# NM_004119.3(FLT3):c.2199A>G (p.Pro733=)

https://sugi.bio/variant/flt3-p-pro733

## Summary

**FLT3 p.Pro733= (c.2199A>G)** is classified **Likely benign** in FLT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-05-07). Ultra-rare (popmax 0.02%, amr).

**At a glance:** Likely benign · review: Single submitter · rsID rs747026657 · 1 submitter · ultra-rare (popmax 0.02%, amr)

## For patients & families {#patients}

This is a change in the FLT3 gene that is classified as likely benign — not considered disease-causing, submitted by 1 submitter.

*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.*

**Support & next steps:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [FLT3](https://sugi.bio/atlas/gene/FLT3/) |
| Protein change (HGVS p.) | p.Pro733= |
| Coding change (HGVS c.) | c.2199A>G |
| MANE Select transcript | [NM_004119](https://www.ncbi.nlm.nih.gov/nuccore/NM_004119) |
| dbSNP | [rs747026657](https://www.ncbi.nlm.nih.gov/snp/rs747026657/) |
| Variant type | single nucleotide variant |
| Location | chr13:28027096-28027096 (GRCh38) |
| ClinVar | [VCV735586](https://www.ncbi.nlm.nih.gov/clinvar/variation/735586/) |

**All HGVS expressions:** `LRG_457:g.78473A>G`, `LRG_457t1:c.2199A>G`, `NC_000013.10:g.28601233T>C`, `NC_000013.11:g.28027096T>C`, `NG_007066.1:g.78473A>G`, `NM_004119.3:c.2199A>G`, `NR_130706.2:n.2265A>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 -0.539, GERP -4.67, phastCons 0.086 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 5.408**. 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 **0.02%** (amr) · FAF95 0.0115% · FAF99 0.009% · 12/59,874 in the highest group · 25/1,613,378 alleles overall — ultra-rare (popmax 0.02%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.02% | 4,989 |
| African / African-American | 0.00134% | 74,900 |
| European (non-Finnish) | 0.00102% | 98,313 |

*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}

**FLT3** population constraint: LOEUF 0.468, pLI 0.99734, missense-Z 1.5509. *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):

- **leukemia, acute myeloid, susceptibility to** — Limited (AD)

## Protein context {#protein}

Residue **733** lies in the protein kinase domain.

AlphaFold model confidence (whole protein): pLDDT 76.19, 30% of residues very-high.

**11 experimental structure(s)** (PDB): [1RJB](https://www.rcsb.org/structure/1RJB), [3QS7](https://www.rcsb.org/structure/3QS7), [3QS9](https://www.rcsb.org/structure/3QS9), [4RT7](https://www.rcsb.org/structure/4RT7), [4XUF](https://www.rcsb.org/structure/4XUF), [5X02](https://www.rcsb.org/structure/5X02) — incl. mutant structure 7ZV9.

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

*Describes the biological roles of FLT3 (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:** p.Pro733= falls in the protein kinase domain. In Reactome, FLT3 is annotated in disease pathway(s) including **Constitutive Signaling by Aberrant PI3K in Cancer**, **FLT3 mutants bind TKIs**.

**Disease mechanism (Reactome):** FLT3 loss or alteration is curated in [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530), [FLT3 mutants bind TKIs](https://reactome.org/content/detail/R-HSA-9702509), [FLT3 signaling by CBL mutants](https://reactome.org/content/detail/R-HSA-9706377).

