Is RUNX1 p.Pro43Ser (c.127C>T) pathogenic?

RUNX1 p.Pro43Ser (c.127C>T) is classified Uncertain significance in RUNX1 (ClinVar, Expert panel, 3 submitters; last evaluated 2024-08-16). AlphaMissense: likely pathogenic (0.9066); Very rare (popmax 0.00144%, nfe); Associated with hereditary thrombocytopenia and hematologic cancer predisposition syndrome.

What condition is associated with RUNX1 p.Pro43Ser (c.127C>T)?

RUNX1 p.Pro43Ser (c.127C>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.Pro43Ser (c.127C>T) in the general population?

RUNX1 p.Pro43Ser (c.127C>T) is very rare (popmax 0.00144%, nfe) (gnomAD).

What do computational predictors say about RUNX1 p.Pro43Ser (c.127C>T)?

AlphaMissense predicts likely pathogenic (score 0.9066) — an in-silico prediction, not a clinical call.

RUNX1 p.Pro43Ser

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.127C>T · rs1555899881 · VCV463980

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 3 submitters

AlphaMissense

likely pathogenic

0.9066 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

hereditary thrombocytopenia and hematologic cancer predisposition syndrome

ClinGen expert panel

Uncertain Significance — Myeloid Malignancy VCEP (hereditary thrombocytopenia and hematologic cancer predisposition syndrome).

Computational evidence

Protein change
AlphaMissense	0.9066	likely pathogenic
REVEL	0.808	moderately pathogenic-leaning
SaProt	LLR -6.20	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 1.7, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 162 kb · p 0.93 · regional, not allelic
Overall
CADD	28.6	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 P16S vs ClinVar P43S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00144% European (non-Finnish) · 17/1,179,884 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000718%

Overall 0.00119% 19/1,599,188 alleles · very rare exomes 19/1,446,850 · genomes 0/152,338 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00321%	31,181
European (non-Finnish)grpmax	0.00144%	69,405

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Pro43Ser
Coding: c.127C>T
MANE Select: NM_001754
dbSNP: rs1555899881
Type: single nucleotide variant
Location: chr21:34887067 (GRCh38)
Gene constraint: LOEUF 0.633 · pLI 0.29 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 61.76 · 5 PDB
Residue 16 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.Pro43Thr 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
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-pro43ser (accessed [today's date]).

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