: rs758935249
Type: single nucleotide variant
Location: chr7:140794421 (GRCh38)
Gene constraint: LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.87 · 135 PDB
Residue 343: 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.Pro343Leu 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-pro343ser (accessed [today's date]).

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