Is BRAF p.Ala712= (c.2136C>T) pathogenic?

BRAF p.Ala712= (c.2136C>T) is classified Benign/Likely benign in BRAF (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-12-22). Ultra-rare (popmax 0.01%, nfe); Associated with Cardiovascular phenotype.

What condition is associated with BRAF p.Ala712= (c.2136C>T)?

BRAF p.Ala712= (c.2136C>T) is associated with Cardiovascular phenotype, colorectal cancer, cardiofaciocutaneous syndrome 1 (ClinVar).

How common is BRAF p.Ala712= (c.2136C>T) in the general population?

BRAF p.Ala712= (c.2136C>T) is ultra-rare (popmax 0.01%, nfe) (gnomAD).

BRAF p.Ala712=

c.2136C>T · rs377165711 · VCV44823

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.01%, nfe)

Conditions

Cardiovascular phenotype

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.049	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.6	GERP 3.1, phastCons 1
Overall
CADD	12.5	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.01% European (non-Finnish) · 110/1,094,672 alleles

Filtering AF 0.00852% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00793%

Overall 0.00777% 111/1,429,086 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.01%	9,952
Remaining individualsnot grpmax-eligible	0.00184%	54,476

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.Ala712=
Coding: c.2136C>T
MANE Select: NM_004333
dbSNP: rs377165711
Type: single nucleotide variant
Location: chr7:140734762 (GRCh38)
Gene constraint: LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.87 · 135 PDB
Residue 712: an α-helix; the protein kinase domain

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: colorectal cancer cardiofaciocutaneous syndrome 1 melanoma, cutaneous malignant, susceptibility to, 1 Noonan syndrome 1 lung cancer Noonan syndrome 7 LEOPARD syndrome 3 RASopathy

Similar variants

BRAF p.Ala712Asp Pathogenic/Likely pathogenic ★★ same residue
BRAF p.Ala712Ser Uncertain significance ★ ⚠ same residue
BRAF p.Ala712Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
BRAF p.Ter712Cys Uncertain significance ★ same residue
BRAF p.Ala712Val Uncertain significance ★ ⚠ same residue
BRAF p.Ala246Pro Pathogenic ★★★ same condition
BRAF p.Asn581Asp Pathogenic ★★★ same condition
BRAF p.Asp594Val 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-ala712 (accessed [today's date]).

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