Is BRAF p.Ser125= (c.375T>G) pathogenic?

BRAF p.Ser125= (c.375T>G) is classified Benign in BRAF (ClinVar, Expert panel, 12 submitters; last evaluated 2017-04-18). Rare (popmax 0.107%, eas); Associated with RASopathy.

What condition is associated with BRAF p.Ser125= (c.375T>G)?

BRAF p.Ser125= (c.375T>G) is associated with RASopathy, Noonan syndrome 7, LEOPARD syndrome 3 (ClinVar).

How common is BRAF p.Ser125= (c.375T>G) in the general population?

BRAF p.Ser125= (c.375T>G) is rare (popmax 0.107%, eas) (gnomAD).

BRAF p.Ser125=

c.375T>G · rs201507202 · VCV44825

Benign Expert panel

Classification

Benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 12 submitters

gnomAD v4.1

Rare

rare (popmax 0.107%, eas)

Conditions

RASopathy

ClinGen expert panel — RASopathy VCEP

Benign for RASopathy. Applied ACMG criteria (verbatim):

BA1

Curation rationale (ClinGen, verbatim)

The filtering allele frequency of the c.375T>G (p.Ser125=) variant in the BRAF gene is 0.054% (9/8644) of East Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

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 2.2	GERP 1.1, phastCons 1
Overall
CADD	8.288	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.107% East Asian · 48/44,878 alleles

Filtering AF 0.0829% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0743%

Overall 0.00737% 119/1,614,216 alleles · rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.107%	935
South Asian	0.0439%	2,277
Remaining individualsnot grpmax-eligible	0.0192%	5,209
Middle Eastern	0.0165%	6,062
Admixed American	0.00167%	60,022
European (non-Finnish)	0.00144%	69,413

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.Ser125=
Coding: c.375T>G
MANE Select: NM_004333
dbSNP: rs201507202
Type: single nucleotide variant
Location: chr7:140834738 (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

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

Also linked: Noonan syndrome 7 LEOPARD syndrome 3 Noonan syndrome and Noonan-related syndrome

Similar variants

BRAF p.Ser125Pro Uncertain significance ★★ ⚠ same residue
BRAF p.Ser125Phe 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

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-ser125 (accessed [today's date]).

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