ClinGen expert panel — RASopathy VCEP
Benign for RASopathy. Applied ACMG criteria (verbatim):
BP7 BP4 BA1
Curation rationale (ClinGen, verbatim)
The c.519T>C variant in the KRAS gene is a synonymous (silent) variant (p.Asp173=) at a nucleotide that is not conserved as shown by UCSC browser, and not predicted by SpliceAI to impact splicing (BP4, BP7). The filtering allele frequency in gnomAD v2.1.1 is 0.2201 (28382/128282 alleles with 3073 homozygotes) in the European (non-Finnish) population, which is higher than the ClinGen RASopathy VCEP threshold (>0.0005) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets criteria to be classified as benign for autosomal dominant RASopathies based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy Variant Curation Expert Panel: BA1, BP4, BP7 (Specification Version 2.3, 12/3/2024)
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Splicing | ||
| SpliceAI | <0.2 | all four deltas below 0.2 · A>T here scores Δ0.87 · evaluated, not missing |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 1.1 | GERP 0.57, phastCons 0.99 |
| Overall | ||
| CADD | 7.906 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Amishnot grpmax-eligible | 39.6% | 3 |
| Middle Easterngrpmax | 23.7% | 4 |
| European (non-Finnish) | 21.7% | 5 |
| Remaining individualsnot grpmax-eligible | 20.1% | 5 |
| South Asian | 19.3% | 5 |
| Admixed American | 18% | 6 |
| African / African-American | 17.6% | 6 |
| Ashkenazi Jewishnot grpmax-eligible | 16.3% | 6 |
| Finnishnot grpmax-eligible | 16% | 6 |
| East Asian | 11.4% | 9 |
Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.
Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.
Variant & gene context
- Gene
- KRAS
- Protein
- p.Asp173=
- Coding
- c.519T>C
- MANE Select
- NM_004985
- dbSNP
- rs1137282
- Type
- single nucleotide variant
- Location
- chr12:25209843 (GRCh38)
- Gene constraint
- LOEUF 0.264 · pLI 1.00 (gnomAD)
- Structure
- AlphaFold pLDDT 91.65 · 549 PDB
- Residue 173
- the 'hypervariable region' region
Similar variants
- KRAS p.Asp153Val Pathogenic ★★★ same condition
- KRAS p.Gln22Arg Pathogenic ★★★ same condition
- KRAS p.Gly60Arg Pathogenic ★★★ same condition
- KRAS p.Lys5Asn Pathogenic ★★★ same condition
- KRAS p.Pro34Leu Pathogenic ★★★ same condition
- KRAS p.Ser65Ile Likely pathogenic ★★★ same condition
- KRAS p.Thr58Ile Pathogenic ★★★ same condition
- KRAS p.Val14Ile 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/kras-p-asp173 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown