RUNX1 p.Pro425=
c.1275G>A · rs886038488 · VCV258183
ClinGen expert panel — Myeloid Malignancy VCEP
Likely Benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome. Applied ACMG criteria (verbatim):
BP7 BP4
Curation rationale (ClinGen, verbatim)
The c.1275G>A (p.Pro425=) variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing (BP4); in addition, an evolutionary conservation algorithm predicts the site as being non-conserved (PhyloP score = -1.62676 in GRCh38), and the variant allele is the reference nucleotide in one primate and/or three mammal species (BP7). The variant also has not been reported in cases or the literature. In summary, this variant meets the criteria to be classified as likely benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: BP4 and BP7.
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 -7.1 | GERP -5.4 |
| Overall | ||
| CADD | 8.349 | PHRED · no single calibrated threshold — expert panels disagree |
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| African / African-Americangrpmax | 0.00277% | 36,137 |
| Finnishnot grpmax-eligible | 0.00191% | 52,258 |
| European (non-Finnish) | 0.00166% | 60,121 |
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
- RUNX1
- Protein
- p.Pro425=
- Coding
- c.1275G>A
- MANE Select
- NM_001754
- dbSNP
- rs886038488
- Type
- single nucleotide variant
- Location
- chr21:34792303 (GRCh38)
- Gene constraint
- LOEUF 0.633 · pLI 0.29 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 61.76 · 5 PDB
- Residue 425
- the 'disordered' region
Disease context
hereditary thrombocytopenia and hematologic cancer predisposition syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1
For Familial platelet disorder with associated myeloid malignancy (Orphanet):
- Inheritance
- Autosomal dominant
Similar variants
- RUNX1 p.Pro425Arg Uncertain significance ★★★ ⚠ same residue
- RUNX1 p.Pro425Leu Likely benign ★★★ same residue
- RUNX1 p.Pro425fs Likely pathogenic ★★★ same residue
- RUNX1 p.Pro425Ser Uncertain significance ★ ⚠ same residue
- RUNX1 c.351+1G>A Pathogenic ★★★ same condition
- RUNX1 c.351+1G>C Likely pathogenic ★★★ same condition
- RUNX1 c.351+1G>T Pathogenic ★★★ same condition
- RUNX1 c.351+2T>A Likely 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/runx1-p-pro425 (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown