Is BRAF p.Pro402His (c.1205C>A) pathogenic?

BRAF p.Pro402His (c.1205C>A) is classified Uncertain significance in BRAF (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-12-06). AlphaMissense: ambiguous (0.5034); Ultra-rare (popmax 0.033%, mid); Associated with hypertrophic cardiomyopathy.

What condition is associated with BRAF p.Pro402His (c.1205C>A)?

BRAF p.Pro402His (c.1205C>A) is associated with hypertrophic cardiomyopathy, colorectal cancer, cardiofaciocutaneous syndrome 1 (ClinVar).

How common is BRAF p.Pro402His (c.1205C>A) in the general population?

BRAF p.Pro402His (c.1205C>A) is ultra-rare (popmax 0.033%, mid) (gnomAD).

What do computational predictors say about BRAF p.Pro402His (c.1205C>A)?

AlphaMissense predicts ambiguous (score 0.5034) — an in-silico prediction, not a clinical call.

BRAF p.Pro402His

c.1205C>A · rs199927105 · VCV691718

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

AlphaMissense

ambiguous

0.5034 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, mid)

Conditions

hypertrophic cardiomyopathy

Computational evidence

Protein change
AlphaMissense	0.5034	ambiguous
REVEL	0.402	indeterminate
SaProt	LLR -8.28	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 3.5, phastCons 1
Overall
CADD	27.9	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% Middle Eastern · 2/6,060 alleles

Filtering AF 0.00582% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00242%

Overall 0.00304% 49/1,614,042 alleles · ultra-rare exomes 48/1,461,794 · genomes 1/152,248 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.033%	3,030
Remaining individualsnot grpmax-eligible	0.0048%	20,836
East Asian	0.00446%	22,433
South Asian	0.00439%	22,769
European (non-Finnish)	0.00314%	31,892
Admixed American	0.00167%	60,016

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.Pro402His
Coding: c.1205C>A
MANE Select: NM_004333
dbSNP: rs199927105
Type: single nucleotide variant
Location: chr7:140783130 (GRCh38)
Gene constraint: LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 67.87 · 135 PDB
Residue 402: the 'disordered' region

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

Disease context

hypertrophic cardiomyopathy — 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 Noonan syndrome Noonan syndrome and Noonan-related syndrome RASopathy

Similar variants

BRAF p.Pro402Arg Uncertain significance ★★ ⚠ same residue
BRAF p.Pro402= Likely benign ★★ same residue
BRAF p.Pro402Leu Uncertain significance ★ ⚠ same residue
BRAF p.Pro402Ser 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

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-pro402his (accessed [today's date]).

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