# NM_004119.3(FLT3):c.2823G>A (p.Ser941=)

https://sugi.bio/variant/flt3-p-ser941

## Summary

**FLT3 p.Ser941= (c.2823G>A)** is classified **Likely benign** in FLT3 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-06-13). Ultra-rare (popmax 0.0201%, eas).

**At a glance:** Likely benign · review: Single submitter · rsID rs201025099 · 1 submitter · ultra-rare (popmax 0.0201%, eas)

## 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.Ser941= |
| Coding change (HGVS c.) | c.2823G>A |
| MANE Select transcript | [NM_004119](https://www.ncbi.nlm.nih.gov/nuccore/NM_004119) |
| dbSNP | [rs201025099](https://www.ncbi.nlm.nih.gov/snp/rs201025099/) |
| Variant type | single nucleotide variant |
| Location | chr13:28014488-28014488 (GRCh38) |
| ClinVar | [VCV710610](https://www.ncbi.nlm.nih.gov/clinvar/variation/710610/) |

**All HGVS expressions:** `LRG_457:g.91081G>A`, `LRG_457t1:c.2823G>A`, `NC_000013.10:g.28588625C>T`, `NC_000013.11:g.28014488C>T`, `NG_007066.1:g.91081G>A`, `NM_004119.3:c.2823G>A`, `NR_130706.2:n.3021G>A`

## 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 -3.918, GERP -4.67 — fast-evolving / accelerated position
- CADD: **PHRED 4.642**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>A, Δ0.50 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.0201%** (eas) · FAF95 0.0104% · FAF99 0.00779% · 9/44,886 in the highest group · 34/1,613,878 alleles overall — ultra-rare (popmax 0.0201%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.0201% | 4,987 |
| Remaining individuals (not grpmax-eligible) | 0.016% | 6,249 |
| African / African-American | 0.00267% | 37,506 |
| Admixed American | 0.00167% | 60,008 |
| South Asian | 0.0011% | 91,076 |
| European (non-Finnish) | 0.000932% | 107,256 |

*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 **941** lies in an α-helix; 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.Ser941= 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 2018-06-13.

**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 | 2018-06-13 |

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

## Similar variants {#similar}

Related FLT3 variant pages (same residue, condition, or type): [FLT3 p.Ser941Leu](/variant/flt3-p-ser941leu), [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).

### 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 710610). 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.*