RAF1 p.Leu613Val
c.1837C>G · rs80338797 · VCV13960
ClinGen expert panel — RASopathy VCEP
Pathogenic for RASopathy. Applied ACMG criteria (verbatim):
PS2_VeryStrong PM2_Supporting PS3_Moderate PS4
Curation rationale (ClinGen, verbatim)
The c.1837C>G (p.Leu613Val) variant in the RAF1 gene is a missense variant predicted to cause substitution of leucine by valine at amino acid 613. This variant is absent from gnomAD v2 (PM2_Supporting). The variant has been reported in at least one confirmed de novo case in an individual with clinical features of a RASopathy (PS2_VeryStrong; PMID:17603483), and its prevalence in affecteds is statistically increased over controls (PS4). In vitro functional studies also provide some evidence that the p.Leu613Val variant may impact protein function (PS3; PMID: 7603482, 17603483, 22826437). 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_VeryStrong, PS4, PS3_Moderate, 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 | 0.5072 | ambiguous |
|---|---|---|
| REVEL | 0.579 | indeterminate |
| SaProt | LLR -4.74 | tolerated |
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 5.8 | GERP 1.7, phastCons 1 |
| Overall | ||
| CADD | 24.1 | 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.Leu613Val
- Coding
- c.1837C>G
- MANE Select
- NM_002935 · reported on NM_002880
- dbSNP
- rs80338797
- Type
- single nucleotide variant
- Location
- chr3:12584624 (GRCh38)
- Structure
- AlphaFold pLDDT 90.69 · 11 PDB
Similar variants
- RAF1 p.Leu613fs Uncertain significance ★★ same residue
- RAF1 p.Leu613Ile Likely pathogenic ★ ⚠ same residue
- RAF1 p.Arg256Ser Likely pathogenic ★★★ same condition
- RAF1 p.Gly361Ala Pathogenic ★★★ ⚠ same condition
- RAF1 p.Pro261Ser Pathogenic ★★★ ⚠ same condition
- RAF1 p.Ser257Leu Pathogenic ★★★ same condition
- RAF1 p.Ser257Pro Likely pathogenic ★★★ same condition
- RAF1 p.Ser259Ala 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-leu613val (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown