# NM_001754.5(RUNX1):c.309T>C (p.Pro103=)

https://sugi.bio/variant/runx1-p-pro103

## Summary

**RUNX1 p.Pro103= (c.309T>C)** is classified **Likely benign** in RUNX1 (ClinVar, Expert panel, 2 submitters; last evaluated 2025-07-14). Very rare (popmax 0.000424%, nfe); Associated with hereditary thrombocytopenia and hematologic cancer predisposition syndrome.

**At a glance:** Likely benign · review: Expert panel · 2 submitters · 1 linked condition · very rare (popmax 0.000424%, nfe)

## For patients & families {#patients}

This is a change in the RUNX1 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to hereditary thrombocytopenia and hematologic cancer predisposition syndrome.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Diagnostic panels | RUNX1 is a diagnostic-grade gene on 5 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010352/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [RUNX1](https://sugi.bio/atlas/gene/RUNX1/) |
| Protein change (HGVS p.) | p.Pro103= |
| Coding change (HGVS c.) | c.309T>C |
| MANE Select transcript | [NM_001754](https://www.ncbi.nlm.nih.gov/nuccore/NM_001754) |
| Variant type | single nucleotide variant |
| Location | chr21:34886885-34886885 (GRCh38) |
| ClinVar | [VCV3791494](https://www.ncbi.nlm.nih.gov/clinvar/variation/3791494/) |

**All HGVS expressions:** `LRG_482:g.1102827T>C`, `LRG_482t1:c.309T>C`, `NC_000021.8:g.36259182A>G`, `NC_000021.9:g.34886885A>G`, `NG_011402.2:g.1102827T>C`, `NG_144242.1:g.360A>G`, `NM_001001890.3:c.228T>C`, `NM_001122607.2:c.228T>C`, `NM_001754.5:c.309T>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 1.862, GERP -1.4, phastCons 1 — weakly conserved position
- CADD: **PHRED 12.38**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.000424%** (nfe) · FAF95 0.000124% · FAF99 9e-05% · 5/1,179,750 in the highest group · 5/1,613,618 alleles overall — very rare (popmax 0.000424%, nfe).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**RUNX1** population constraint: LOEUF 0.633, pLI 0.29231, missense-Z 1.4853; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **hereditary thrombocytopenia and hematologic cancer predisposition syndrome** — Definitive (AD)

## Protein context {#protein}

Residue **103** lies in the runt domain; a β-strand.

AlphaFold model confidence (whole protein): pLDDT 61.76, 27% of residues very-high.

**5 experimental structure(s)** (PDB): [1CMO](https://www.rcsb.org/structure/1CMO), [1CO1](https://www.rcsb.org/structure/1CO1), [1E50](https://www.rcsb.org/structure/1E50), [1H9D](https://www.rcsb.org/structure/1H9D), [1LJM](https://www.rcsb.org/structure/1LJM).

## What this gene does {#gene-function}

*Describes the biological roles of RUNX1 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** RUNX1's established molecular role includes transcription cis-regulatory region binding. p.Pro103= falls in the runt domain. In Reactome, RUNX1 is annotated in disease pathway(s) including **SARS-CoV-1 activates/modulates innate immune responses**.

**Disease mechanism (Reactome):** RUNX1 loss or alteration is curated in [SARS-CoV-1 activates/modulates innate immune responses](https://reactome.org/content/detail/R-HSA-9692916).

