RAF1 p.Thr491Ile
c.1472C>T · rs80338799 · VCV21342
ClinGen expert panel — RASopathy VCEP
Pathogenic for RASopathy. Applied ACMG criteria (verbatim):
PM2_Supporting PS3_Moderate PS2 PS4 PM1 PP3
Curation rationale (ClinGen, verbatim)
The c.1472C>T (p.Thr491Ile variant in the RAF1 gene is a missense variant predicted to cause substitution of threonine by isoleucine at amino acid 491. This variant is absent from gnomAD v2 (PM2_Supporting). Computational prediction tools and conservation analysis suggest that the p.Thr491Ile variant may impact the RAF1 protein (PP3). In vitro functional studies provide some evidence that the p.Thr491Ile variant may impact protein function (PS3_Moderate; PMID:20679480). 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). The variant has also been identified as a de novo occurrence with confirmed parental relationships in an individual with features of RASopathy (PS2), and the prevalence of the variant in affected individuals is significantly increased compared with the prevalence in controls (PS4). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathies based on ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: PS2, PS4, PM1, PS3_Moderate, PP3, PM2_Supporting. (Specification Version 2.3, 12/3/2024)
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9957 | likely pathogenic ✓ concordant with ClinVar · top 1% in RAF1 |
|---|---|---|
| REVEL | 0.859 | moderately pathogenic-leaning |
| SaProt | LLR -13.50 | damaging |
| ⇒ AlphaMissense, REVEL and SaProt all call this damaging. | ||
| 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 | 32.0 | 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.Thr491Ile
- Coding
- c.1472C>T
- MANE Select
- NM_002935 · reported on NM_002880
- dbSNP
- rs80338799
- Type
- single nucleotide variant
- Location
- chr3:12585745 (GRCh38)
- Structure
- AlphaFold pLDDT 90.69 · 11 PDB
Similar variants
- RAF1 p.Thr491Arg Likely pathogenic ★★ same residue
- RAF1 p.Thr491Pro Uncertain significance ★ ⚠ same residue
- RAF1 p.Thr491= Likely benign ★ 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
- RAF1 p.Ser257Leu 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-thr491ile (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown