Is BRAF p.Pro44Thr (c.130C>A) pathogenic?

BRAF p.Pro44Thr (c.130C>A) is classified Uncertain significance in BRAF (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-11). AlphaMissense: likely benign (0.2645); Very rare (popmax 0.000437%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with BRAF p.Pro44Thr (c.130C>A)?

BRAF p.Pro44Thr (c.130C>A) is associated with Cardiovascular phenotype (ClinVar).

How common is BRAF p.Pro44Thr (c.130C>A) in the general population?

BRAF p.Pro44Thr (c.130C>A) is very rare (popmax 0.000437%, nfe) (gnomAD).

What do computational predictors say about BRAF p.Pro44Thr (c.130C>A)?

AlphaMissense predicts likely benign (score 0.2645) — an in-silico prediction, not a clinical call.

BRAF p.Pro44Thr

c.130C>A · rs1279627804 · VCV2566898

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2645 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000437%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
AlphaMissense	0.2645	likely benign
REVEL	0.174	moderately benign-leaning
SaProt	LLR -5.92	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 11	GERP 2.6, phastCons 1
Overall
CADD	24.7	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 0.000437% European (non-Finnish) · 5/1,144,150 alleles

Filtering AF 0.000128% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.3e-05%

Overall 0.000327% 5/1,529,630 alleles · very rare exomes 4/1,377,880 · genomes 1/151,750 · joint denominator

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.Pro44Thr
Coding: c.130C>A
MANE Select: NM_004333
dbSNP: rs1279627804
Type: single nucleotide variant
Location: chr7:140924574 (GRCh38)
Gene constraint: LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.87 · 135 PDB
Residue 44: an α-helix

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

Similar variants

BRAF p.Pro44Leu Uncertain significance ★ ⚠ same residue
BRAF p.Pro44= Likely benign ★ same residue
BRAF p.Asn236Lys Likely pathogenic ★★ same condition
BRAF p.Gln262Arg Pathogenic/Likely pathogenic ★★ same condition
BRAF p.Glu501Lys Pathogenic/Likely pathogenic ★★ same condition
BRAF c.2127+4A>G Uncertain significance ★★ same condition
BRAF p.Ala27Gly Uncertain significance ★★ ⚠ same condition
BRAF p.Ala42Ser Uncertain significance ★★ ⚠ 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-pro44thr (accessed [today's date]).

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