ClinGen expert panel — RASopathy VCEP
Pathogenic for RASopathy. Applied ACMG criteria (verbatim):
PM2 PS2_VeryStrong PS4_Supporting PM5_Strong PP2
Curation rationale (ClinGen, verbatim)
The c.775T>G (p.Ser259Ala) variant in RAF1 was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). It has been reported as a confirmed de novo occurrence in 2 probands (PS2_VeryStrong; SCV000808501.1). The variant has been identified in 1 proband with Noonan syndrome (PS4_Supporting; SCV000710868.2). At least 2 other pathogenic missense variants have been previously identified at the Ser259 codon of RAF1 which may indicate that this residue is critical to the function of the protein (PM5_Strong; ClinVar 40601, 44633). A functional assay has been performed on c.775T>G (p.Ser259Ala), but given that it is not currently an approved assay outlined by the RASopathy VCEP, it has not been assessed for PS3 at this time (PMID:23391722). Finally, the 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 missense variants are common (PP2; PMID: 29493581). Of note, this variant has also been observed in association with somatic malignancies; however, analysis and classification of somatic variation is currently not used to inform germline classifications for the RASopathies. In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PS2_VeryStrong, PS4_Supporting, PM5_Strong, PM2, PP2.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.8728 | likely pathogenic ✓ concordant with ClinVar · top 9% in RAF1 |
|---|---|---|
| REVEL | 0.601 | indeterminate |
| SaProt | LLR -9.72 | tolerated |
| ⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call. | ||
| 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 | 27.5 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
Population frequency
Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.
Variant & gene context
- Gene
- RAF1
- Protein
- p.Ser259Ala
- Coding
- c.775T>G
- MANE Select
- NM_002935 · reported on NM_002880
- dbSNP
- rs3730271
- Type
- single nucleotide variant
- Location
- chr3:12604195 (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 5
Similar variants
- RAF1 p.Ser259Thr Pathogenic ★★★ same residue
- RAF1 p.Ser259Tyr Pathogenic ★★★ same residue
- RAF1 p.Ser259Cys Pathogenic/Likely pathogenic ★★ same residue
- RAF1 p.Ser259Phe Pathogenic ★★ same residue
- RAF1 p.Ser259Pro Pathogenic/Likely pathogenic ★★ same residue
- RAF1 p.Arg256Ser Likely pathogenic ★★★ same condition
- RAF1 p.Gly361Ala Pathogenic ★★★ ⚠ same condition
- RAF1 p.Leu613Val 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-ser259ala (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown