# NM_000222.3(KIT):c.2873A>G (p.Asn958Ser)

https://sugi.bio/variant/kit-p-asn958ser

## Summary

**KIT p.Asn958Ser (c.2873A>G)** is classified **Conflicting classifications of pathogenicity** in KIT (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-11-17). AlphaMissense: likely benign (0.1101); Very rare (popmax 0.00669%, eas); Associated with hereditary neoplastic syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1060502563 · 6 submitters · 3 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00669%, eas)

## 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 6 submitters, and is linked to hereditary neoplastic 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.*

|  |  |
| --- | --- |
| Clinical trials | 31 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019921/index) · [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.Asn958Ser |
| Coding change (HGVS c.) | c.2873A>G |
| MANE Select transcript | [NM_000222](https://www.ncbi.nlm.nih.gov/nuccore/NM_000222) |
| dbSNP | [rs1060502563](https://www.ncbi.nlm.nih.gov/snp/rs1060502563/) |
| Variant type | single nucleotide variant |
| Location | chr4:54738499-54738499 (GRCh38) |
| ClinVar | [VCV409772](https://www.ncbi.nlm.nih.gov/clinvar/variation/409772/) |

**All HGVS expressions:** `LRG_307:g.85505A>G`, `LRG_307t1:c.2873A>G`, `NC_000004.11:g.55604665A>G`, `NC_000004.12:g.54738499A>G`, `NG_007456.1:g.85505A>G`, `NM_000222.3:c.2873A>G`, `NM_001093772.2:c.2861A>G`, `NM_001385284.1:c.2876A>G`, `NM_001385285.1:c.2870A>G`, `NM_001385286.1:c.2858A>G`, `NM_001385288.1:c.2864A>G`, `NM_001385290.1:c.2873A>G`, `NM_001385292.1:c.2861A>G`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- AlphaMissense **likely benign** (0.1101)
- REVEL 0.331 (indeterminate)
- SaProt LLR -5.708 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this tolerated; REVEL makes no call
- Conservation: phyloP 11.239, GERP 2.46, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 22.5**. 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 1.01** across the covering region of the MANE Select transcript (54,736,808–54,738,554), spanning 1,746 bp. Chi-square p 0.88. 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 **0.00669%** (eas) · FAF95 0.00177% · FAF99 0.000891% · 3/44,866 in the highest group · 15/1,613,984 alleles overall — very rare (popmax 0.00669%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00669% | 14,955 |
| Remaining individuals (not grpmax-eligible) | 0.0048% | 20,828 |
| African / African-American | 0.00267% | 37,457 |
| European (non-Finnish) | 0.000593% | 168,573 |

*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}


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. 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 2025-11-17.

**Submitter consensus:** conflicting (5 Uncertain significance, 1 Likely pathogenic).

**Submission history:** 6 submissions (2021–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-01-01 |
| Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-11-03 |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-18 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-08-14 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-10-30 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-17 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [ovarian cancer](https://sugi.bio/atlas/disease/ovarian-cancer/), [gastrointestinal stromal tumor](https://sugi.bio/atlas/disease/gastrointestinal-stromal-tumor/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Gastrointestinal stromal tumor, Ovarian cancer, not provided, Neoplastic Syndromes, Hereditary, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome, Tumor predisposition, Gastrointestinal stroma tumor, Gastrointestinal stromal tumor, somatic.

## Similar variants {#similar}

Related KIT variant pages (same residue, condition, or type): [KIT p.Asn958Asp](/variant/kit-p-asn958asp), [KIT p.Asn958Ile](/variant/kit-p-asn958ile), [KIT p.Ala621Thr](/variant/kit-p-ala621thr), [KIT p.Asp820Tyr](/variant/kit-p-asp820tyr), [KIT p.Gln190Ter](/variant/kit-p-gln190ter), [KIT p.Leu576Pro](/variant/kit-p-leu576pro), [KIT p.Lys642Glu](/variant/kit-p-lys642glu), [KIT p.Trp557Arg](/variant/kit-p-trp557arg).

### 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 409772). 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.*