Is BRAF p.Arg252Pro (c.755G>C) pathogenic?

BRAF p.Arg252Pro (c.755G>C) is classified Conflicting classifications of pathogenicity in BRAF (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2023-05-05). AlphaMissense: likely pathogenic (0.9968); Absent from gnomAD v4.1; Associated with Global developmental delay.

What condition is associated with BRAF p.Arg252Pro (c.755G>C)?

BRAF p.Arg252Pro (c.755G>C) is associated with Global developmental delay, Noonan syndrome and Noonan-related syndrome (ClinVar).

How common is BRAF p.Arg252Pro (c.755G>C) in the general population?

BRAF p.Arg252Pro (c.755G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about BRAF p.Arg252Pro (c.755G>C)?

AlphaMissense predicts likely pathogenic (score 0.9968) — an in-silico prediction, not a clinical call.

BRAF p.Arg252Pro

c.755G>C · rs1325951163 · VCV451504

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9968 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Global developmental delay

Computational evidence

Protein change
AlphaMissense	0.9968	likely pathogenic
REVEL	0.78	moderately pathogenic-leaning
SaProt	LLR -17.68	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	Δ0.41	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 5.9	GERP 2.9, phastCons 1
Overall
CADD	34.0	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

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.Arg252Pro
Coding: c.755G>C
MANE Select: NM_004333
dbSNP: rs1325951163
Type: single nucleotide variant
Location: chr7:140801517 (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

Global developmental delay — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Noonan syndrome and Noonan-related syndrome

Similar variants

BRAF p.Arg252Gln Uncertain significance ★★ ⚠ same residue
BRAF p.Arg252Gly Uncertain significance ★★ ⚠ same residue
BRAF p.Arg252Ter Uncertain significance ★★ same residue
BRAF p.Gln257Arg Pathogenic ★★★ same condition
BRAF p.Gly469Glu Pathogenic ★★★ same condition
BRAF p.Leu245Phe Pathogenic ★★★ same condition
BRAF p.Leu485Ser Likely pathogenic ★★★ same condition
BRAF p.Phe247Leu 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-arg252pro (accessed [today's date]).

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