Is BRAF p.Pro25= (c.75C>G) pathogenic?

BRAF p.Pro25= (c.75C>G) is classified Likely benign in BRAF (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-28). Very rare (popmax 0.00397%, amr); Associated with Cardiovascular phenotype.

What condition is associated with BRAF p.Pro25= (c.75C>G)?

BRAF p.Pro25= (c.75C>G) is associated with Cardiovascular phenotype, RASopathy (ClinVar).

How common is BRAF p.Pro25= (c.75C>G) in the general population?

BRAF p.Pro25= (c.75C>G) is very rare (popmax 0.00397%, amr) (gnomAD).

BRAF p.Pro25=

c.75C>G · rs1200645704 · VCV1759725

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00397%, amr)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.21	GERP 1, phastCons 0.96
Overall
CADD	12.45	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00397% Admixed American · 2/50,412 alleles

Filtering AF 0.000658% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000246%

Overall 0.000726% 11/1,514,386 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00397%	25,206
Remaining individualsnot grpmax-eligible	0.00169%	59,018
South Asian	0.0012%	83,498
European (non-Finnish)	0.000618%	161,682

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.Pro25=
Coding: c.75C>G
MANE Select: NM_004333
dbSNP: rs1200645704
Type: single nucleotide variant
Location: chr7:140924629 (GRCh38)
Gene constraint: LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.87 · 135 PDB
Residue 25: the 'disordered' region

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

Disease context

Cardiovascular phenotype — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: RASopathy

Similar variants

BRAF p.Pro25Ser Uncertain significance ★★ ⚠ same residue
BRAF p.Pro25Leu Uncertain significance ★ ⚠ same residue
BRAF p.Pro25Thr 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-pro25 (accessed [today's date]).

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