NRAS p.Leu53=
c.159G>A · rs114668710 · VCV164807
ClinGen expert panel — RASopathy VCEP
Benign for RASopathy. Applied ACMG criteria (verbatim):
BA1
Curation rationale (ClinGen, verbatim)
The NM_002524.5:c.159G>A variant is a synonymous (silent) variant (p.Leu53=) that is not predicted by SpliceAI to impact splicing, however, this nucleotide is highly conserved. The filtering allele frequency (the lower threshold of the 95% CI of 25/19928) of the c.159G>A variant in NRAS is 0.0009003 for East Asian chromosomes by gnomAD v2.1.1, which is higher than the ClinGen RASopathy VCEP threshold (≥0.0005) for BA1, and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as benign for autosomal dominant RASopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen RASopathy VCEP: BA1. (ClinGen RASopathy VCEP specifications 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 | — | not assessed · no allele here is in the release |
|---|---|---|
| Constraint at this position | ||
| Conservation | phyloP 4 | GERP 1.7, phastCons 1 |
| Overall | ||
| CADD | 13.65 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| East Asiangrpmax | 0.0618% | 1,618 |
| Remaining individualsnot grpmax-eligible | 0.00353% | 28,367 |
| European (non-Finnish) | 8.91e-05% | 1,122,562 |
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
- NRAS
- Protein
- p.Leu53=
- Coding
- c.159G>A
- MANE Select
- NM_002524
- dbSNP
- rs114668710
- Type
- single nucleotide variant
- Location
- chr1:114713931 (GRCh38)
- Gene constraint
- LOEUF 0.55 · pLI 0.94 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 92.56 · 36 PDB
- Residue 53
- a β-strand
Similar variants
- NRAS p.Gly12Ser Pathogenic ★★★ same condition
- NRAS p.Gly60Glu Pathogenic ★★★ same condition
- NRAS p.Ile24Asn Likely pathogenic ★★★ same condition
- NRAS p.Thr50Ile Pathogenic ★★★ ⚠ same condition
- NRAS p.Thr58Ile Pathogenic ★★★ same condition
- NRAS p.Ala11Thr Uncertain significance ★★★ ⚠ same condition
- NRAS p.Ala91Val Uncertain significance ★★★ ⚠ same condition
- NRAS p.Arg123Lys Uncertain significance ★★★ ⚠ 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/nras-p-leu53 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown