RUNX1 p.Ala467Glu
c.1400C>A · rs1442794209 · VCV463983
ClinGen expert panel — Myeloid Malignancy VCEP
Uncertain Significance for hereditary thrombocytopenia and hematologic cancer predisposition syndrome. Applied ACMG criteria (verbatim):
BP4
Curation rationale (ClinGen, verbatim)
NM_001754.5(RUNX1):c.1400C>A (p.Ala467Glu) is a missense variant which has a REVEL score ≤0.50 (0.09) and a SpliceAI score ≤ 0.20 (0.00) (BP4). In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BP4.
ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.
Computational evidence
| Protein change | ||
| AlphaMissense | 0.4066 | ambiguous |
|---|---|---|
| REVEL | 0.085 | moderately benign-leaning |
| SaProt | LLR -5.95 | tolerated |
| ⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call. | ||
| Splicing | ||
| SpliceAI | — | not assessed · no allele here is in the release |
| Constraint at this position | ||
| Conservation | phyloP 7.5 | GERP -3.2, phastCons 1 |
| Regional constraint | o/e 0.87 | unconstrained · MANE · 42 kb · p 0.0085 · regional, not allelic |
| Overall | ||
| CADD | 22.1 | PHRED · no single calibrated threshold — expert panels disagree |
AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.
⚠ Isoform check: AlphaMissense numbered on a different transcript (AM A440E vs ClinVar A467E) — verify the residue.
Population frequency
| Ancestry group | Frequency | 1 in |
|---|---|---|
| Admixed Americangrpmax | 0.00196% | 51,068 |
| European (non-Finnish) | 8.73e-05% | 1,145,500 |
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.Ala467Glu
- Coding
- c.1400C>A
- MANE Select
- NM_001754
- dbSNP
- rs1442794209
- Type
- single nucleotide variant
- Location
- chr21:34792178 (GRCh38)
- Gene constraint
- LOEUF 0.633 · pLI 0.29 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 61.76 · 5 PDB
Disease context
hereditary thrombocytopenia and hematologic cancer predisposition syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: acute myeloid leukemiahereditary 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.Ala467Thr Uncertain significance ★★★ ⚠ same residue
- RUNX1 p.Ala467= Likely benign ★★★ same residue
- RUNX1 p.Ala467Val Likely benign ★ 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
- RUNX1 c.351+2T>C 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-ala467glu (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown