# NM_032638.5(GATA2):c.123T>G (p.Pro41=)

https://sugi.bio/variant/gata2-p-pro41

## Summary

**GATA2 p.Pro41= (c.123T>G)** is classified **Likely benign** in GATA2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-31). Very rare (popmax 0.00017%, nfe); Associated with monocytopenia with susceptibility to infections.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs1022734850 · 2 submitters · 2 linked conditions · very rare (popmax 0.00017%, nfe)

## For patients & families {#patients}

This is a change in the GATA2 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to monocytopenia with susceptibility to infections.

*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, Not applicable |
| Age of onset (of this condition) | Adult |
| Diagnostic panels | GATA2 is a diagnostic-grade gene on 12 Genomics England panels |

**Commonly reported features of GATA2 deficiency spectrum** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Sensorineural hearing impairment — Very frequent (99-80%)
- Lymphedema — Very frequent (99-80%)
- Thrombocytopenia — Very frequent (99-80%)
- Abnormality of speech or vocalization — Very frequent (99-80%)
- Acute leukemia — Very frequent (99-80%)
- Respiratory failure — Very frequent (99-80%)
- Prolonged bleeding time — Very frequent (99-80%)
- Bone marrow hypocellularity — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0010934/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [GATA2](https://sugi.bio/atlas/gene/GATA2/) |
| Protein change (HGVS p.) | p.Pro41= |
| Coding change (HGVS c.) | c.123T>G |
| MANE Select transcript | [NM_032638](https://www.ncbi.nlm.nih.gov/nuccore/NM_032638) |
| dbSNP | [rs1022734850](https://www.ncbi.nlm.nih.gov/snp/rs1022734850/) |
| Variant type | single nucleotide variant |
| Location | chr3:128486909-128486909 (GRCh38) |
| ClinVar | [VCV1598134](https://www.ncbi.nlm.nih.gov/clinvar/variation/1598134/) |

**All HGVS expressions:** `LRG_295:g.11279T>G`, `LRG_295t2:c.123T>G`, `NC_000003.11:g.128205752A>C`, `NC_000003.12:g.128486909A>C`, `NG_029334.1:g.11279T>G`, `NM_001145661.2:c.123T>G`, `NM_001145662.1:c.123T>G`, `NM_032638.4:c.123T>G`, `NM_032638.5:c.123T>G`

## 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 -1.861, GERP -2.62 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 4.567**. 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 **0.00017%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,179,586 in the highest group · 2/1,612,856 alleles overall — very rare (popmax 0.00017%, 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}

**GATA2** population constraint: LOEUF 0.335, pLI 0.99993, missense-Z 1.7347; 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):

- **GATA2 deficiency with susceptibility to MDS/AML** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 57.11, 17% of residues very-high.

**2 experimental structure(s)** (PDB): [5O9B](https://www.rcsb.org/structure/5O9B), [6ZFV](https://www.rcsb.org/structure/6ZFV).

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

*Describes the biological roles of GATA2 (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:** GATA2's established molecular role includes DNA-binding transcription factor activity, RNA polymerase II-specific.


### Pathways affected {#pathways}

GATA2 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Factors involved in megakaryocyte development and platelet production](https://reactome.org/content/detail/R-HSA-983231) | curated |
| [RUNX1 regulates transcription of genes involved in differentiation of HSCs](https://reactome.org/content/detail/R-HSA-8939236) | curated |
| [Transcriptional regulation of granulopoiesis](https://reactome.org/content/detail/R-HSA-9616222) | electronic |

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

**Molecular function:** DNA-binding transcription factor activity, RNA polymerase II-specific, transcription coregulator binding, chromatin binding, DNA-binding transcription factor activity, RNA polymerase II-specific DNA-binding transcription factor binding, C2H2 zinc finger domain binding.

**Biological process:** positive regulation of gene expression, negative regulation of gene expression, eosinophil fate commitment, positive regulation of blood vessel endothelial cell migration, fat cell differentiation, negative regulation of Notch signaling pathway.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-05-31.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2021–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-05-31 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2021-11-26 |

## Associated conditions {#conditions}

[monocytopenia with susceptibility to infections](https://sugi.bio/atlas/disease/monocytopenia-with-susceptibility-to-infections/), [deafness-lymphedema-leukemia syndrome](https://sugi.bio/atlas/disease/deafness-lymphedema-leukemia-syndrome/).

**Reported phenotype names (ClinVar):** Monocytopenia with susceptibility to infections, Deafness-lymphedema-leukemia syndrome, Inborn genetic diseases, MONOCYTOPENIA AND MYCOBACTERIAL INFECTION SYNDROME, MONOCYTOPENIA WITH SUSCEPTIBILITY TO MYCOBACTERIAL, FUNGAL, AND PAPILLOMAVIRUS INFECTIONS AND MYELODYSPLASIA, COMBINED IMMUNODEFICIENCY WITH SUSCEPTIBILITY TO MYCOBACTERIAL, VIRAL, AND FUNGAL INFECTIONS, Dendritic cell, monocyte, B lymphocyte, and natural killer lymphocyte deficiency, IMMUNODEFICIENCY 21, GATA2 DEFICIENCY, Emberger syndrome.

## Similar variants {#similar}

Related GATA2 variant pages (same residue, condition, or type): [GATA2 p.Pro41Ser](/variant/gata2-p-pro41ser), [GATA2 p.Pro41Ala](/variant/gata2-p-pro41ala), [GATA2 p.Pro41Thr](/variant/gata2-p-pro41thr), [GATA2 c.1017+572C>T](/variant/gata2-c-1017-plus-572c-t), [GATA2 c.1018-1G>T](/variant/gata2-c-1018-minus-1g-t), [GATA2 c.1018-2A>G](/variant/gata2-c-1018-minus-2a-g), [GATA2 c.1018-2A>T](/variant/gata2-c-1018-minus-2a-t), [GATA2 c.1143+2T>A](/variant/gata2-c-1143-plus-2t-a).

### 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 1598134). 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.*