Is RUNX1 p.Pro263Ser (c.787C>T) pathogenic?

RUNX1 p.Pro263Ser (c.787C>T) is classified Uncertain significance in RUNX1 (ClinVar, Expert panel, 9 submitters; last evaluated 2025-05-02). AlphaMissense: likely benign (0.0606); Ultra-rare (popmax 0.0661%, mid); Associated with hereditary thrombocytopenia and hematologic cancer predisposition syndrome.

What condition is associated with RUNX1 p.Pro263Ser (c.787C>T)?

RUNX1 p.Pro263Ser (c.787C>T) is associated with hereditary thrombocytopenia and hematologic cancer predisposition syndrome, acute myeloid leukemia, hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1 (ClinVar).

How common is RUNX1 p.Pro263Ser (c.787C>T) in the general population?

RUNX1 p.Pro263Ser (c.787C>T) is ultra-rare (popmax 0.0661%, mid) (gnomAD).

What do computational predictors say about RUNX1 p.Pro263Ser (c.787C>T)?

AlphaMissense predicts likely benign (score 0.0606) — an in-silico prediction, not a clinical call.

RUNX1 p.Pro263Ser

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.787C>T · rs370315332 · VCV464008

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0606 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0661%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary thrombocytopenia and hematologic cancer predisposition syndrome

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.787C>T (p.Pro263Ser) is a missense variant which has a REVEL score of 0.286 and a SpliceAI score ≤ 0.20, meeting the threshold for BP4. It is reported at a frequency of 0.0002620 (4/15268 alleles) in the Admixed American population in gnomAD v2.1.1, which does not meet population-based criteria. Although reported in a patient with chronic myelomonocytic leukemia (PMID: 24764152), germline status is not confirmed and other reports concern acquired variants. 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	0.0606	likely benign
REVEL	0.286	benign-leaning
SaProt	LLR -5.88	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.3	GERP 1.2, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 42 kb · p 0.0085 · regional, not allelic
Overall
CADD	23.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P236S vs ClinVar P263S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0661% Middle Eastern · 4/6,048 alleles

Filtering AF 0.0226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0135%

Overall 0.0023% 37/1,609,224 alleles · ultra-rare exomes 31/1,457,018 · genomes 6/152,206 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0661%	1,512
Admixed American	0.01%	9,989
Remaining individualsnot grpmax-eligible	0.00803%	12,458
European (non-Finnish)	0.0017%	58,798
African / African-American	0.00134%	74,900
South Asian	0.0011%	91,022

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.Pro263Ser
Coding: c.787C>T
MANE Select: NM_001754
dbSNP: rs370315332
Type: single nucleotide variant
Location: chr21:34834428 (GRCh38)
Gene constraint: LOEUF 0.633 · pLI 0.29 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.76 · 5 PDB
Residue 236 UniProt numbering: the 'disordered' 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: acute myeloid leukemia 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 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
RUNX1 c.352-1G>A Pathogenic ★★★ same condition
RUNX1 c.352-1G>T Pathogenic ★★★ same condition
RUNX1 c.508+1G>A 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-pro263ser (accessed [today's date]).

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