HRAS p.Ala59Ser
c.175G>T · rs727503093 · VCV1334242
ClinGen expert panel — RASopathy VCEP
Uncertain Significance for RASopathy. Applied ACMG criteria (verbatim):
PM2 PM1 PP2
Curation rationale (ClinGen, verbatim)
The c.175G>T (p.Ala59Ser) variant in HRAS was absent from large population studies (PM2; gnomad.broadinstitute.org). It was identified in 1 fetus with clinical features of a RASopathy; however, it was also observed in the proband’s unaffected mother (PS4 not met; Hospital for Sick Children internal data). The variant is located in HRAS, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). 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 HRAS (PM1; PMID: 29493581). Of note, 3 different likely pathogenic missense variants have been previously reported at this codon of HRAS (p.Ala59Thr, ClinVar ID: 40435; p.Ala59Leu, and p.Ala59Phe), which may indicate that this residue is critical to the function of the protein; however, these variants have not yet met criteria to be classified as pathogenic (PM5 not met). In summary, the clinical significance of the p.Ala59Ser variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PM1, PM2, PP2.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.9532 | likely pathogenic |
|---|---|---|
| REVEL | 0.694 | pathogenic-leaning |
| SaProt | LLR -12.83 | 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 5.8 | GERP 1.9, phastCons 1 |
| Regional constraint | o/e 0.65 | unconstrained · MANE · 435 bp · p 0.0016 · regional, not allelic |
| Overall | ||
| CADD | 21.6 | PHRED · no single calibrated threshold — expert panels disagree |
ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification
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
- HRAS
- Protein
- p.Ala59Ser
- Coding
- c.175G>T
- MANE Select
- NM_005343
- dbSNP
- rs727503093
- Type
- single nucleotide variant
- Location
- chr11:533881 (GRCh38)
- Gene constraint
- LOEUF 0.893 · pLI 0.02 · ClinGen HI 0/3 (gnomAD)
- Structure
- AlphaFold pLDDT 92.50 · 256 PDB
- Residue 59
- a binding site
Similar variants
- HRAS p.Ala59Thr Likely pathogenic ★★★ same residue
- HRAS p.Ala59= Likely benign ★★ same residue
- HRAS p.Ala59Leu Likely pathogenic ★ same residue
- HRAS p.Ala59Gly Pathogenic ★★ same residue
- HRAS p.Gly12Ser Pathogenic ★★★ same condition
- HRAS p.Gly13Cys Pathogenic ★★★ same condition
- HRAS p.Lys117Arg Pathogenic ★★★ same condition
- HRAS p.Thr58Ile 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/hras-p-ala59ser (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown