Is BRAF p.Ala33Val (c.98C>T) pathogenic?

BRAF p.Ala33Val (c.98C>T) is classified Uncertain significance in BRAF (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-05-01). AlphaMissense: likely benign (0.1085); Ultra-rare (popmax 0.0227%, mid); Associated with Noonan syndrome and Noonan-related syndrome.

What condition is associated with BRAF p.Ala33Val (c.98C>T)?

BRAF p.Ala33Val (c.98C>T) is associated with Noonan syndrome and Noonan-related syndrome (ClinVar).

How common is BRAF p.Ala33Val (c.98C>T) in the general population?

BRAF p.Ala33Val (c.98C>T) is ultra-rare (popmax 0.0227%, mid) (gnomAD).

What do computational predictors say about BRAF p.Ala33Val (c.98C>T)?

AlphaMissense predicts likely benign (score 0.1085) — an in-silico prediction, not a clinical call.

BRAF p.Ala33Val

c.98C>T · rs2129153230 · VCV1334221

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1085 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0227%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Noonan syndrome and Noonan-related syndrome

Computational evidence

Protein change
AlphaMissense	0.1085	likely benign
REVEL	0.08	moderately benign-leaning
SaProt	LLR -8.93	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 0.77	GERP 1.5, phastCons 1
Overall
CADD	19.67	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 0.0227% Middle Eastern · 1/4,412 alleles

Overall 7.27e-05% 1/1,375,780 alleles · ultra-rare

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.Ala33Val
Coding: c.98C>T
MANE Select: NM_004333
dbSNP: rs2129153230
Type: single nucleotide variant
Location: chr7:140924606 (GRCh38)
Gene constraint: LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.87 · 135 PDB
Residue 33: the 'disordered' region

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

Disease context

Noonan syndrome and Noonan-related syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

BRAF p.Ala33Pro Uncertain significance ★ ⚠ same residue
BRAF p.Ala33= Likely benign ★ 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
BRAF p.Phe247Ser 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-ala33val (accessed [today's date]).

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