Is RUNX1 p.Pro325Ser (c.973C>T) pathogenic?

RUNX1 p.Pro325Ser (c.973C>T) is classified Uncertain significance in RUNX1 (ClinVar, Expert panel, 4 submitters; last evaluated 2024-07-25). AlphaMissense: likely benign (0.0492); Very rare (popmax 0.00229%, eas); Associated with hereditary thrombocytopenia and hematologic cancer predisposition syndrome.

What condition is associated with RUNX1 p.Pro325Ser (c.973C>T)?

RUNX1 p.Pro325Ser (c.973C>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.Pro325Ser (c.973C>T) in the general population?

RUNX1 p.Pro325Ser (c.973C>T) is very rare (popmax 0.00229%, eas) (gnomAD).

What do computational predictors say about RUNX1 p.Pro325Ser (c.973C>T)?

AlphaMissense predicts likely benign (score 0.0492) — an in-silico prediction, not a clinical call.

RUNX1 p.Pro325Ser

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.973C>T · rs746531841 · VCV651472

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0492 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00229%, eas)

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):

PS4_Supporting BP4

Curation rationale (ClinGen, verbatim)

NM_001754.4(RUNX1):c.973C>T (p.Pro325Ser) is a missense variant which is absent from gnomAD v2, but has a highest population minor allele frequency of 0.006543% (1/15284 alleles) in the African American/African population from gnomAD v3. This variant is not published, and out of 19 carriers reported in clinical laboratories, only one was diagnosed with MDS in their 40s and is a confirmed germline carrier (PS4_supporting). The computational predictor REVEL gives a score of 0.05, which is below the threshold of 0.50, and the splice site predictor SpliceAI indicated that the variant has no impact on splicing, evidence that does not predict a damaging effect on RUNX1 function (BP4). In summary, this variant meets the criteria to be classified as a variant of uncertain significance (VUS) for autosomal dominant hereditary thrombocytopenia and hematologic cancer predisposition syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen Myeloid Malignancy VCEP: PS4_supporting and BP4.

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

Computational evidence

Protein change
AlphaMissense	0.0492	likely benign
REVEL	0.05	moderately benign-leaning
SaProt	LLR -6.04	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 4.4	GERP -1.4, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 42 kb · p 0.0085 · regional, not allelic
Overall
CADD	14.52	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 P298S vs ClinVar P325S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00229% East Asian · 1/43,690 alleles

Overall 0.000189% 3/1,589,438 alleles · very rare exomes 2/1,437,304 · genomes 1/152,134 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00229%	43,690
Admixed American	0.00177%	56,376
Remaining individualsnot grpmax-eligible	0.00163%	61,484

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.Pro325Ser
Coding: c.973C>T
MANE Select: NM_001754
dbSNP: rs746531841
Type: single nucleotide variant
Location: chr21:34792605 (GRCh38)
Gene constraint: LOEUF 0.633 · pLI 0.29 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.76 · 5 PDB
Residue 298 UniProt numbering: the 'interaction with kat6a' 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 p.Pro325= 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
RUNX1 c.352-1G>A Pathogenic ★★★ same condition
RUNX1 c.352-1G>T 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-pro325ser (accessed [today's date]).

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