Is RUNX1 p.Pro425Leu (c.1274C>T) pathogenic?

RUNX1 p.Pro425Leu (c.1274C>T) is classified Likely benign in RUNX1 (ClinVar, Expert panel, 3 submitters; last evaluated 2025-01-15). AlphaMissense: likely benign (0.3257); No allele count reported in gnomAD v4.1 (AN 1,543,646); Associated with hereditary thrombocytopenia and hematologic cancer predisposition syndrome.

What condition is associated with RUNX1 p.Pro425Leu (c.1274C>T)?

RUNX1 p.Pro425Leu (c.1274C>T) is associated with hereditary thrombocytopenia and hematologic cancer predisposition syndrome, hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (ClinVar).

How common is RUNX1 p.Pro425Leu (c.1274C>T) in the general population?

RUNX1 p.Pro425Leu (c.1274C>T) is no allele count reported in gnomAD v4.1 (AN 1,543,646) (gnomAD).

What do computational predictors say about RUNX1 p.Pro425Leu (c.1274C>T)?

AlphaMissense predicts likely benign (score 0.3257) — an in-silico prediction, not a clinical call.

RUNX1 p.Pro425Leu

Q: How is Familial platelet disorder with associated myeloid malignancy inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

c.1274C>T · rs2056451344 · VCV1510069

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.3257 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,543,646)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

hereditary thrombocytopenia and hematologic cancer predisposition syndrome

ClinGen expert panel — Myeloid Malignancy VCEP

Likely Benign for hereditary thrombocytopenia and hematologic cancer predisposition syndrome. Applied ACMG criteria (verbatim):

PM2_Supporting BS3 BP4

Curation rationale (ClinGen, verbatim)

NM_001754.5(RUNX1):c.1274C>T (p.Pro425Leu) is a missense variant in which transactivation assays demonstrating normal transactivation (80-115% of wt) and data from a secondary DNA and CBFβ dimerization assay demonstrating normal binding and dimerization (BS3; PMID: 25840971). This missense variant has a REVEL score < 0.50 (0.485) and a SpliceAI score ≤ 0.20 (0.0) (BP4). This variant is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign. ACMG/AMP criteria applied, as specified by the Myeloid Malignancy Variant Curation Expert Panel for RUNX1: BS3, BP4, PM2_supporting.

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

Computational evidence

Protein change
AlphaMissense	0.3257	likely benign
REVEL	0.485	indeterminate
SaProt	LLR -8.18	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 42 kb · p 0.0085 · regional, not allelic
Overall
CADD	28.1	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 P398L vs ClinVar P425L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,543,646). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: RUNX1
Protein: p.Pro425Leu
Coding: c.1274C>T
MANE Select: NM_001754
dbSNP: rs2056451344
Type: single nucleotide variant
Location: chr21:34792304 (GRCh38)
Gene constraint: LOEUF 0.633 · pLI 0.29 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.76 · 5 PDB
Residue 398 UniProt numbering: the 'interaction with foxp3' region; the 'interaction with kat6b' region

Full RUNX1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary thrombocytopenia and hematologic cancer predisposition syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also 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.Pro425= 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-pro425leu (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown