Is BRAF p.Pro25Ser (c.73C>T) pathogenic?

BRAF p.Pro25Ser (c.73C>T) is classified Uncertain significance in BRAF (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-10-10). AlphaMissense: likely benign (0.0881); Very rare (popmax 0.00198%, amr); Associated with RASopathy.

What condition is associated with BRAF p.Pro25Ser (c.73C>T)?

BRAF p.Pro25Ser (c.73C>T) is associated with RASopathy (ClinVar).

How common is BRAF p.Pro25Ser (c.73C>T) in the general population?

BRAF p.Pro25Ser (c.73C>T) is very rare (popmax 0.00198%, amr) (gnomAD).

What do computational predictors say about BRAF p.Pro25Ser (c.73C>T)?

AlphaMissense predicts likely benign (score 0.0881) — an in-silico prediction, not a clinical call.

BRAF p.Pro25Ser

c.73C>T · rs730880412 · VCV180782

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0881 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00198%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

RASopathy

Computational evidence

Protein change
AlphaMissense	0.0881	likely benign
REVEL	0.146	moderately benign-leaning
SaProt	LLR -6.94	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1.1, phastCons 1
Overall
CADD	20.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00198% Admixed American · 1/50,504 alleles

Filtering AF 2.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000294% 4/1,362,002 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00198%	50,504
Remaining individualsnot grpmax-eligible	0.00169%	59,028
European (non-Finnish)	0.000177%	565,119

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.Pro25Ser
Coding: c.73C>T
MANE Select: NM_004333
dbSNP: rs730880412
Type: single nucleotide variant
Location: chr7:140924631 (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

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

Similar variants

BRAF p.Pro25= Likely benign ★★ 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-pro25ser (accessed [today's date]).

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