### Pathways affected {#pathways}

FLT3 participates in **27 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530) | curated |
| ⚕ [FLT3 mutants bind TKIs](https://reactome.org/content/detail/R-HSA-9702509) | curated |
| ⚕ [FLT3 signaling by CBL mutants](https://reactome.org/content/detail/R-HSA-9706377) | curated |
| ⚕ [KW2449-resistant FLT3 mutants](https://reactome.org/content/detail/R-HSA-9702569) | curated |
| ⚕ [STAT5 activation downstream of FLT3 ITD mutants](https://reactome.org/content/detail/R-HSA-9702518) | curated |
| ⚕ [crenolanib-resistant FLT3 mutants](https://reactome.org/content/detail/R-HSA-9702581) | curated |
| ⚕ [gilteritinib-resistant FLT3 mutants](https://reactome.org/content/detail/R-HSA-9702590) | curated |
| ⚕ [lestaurtinib-resistant FLT3 mutants](https://reactome.org/content/detail/R-HSA-9702596) | curated |
| ⚕ [linifanib-resistant FLT3 mutants](https://reactome.org/content/detail/R-HSA-9702998) | curated |
| ⚕ [midostaurin-resistant FLT3 mutants](https://reactome.org/content/detail/R-HSA-9702600) | curated |
| ⚕ [pexidartinib-resistant FLT3 mutants](https://reactome.org/content/detail/R-HSA-9702605) | curated |
| ⚕ [ponatinib-resistant FLT3 mutants](https://reactome.org/content/detail/R-HSA-9702614) | curated |
| ⚕ [quizartinib-resistant FLT3 mutants](https://reactome.org/content/detail/R-HSA-9702620) | curated |
| ⚕ [semaxanib-resistant FLT3 mutants](https://reactome.org/content/detail/R-HSA-9702577) | curated |
| ⚕ [sorafenib-resistant FLT3 mutants](https://reactome.org/content/detail/R-HSA-9702624) | curated |
| ⚕ [sunitinib-resistant FLT3 mutants](https://reactome.org/content/detail/R-HSA-9702632) | curated |
| ⚕ [tamatinib-resistant FLT3 mutants](https://reactome.org/content/detail/R-HSA-9703009) | curated |
| ⚕ [tandutinib-resistant FLT3 mutants](https://reactome.org/content/detail/R-HSA-9702636) | curated |
| ⚕ [Signaling by FLT3 ITD and TKD mutants](https://reactome.org/content/detail/R-HSA-9703648) | electronic |
| [Negative regulation of FLT3](https://reactome.org/content/detail/R-HSA-9706369) | curated |
| [PI3K Cascade](https://reactome.org/content/detail/R-HSA-109704) | curated |
| [PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling](https://reactome.org/content/detail/R-HSA-6811558) | curated |
| [PIP3 activates AKT signaling](https://reactome.org/content/detail/R-HSA-1257604) | curated |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [FLT3 Signaling](https://reactome.org/content/detail/R-HSA-9607240) | electronic |
| [FLT3 signaling through SRC family kinases](https://reactome.org/content/detail/R-HSA-9706374) | electronic |
| [STAT5 Activation](https://reactome.org/content/detail/R-HSA-9645135) | electronic |

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

**Biological process:** hemopoiesis.

## Clinical significance {#significance}

**Likely benign** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2018-05-07.

**Submitter consensus:** unanimous (1/1 Likely benign).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2018-05-07 |

**Reported phenotype names (ClinVar):** not provided, RECLASSIFIED - ADRA2C POLYMORPHISM, RECLASSIFIED - ADRB1 POLYMORPHISM, none provided.

## Similar variants {#similar}

Related FLT3 variant pages (same residue, condition, or type): [FLT3 c.1205+56C>T](/variant/flt3-c-1205-plus-56c-t), [FLT3 c.1310-3T>C](/variant/flt3-c-1310-minus-3t-c), [FLT3 c.1418+75A>G](/variant/flt3-c-1418-plus-75a-g), [FLT3 c.1418+81A>G](/variant/flt3-c-1418-plus-81a-g), [FLT3 c.1419-15T>C](/variant/flt3-c-1419-minus-15t-c), [FLT3 c.1419-36T>A](/variant/flt3-c-1419-minus-36t-a), [FLT3 c.1597+8A>G](/variant/flt3-c-1597-plus-8a-g), [FLT3 c.165+118G>T](/variant/flt3-c-165-plus-118g-t).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 735586). 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.*