### Pathways affected {#pathways}

RUNX1 participates in **20 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [SARS-CoV-1 activates/modulates innate immune responses](https://reactome.org/content/detail/R-HSA-9692916) | curated |
| [Estrogen-dependent gene expression](https://reactome.org/content/detail/R-HSA-9018519) | curated |
| [Pre-NOTCH Transcription and Translation](https://reactome.org/content/detail/R-HSA-1912408) | curated |
| [RUNX1 and FOXP3 control the development of regulatory T lymphocytes (Tregs)](https://reactome.org/content/detail/R-HSA-8877330) | curated |
| [RUNX1 interacts with co-factors whose precise effect on RUNX1 targets is not known](https://reactome.org/content/detail/R-HSA-8939243) | curated |
| [RUNX1 regulates estrogen receptor mediated transcription](https://reactome.org/content/detail/R-HSA-8931987) | curated |
| [RUNX1 regulates expression of components of tight junctions](https://reactome.org/content/detail/R-HSA-8935964) | curated |
| [RUNX1 regulates genes involved in megakaryocyte differentiation and platelet function](https://reactome.org/content/detail/R-HSA-8936459) | curated |
| [RUNX1 regulates transcription of genes involved in BCR signaling](https://reactome.org/content/detail/R-HSA-8939245) | curated |
| [RUNX1 regulates transcription of genes involved in WNT signaling](https://reactome.org/content/detail/R-HSA-8939256) | curated |
| [RUNX1 regulates transcription of genes involved in differentiation of myeloid cells](https://reactome.org/content/detail/R-HSA-8939246) | curated |
| [RUNX1 regulates transcription of genes involved in interleukin signaling](https://reactome.org/content/detail/R-HSA-8939247) | curated |
| [RUNX2 regulates genes involved in differentiation of myeloid cells](https://reactome.org/content/detail/R-HSA-8941333) | curated |
| [RUNX3 regulates p14-ARF](https://reactome.org/content/detail/R-HSA-8951936) | curated |
| [SLC-mediated transport of organic cations](https://reactome.org/content/detail/R-HSA-549127) | curated |
| [Differentiation of naive CD4+ T cells to T helper 1 cells (Th1 cells)](https://reactome.org/content/detail/R-HSA-9942503) | electronic |
| [RUNX1 regulates transcription of genes involved in differentiation of HSCs](https://reactome.org/content/detail/R-HSA-8939236) | electronic |
| [RUNX1 regulates transcription of genes involved in differentiation of keratinocytes](https://reactome.org/content/detail/R-HSA-8939242) | electronic |
| [Regulation of RUNX1 Expression and Activity](https://reactome.org/content/detail/R-HSA-8934593) | electronic |
| [Transcriptional regulation of granulopoiesis](https://reactome.org/content/detail/R-HSA-9616222) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** transcription cis-regulatory region binding, RNA polymerase II transcription regulatory region sequence-specific DNA binding, RNA polymerase II cis-regulatory region sequence-specific DNA binding, transcription corepressor binding, transcription coactivator binding, DNA-binding transcription activator activity, RNA polymerase II-specific.

**Biological process:** myeloid leukocyte differentiation, regulation of transcription by RNA polymerase II, hemopoiesis, myeloid cell differentiation, negative regulation of granulocyte differentiation, positive regulation of granulocyte differentiation.

## Clinical significance {#significance}

**Likely benign** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2025-07-14.

**Submitter consensus:** conflicting (1 Likely benign, 1 Likely Benign).

**Submission history:** 2 submissions (2025); classifications have been stable.

**ClinGen expert panel:** Likely Benign — Myeloid Malignancy VCEP (hereditary thrombocytopenia and hematologic cancer predisposition syndrome). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2_Supporting`, `BP7`, `BP4`.
*Considered but not met:* `PM6`, `PVS1`, `PS1`, `PS2`, `PS3`, `PS4`, `PM1`, `PP1`, `PP2`, `PP3`, `PP4`, `BS2`, `PM3`, `BS1`, `BS4`, `BS3`, `BP5`, `PM5`, `BP3`, `BP1`, `BP2`, `BA1`, `PM4`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** NM_001754.5(RUNX1):c.309T>C (p.Pro103=) is a synonymous variant which has a SpliceAI score ≤ 0.20 (0.01) (BP4). This variant has a SpliceAI score ≤ 0.20 (0.01) and evolutionary conservation prediction algorithms predict the site as not being conserved (PhyloP score ≤ 2.0 (0.64) (BP7). 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: BP4, BP7, PM2_supporting.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50034 · approved 2025-07-14 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/4ab0db4f-7326-4498-800e-9415ea8908d8).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-02-02 |
| ClinGen Myeloid Malignancy Variant Curation Expert Panel | Likely Benign | reviewed by expert panel | curation | 2025-07-14 |

## Associated conditions {#conditions}

[hereditary thrombocytopenia and hematologic cancer predisposition syndrome](https://sugi.bio/atlas/disease/hereditary-thrombocytopenia-and-hematologic-cancer-predisposition-syndrome/).

**Reported phenotype names (ClinVar):** Hereditary thrombocytopenia and hematologic cancer predisposition syndrome, Inborn genetic diseases.

## Similar variants {#similar}

Related RUNX1 variant pages (same residue, condition, or type): [RUNX1 c.351+1G>A](/variant/runx1-c-351-plus-1g-a), [RUNX1 c.351+1G>C](/variant/runx1-c-351-plus-1g-c), [RUNX1 c.351+1G>T](/variant/runx1-c-351-plus-1g-t), [RUNX1 c.351+2T>A](/variant/runx1-c-351-plus-2t-a), [RUNX1 c.351+2T>C](/variant/runx1-c-351-plus-2t-c), [RUNX1 c.352-1G>A](/variant/runx1-c-352-minus-1g-a), [RUNX1 c.508+1G>A](/variant/runx1-c-508-plus-1g-a), [RUNX1 c.508+1G>C](/variant/runx1-c-508-plus-1g-c).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 3791494). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*