Pathogenic/Likely pathogenic
Multiple submitters
Classification
Pathogenic/Likely pathogenic
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 5 submitters
AlphaMissense
likely pathogenic
0.9948 · ACMG-weighted
gnomAD v4.1
Absent
absent from gnomAD v4.1
Missense predictors
2/3 damaging
AlphaMissense, REVEL, SaProt
Conditions
3
RASopathy
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9948 | likely pathogenic ✓ concordant with ClinVar · top 1% in RAF1 |
|---|---|---|
| REVEL | 0.703 | pathogenic-leaning |
| SaProt | LLR -9.98 | 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 | 25.9 | 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
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.Ser259Pro
- Coding
- c.775T>C
- 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
Similar variants
- RAF1 p.Ser259Ala Pathogenic ★★★ same residue
- 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.Ser259_Thr260delinsArgAla Likely pathogenic 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-ser259pro (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown