RAF1 p.Pro261Ser
c.781C>T · rs121434594 · VCV13958
ClinGen expert panel — RASopathy VCEP
Pathogenic for Noonan syndrome. Applied ACMG criteria (verbatim):
PM2 PM6_Strong PS3 PM1 PP2
Curation rationale (ClinGen, verbatim)
The c.781C>T (p.Pro261Ser) variant in RAF1 has been reported in the literature in at least 2 unconfirmed de novo occurrences in patients with clinical features of a RASopathy (PM6_Strong; PMID 17603482, 20683980). In vitro functional studies provide some evidence that the p.Pro261Leu variant may impact protein function (PS3; PMID 17603483, 17603482). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of RAF1 (PM1; PMID 29493581). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the RAF1 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 criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. ACMG/AMP criteria applied: PP2, PM1, PM2, PS3, PM6_Strong.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9986 | likely pathogenic ✓ concordant with ClinVar · top 10% in RAF1 |
|---|---|---|
| REVEL | 0.823 | moderately pathogenic-leaning |
| SaProt | LLR -5.36 | 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 12 | GERP 2.8, phastCons 1 |
| Overall | ||
| CADD | 29.6 | 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.Pro261Ser
- Coding
- c.781C>T
- MANE Select
- NM_002880
- dbSNP
- rs121434594
- Type
- single nucleotide variant
- Location
- chr3:12604189 (GRCh38)
- Gene constraint
- LOEUF 0.353 · pLI 1.00 (gnomAD)
- Structure
- AlphaFold pLDDT 68.24 · 76 PDB
- Residue 261
- the 'disordered' region; a UniProt-annotated variant site (in ns5; shows in vitro greater kinase activity and enhanced mapk1 activation than wild-type); a UniProt-annotated variant site (in ns5; shows greater kinase activity and enhanced mapk1 activation than wild-type); an α-helix
Similar variants
- RAF1 p.Pro261Ala Pathogenic/Likely pathogenic ★★ ⚠ same residue
- RAF1 p.Pro261Arg Pathogenic/Likely pathogenic ★★ ⚠ same residue
- RAF1 p.Pro261His Pathogenic/Likely pathogenic ★★ ⚠ same residue
- RAF1 p.Pro261Leu Pathogenic/Likely pathogenic ★★ ⚠ same residue
- RAF1 p.Pro261Thr Pathogenic/Likely pathogenic ★★ ⚠ same residue
- RAF1 p.Pro261= Likely benign ★ same residue
- RAF1 p.Arg256Ser Likely pathogenic ★★★ ⚠ same condition
- RAF1 p.Gly361Ala 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-pro261ser (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown