RAF1 p.Ser257Pro
c.769T>C · rs727505017 · VCV40600
ClinGen expert panel — RASopathy VCEP
Likely Pathogenic for RASopathy. Applied ACMG criteria (verbatim):
PM6 PM2 PS4_Moderate PP2
Curation rationale (ClinGen, verbatim)
The c.769T>C (p.Ser257Pro) variant in RAF1 was absent from large population studies (PM2; gnomAD.broadinstitute.org). It has been identified in 3 patients with clinical features of a RASopathy (PS4_Moderate, SCV000206160.5; SCV000209015.10; PMID 23321623). In one proband the variant occurred de novo without parental confirmation (PM6). A different pathogenic missense variant has been previously identified at this codon which may indicate that this residue is critical to the function of the protein (PM5; ClinVar 13957) Furthermore, the p.Ser257Pro variant is located in RAF1, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as likely pathogenic for RASopathies in an autosomal dominant manner. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS4_Moderate, PM1, PM2, PM6, PP2.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9797 | likely pathogenic ✓ concordant with ClinVar · top 1% in RAF1 |
|---|---|---|
| REVEL | 0.667 | pathogenic-leaning |
| SaProt | LLR -7.78 | tolerated |
| ⇒ AlphaMissense and REVEL call this damaging; SaProt does not. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 11 | GERP 2.8, phastCons 1 |
| Overall | ||
| CADD | 29.3 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
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
- RAF1
- Protein
- p.Ser257Pro
- Coding
- c.769T>C
- MANE Select
- NM_002935 · reported on NM_002880
- dbSNP
- rs727505017
- Type
- single nucleotide variant
- Location
- chr3:12604201 (GRCh38)
- Structure
- AlphaFold pLDDT 90.69 · 11 PDB
Disease context
RASopathy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: Noonan syndrome
Similar variants
- RAF1 p.Ser257Leu Pathogenic ★★★ same residue
- RAF1 p.Ser257Thr Likely pathogenic ★★ ⚠ same residue
- RAF1 p.Ser257= Likely benign ★★ same residue
- RAF1 p.Ser257Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
- RAF1 p.Arg256Ser Likely pathogenic ★★★ same condition
- RAF1 p.Gly361Ala Pathogenic ★★★ ⚠ same condition
- RAF1 p.Leu613Val Pathogenic ★★★ ⚠ same condition
- RAF1 p.Pro261Ser 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/raf1-p-ser257pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown