# NM_001754.5(RUNX1):c.1400C>A (p.Ala467Glu)

https://sugi.bio/variant/runx1-p-ala467glu

## Summary

**RUNX1 p.Ala467Glu (c.1400C>A)** is classified **Uncertain significance** in RUNX1 (ClinVar, Expert panel, 4 submitters; last evaluated 2024-07-11). AlphaMissense: ambiguous (0.4066); Very rare (popmax 0.00196%, amr); Associated with hereditary thrombocytopenia and hematologic cancer predisposition syndrome.

**At a glance:** Uncertain significance · review: Expert panel · rsID rs1442794209 · 4 submitters · 3 linked conditions · AlphaMissense ambiguous · very rare (popmax 0.00196%, amr)

## For patients & families {#patients}

This is a change in the RUNX1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 4 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.Ala467Glu |
| Coding change (HGVS c.) | c.1400C>A |
| MANE Select transcript | [NM_001754](https://www.ncbi.nlm.nih.gov/nuccore/NM_001754) |
| dbSNP | [rs1442794209](https://www.ncbi.nlm.nih.gov/snp/rs1442794209/) |
| Variant type | single nucleotide variant |
| Location | chr21:34792178-34792178 (GRCh38) |
| ClinVar | [VCV463983](https://www.ncbi.nlm.nih.gov/clinvar/variation/463983/) |

**All HGVS expressions:** `LRG_482:g.1197534C>A`, `LRG_482t1:c.1400C>A`, `NC_000021.8:g.36164475G>T`, `NC_000021.9:g.34792178G>T`, `NG_011402.2:g.1197534C>A`, `NM_001001890.3:c.1319C>A`, `NM_001754.5:c.1400C>A`

## Computational & population evidence {#evidence}

**Concordance:** AlphaMissense makes no call; REVEL and SaProt both call this tolerated; AlphaMissense makes no call — descriptive only.

- AlphaMissense **ambiguous** (0.4066) — no call either way
- REVEL 0.085 (moderately benign-leaning)
- SaProt LLR -5.945 (tolerated)
- → **In-silico consensus:** REVEL and SaProt both call this tolerated; AlphaMissense makes no call
- Conservation: phyloP 7.481, GERP -3.22, phastCons 1 — highly conserved
- ⚠ **Isoform check:** AlphaMissense is numbered on a different transcript (AM **A440E** vs ClinVar **A467E**) — the AlphaMissense read here may be for a different residue; verify against the ClinVar transcript.
- CADD: **PHRED 22.1**. 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.*
- Regional missense constraint: **o/e 0.87** across the covering region of the MANE Select transcript (34,792,138–34,834,574), spanning 42,436 bp. Chi-square p 0.0085. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.00196%** (amr) · 1/51,068 in the highest group · 2/1,530,580 alleles overall — very rare (popmax 0.00196%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.00196% | 51,068 |
| European (non-Finnish) | 8.73e-05% | 1,145,500 |

*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 **440** lies in the 'disordered' region.

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. 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}

**Uncertain significance** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2024-07-11.

**Submitter consensus:** conflicting (3 Uncertain significance, 1 Uncertain Significance).

**Submission history:** 4 submissions (2023–2025); classifications have been stable.

**ClinGen expert panel:** Uncertain Significance — Myeloid Malignancy VCEP (hereditary thrombocytopenia and hematologic cancer predisposition syndrome). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `BP4`.
*Considered but not met:* `PM6`, `PM2`, `PVS1`, `PS1`, `PS2`, `PS3`, `PS4`, `PM1`, `PP1`, `PP2`, `PP3`, `PP4`, `BS2`, `PM3`, `BS1`, `BS4`, `BS3`, `BP5`, `BP7`, `PM5`, `BP3`, `BP1`, `BP2`, `BA1`, `PM4`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** NM_001754.5(RUNX1):c.1400C>A (p.Ala467Glu) is a missense variant which has a REVEL score ≤0.50 (0.09) and a SpliceAI score ≤ 0.20 (0.00) (BP4). 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.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50034 · approved 2024-07-11 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/ce0016e0-4c01-4ac9-8859-fe7b3348533e).*
*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 |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-07 |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-11-23 |
| ClinGen Myeloid Malignancy Variant Curation Expert Panel | Uncertain Significance | reviewed by expert panel | curation | 2024-07-11 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-11-18 |

## Associated conditions {#conditions}

[hereditary thrombocytopenia and hematologic cancer predisposition syndrome](https://sugi.bio/atlas/disease/hereditary-thrombocytopenia-and-hematologic-cancer-predisposition-syndrome/), [acute myeloid leukemia](https://sugi.bio/atlas/disease/acute-myeloid-leukemia/), [hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1](https://sugi.bio/atlas/disease/hereditary-thrombocytopenia-and-hematological-cancer-predisposition-syndrome-associated-with-runx1/).

**Reported phenotype names (ClinVar):** Hereditary thrombocytopenia and hematologic cancer predisposition syndrome, Hereditary thrombocytopenia and hematological cancer predisposition syndrome associated with RUNX1, Acute myeloid leukemia, Inborn genetic diseases, Leukemia, acute myelogenous, somatic, CEBPA-Associated Familial Acute Myeloid Leukemia (AML), Leukemia, acute myeloid, somatic, Acute myeloid leukemia, adult, AML adult, Acute non-lymphocytic leukemia.

## Similar variants {#similar}

Related RUNX1 variant pages (same residue, condition, or type): [RUNX1 p.Ala467Thr](/variant/runx1-p-ala467thr), [RUNX1 p.Ala467=](/variant/runx1-p-ala467), [RUNX1 p.Ala467Val](/variant/runx1-p-ala467val), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 463983). 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.*