BRAF p.Ile208Val
c.622A>G · rs727504571 · VCV178963
ClinGen expert panel — RASopathy VCEP
Likely Benign for RASopathy. Applied ACMG criteria (verbatim):
PP2 BS2
Curation rationale (ClinGen, verbatim)
The c.622A>G (p.Ile208Val) variant in BRAF is present in 0.00001% (2/128934) European alleles in gnomAD. The computational predictor REVEL gives a score of 0.318, which is neither above nor below the thresholds predicting a damaging or benign impact on BRAF function. This variant was observed in two healthy adult individuals who did not have clinical features of a RASopathy (SCV000205449.5; PMID:29945942). Additionally, 12 apparently unaffected parental samples were observed with this variant (BS2; SCV000329576.8, SCV001011557.1). The variant is located in the BRAF gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets the criteria to be classified as likely benign for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BS2, PP2 (RASopathy VCEP specifications version 1; 8/11/22).
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.0918 | likely benign |
|---|---|---|
| REVEL | 0.318 | indeterminate |
| SaProt | LLR -7.13 | tolerated |
| ⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 7.8 | GERP 2.5, phastCons 1 |
| Overall | ||
| CADD | 24.6 | 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
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.00267% | 37,430 |
| European (non-Finnish) | 0.00178% | 56,134 |
| South Asian | 0.0011% | 91,040 |
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.Ile208Val
- Coding
- c.622A>G
- MANE Select
- NM_004333
- dbSNP
- rs727504571
- Type
- single nucleotide variant
- Location
- chr7:140808049 (GRCh38)
- Gene constraint
- LOEUF 0.237 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 67.87 · 135 PDB
- Residue 208
- a β-strand; the rbd domain
Similar variants
- BRAF p.Ile208= Likely benign ★ 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
- BRAF p.Gly464Glu 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-ile208val (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown