# NM_000222.3(KIT):c.753_756del (p.Ser251fs)

https://sugi.bio/variant/kit-p-ser251fs

## Summary

**KIT p.Ser251fs (c.753_756del)** is classified **Conflicting classifications of pathogenicity** in KIT (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-10-23). Very rare (popmax 0.00017%, nfe); Associated with KIT-related disorder.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1553887960 · 4 submitters · 3 linked conditions · very rare (popmax 0.00017%, nfe)

## For patients & families {#patients}

This is a change in the KIT gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 submitters, and is linked to KIT-related disorder.

*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 | [KIT](https://sugi.bio/atlas/gene/KIT/) |
| Protein change (HGVS p.) | p.Ser251fs |
| Coding change (HGVS c.) | c.753_756del |
| MANE Select transcript | [NM_000222](https://www.ncbi.nlm.nih.gov/nuccore/NM_000222) |
| dbSNP | [rs1553887960](https://www.ncbi.nlm.nih.gov/snp/rs1553887960/) |
| Variant type | Deletion |
| Location | chr4:54699760-54699763 (GRCh38) |
| ClinVar | [VCV458966](https://www.ncbi.nlm.nih.gov/clinvar/variation/458966/) |

**All HGVS expressions:** `LRG_307:g.46769_46772del`, `LRG_307t1:c.753_756del`, `NC_000004.11:g.55565929_55565932del`, `NC_000004.12:g.54699763_54699766del`, `NG_007456.1:g.46769_46772del`, `NM_000222.2:c.753_756delTCAG`, `NM_000222.3:c.753_756del`, `NM_001093772.2:c.753_756del`, `NM_001385284.1:c.753_756del`, `NM_001385285.1:c.753_756del`, `NM_001385286.1:c.753_756del`, `NM_001385288.1:c.753_756del`, `NM_001385290.1:c.753_756del`, `NM_001385292.1:c.753_756del`

## 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 1.776, GERP -2.1, phastCons 0.306 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene (constraint LOEUF 0.24, pLI 1), supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 21**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.00017%** (nfe) · FAF95 2.8e-05% · FAF99 1.1e-05% · 2/1,179,768 in the highest group · 2/1,461,600 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}

**KIT** population constraint: LOEUF 0.24, pLI 1, missense-Z 4.1661; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *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):

- **gastrointestinal stromal tumor** — Definitive (AD)

## Protein context {#protein}

Residue **251** lies in a disulfide bond; the ig-like c2-type 3 domain.

AlphaFold model confidence (whole protein): pLDDT 78.52, 51% of residues very-high.

**65 experimental structure(s)** (PDB): [12FJ](https://www.rcsb.org/structure/12FJ), [1PKG](https://www.rcsb.org/structure/1PKG), [1T45](https://www.rcsb.org/structure/1T45), [1T46](https://www.rcsb.org/structure/1T46), [2E9W](https://www.rcsb.org/structure/2E9W), [2EC8](https://www.rcsb.org/structure/2EC8) — incl. mutant structure 3G0F.

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

*Describes the biological roles of KIT (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:** KIT's established molecular role includes transmembrane receptor protein tyrosine kinase activity. p.Ser251fs falls in the ig-like c2-type 3 domain. In Reactome, KIT is annotated in disease pathway(s) including **Constitutive Signaling by Aberrant PI3K in Cancer**, **Dasatinib-resistant KIT mutants**.

**Disease mechanism (Reactome):** KIT loss or alteration is curated in [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530), [Dasatinib-resistant KIT mutants](https://reactome.org/content/detail/R-HSA-9669914), [Imatinib-resistant KIT mutants](https://reactome.org/content/detail/R-HSA-9669917).

### Pathways affected {#pathways}

KIT participates in **22 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Constitutive Signaling by Aberrant PI3K in Cancer](https://reactome.org/content/detail/R-HSA-2219530) | curated |
| ⚕ [Dasatinib-resistant KIT mutants](https://reactome.org/content/detail/R-HSA-9669914) | curated |
| ⚕ [Imatinib-resistant KIT mutants](https://reactome.org/content/detail/R-HSA-9669917) | curated |
| ⚕ [KIT mutants bind TKIs](https://reactome.org/content/detail/R-HSA-9669921) | curated |
| ⚕ [Masitinib-resistant KIT mutants](https://reactome.org/content/detail/R-HSA-9669924) | curated |
| ⚕ [Nilotinib-resistant KIT mutants](https://reactome.org/content/detail/R-HSA-9669926) | curated |
| ⚕ [Regorafenib-resistant KIT mutants](https://reactome.org/content/detail/R-HSA-9669929) | curated |
| ⚕ [Signaling by extracellular domain mutants of KIT](https://reactome.org/content/detail/R-HSA-9680187) | curated |
| ⚕ [Signaling by juxtamembrane domain KIT mutants](https://reactome.org/content/detail/R-HSA-9669935) | curated |
| ⚕ [Signaling by kinase domain mutants of KIT](https://reactome.org/content/detail/R-HSA-9669933) | curated |
| ⚕ [Signaling by phosphorylated juxtamembrane, extracellular and kinase domain KIT mutants](https://reactome.org/content/detail/R-HSA-9670439) | curated |
| ⚕ [Sorafenib-resistant KIT mutants](https://reactome.org/content/detail/R-HSA-9669936) | curated |
| ⚕ [Sunitinib-resistant KIT mutants](https://reactome.org/content/detail/R-HSA-9669934) | curated |
| [Developmental Lineage of Mammary Gland Alveolar Cells](https://reactome.org/content/detail/R-HSA-9927426) | curated |
| [Developmental Lineage of Mammary Gland Luminal Epithelial Cells](https://reactome.org/content/detail/R-HSA-9927418) | 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 |
| [TFAP2 (AP-2) family regulates transcription of growth factors and their receptors](https://reactome.org/content/detail/R-HSA-8866910) | curated |
| [Transcriptional and post-translational regulation of MITF-M expression and activity](https://reactome.org/content/detail/R-HSA-9856649) | curated |
| [Regulation of KIT signaling](https://reactome.org/content/detail/R-HSA-1433559) | electronic |
| [Signaling by SCF-KIT](https://reactome.org/content/detail/R-HSA-1433557) | electronic |

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

**Molecular function:** transmembrane receptor protein tyrosine kinase activity, cytokine binding, protein homodimerization activity.

**Biological process:** mast cell chemotaxis, male gonad development, cytokine-mediated signaling pathway, actin cytoskeleton organization, positive regulation of mast cell cytokine production, Fc receptor signaling pathway.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-10-23.

**Submitter consensus:** conflicting (3 Pathogenic, 1 Likely benign).

**Submission history:** 4 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Blueprint Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2018-05-03 |
| Revvity Omics, Revvity | Pathogenic | criteria provided, single submitter | clinical testing | 2019-04-18 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-08-06 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-10-23 |

## Associated conditions {#conditions}

[KIT-related disorder](https://sugi.bio/atlas/disease/kit-related-disorder/), [gastrointestinal stromal tumor](https://sugi.bio/atlas/disease/gastrointestinal-stromal-tumor/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** KIT-related disorder, Gastrointestinal stromal tumor, not provided, Hereditary cancer-predisposing syndrome, KIT-related condition, Neoplastic Syndromes, Hereditary, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome, Tumor predisposition, none provided.

## Similar variants {#similar}

Related KIT variant pages (same residue, condition, or type): [KIT p.Ser251Gly](/variant/kit-p-ser251gly), [KIT p.Ser251=](/variant/kit-p-ser251), [KIT p.Asn819fs](/variant/kit-p-asn819fs), [KIT p.Asp579del](/variant/kit-p-asp579del), [KIT p.Asn945fs](/variant/kit-p-asn945fs), [KIT p.Asp458_Val459del](/variant/kit-p-asp458-val459del), [KIT c.1115+16del](/variant/kit-c-1115-plus-16del), [KIT c.1116-16_1116-14del](/variant/kit-c-1116-minus-16-1116-minus-14del).

### 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 458966). 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.*