Is RUNX1 p.Pro463Ser (c.1387C>T) pathogenic?

RUNX1 p.Pro463Ser (c.1387C>T) is classified Uncertain significance in RUNX1 (ClinVar, Expert panel, 2 submitters; last evaluated 2024-08-16). AlphaMissense: likely pathogenic (0.7063); No allele count reported in gnomAD v4.1 (AN 1,537,356); Associated with hereditary thrombocytopenia and hematologic cancer predisposition syndrome.

What condition is associated with RUNX1 p.Pro463Ser (c.1387C>T)?

RUNX1 p.Pro463Ser (c.1387C>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.Pro463Ser (c.1387C>T) in the general population?

RUNX1 p.Pro463Ser (c.1387C>T) is no allele count reported in gnomAD v4.1 (AN 1,537,356) (gnomAD).

What do computational predictors say about RUNX1 p.Pro463Ser (c.1387C>T)?

AlphaMissense predicts likely pathogenic (score 0.7063) — an in-silico prediction, not a clinical call.

RUNX1 p.Pro463Ser

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.1387C>T · rs868387185 · VCV409816

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.7063 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,537,356)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

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):

PM2_Supporting

Curation rationale (ClinGen, verbatim)

NM_001754.5(RUNX1):c.1387C>T (p.Pro463Ser) is a missense variant which is completely absent from all population databases with at least 20x coverage for RUNX1 (PM2_supporting). 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: PM2_supporting.

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

Computational evidence

Protein change
AlphaMissense	0.7063	likely pathogenic
REVEL	0.574	indeterminate
SaProt	LLR -6.00	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.6, 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

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P436S vs ClinVar P463S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

No allele count reported in gnomAD v4.1 (AN 1,537,356). 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.Pro463Ser
Coding: c.1387C>T
MANE Select: NM_001754
dbSNP: rs868387185
Type: single nucleotide variant
Location: chr21:34792191 (GRCh38)
Gene constraint: LOEUF 0.633 · pLI 0.29 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.76 · 5 PDB
Residue 436 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: 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.Pro463Leu Uncertain significance ★★★ ⚠ same residue
RUNX1 p.Pro463= 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

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-pro463ser (accessed [today's date]).

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