# NM_000222.3(KIT):c.1679T>C (p.Val560Ala)

https://sugi.bio/variant/kit-p-val560ala

## Summary

**KIT p.Val560Ala (c.1679T>C)** is classified **Uncertain significance** in KIT (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-03-02). AlphaMissense: likely pathogenic (0.8923); Very rare (popmax 8.47e-05%, nfe); Associated with gastrointestinal stromal tumor.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs121913521 · 2 submitters · 2 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the KIT gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 2 submitters, and is linked to gastrointestinal stromal tumor.

*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) | Adolescent, Adult, Childhood |
| Prevalence | 1-5 / 10 000 (Europe) |
| Clinical trials | 310 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | KIT is a diagnostic-grade gene on 8 Genomics England panels |

**Commonly reported features of Gastrointestinal stromal tumor** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Neoplasm of the stomach — Very frequent (99-80%)
- Sarcoma — Very frequent (99-80%)
- Gastrointestinal stroma tumor — Very frequent (99-80%)
- Dysphagia — Frequent (79-30%)
- Nausea and vomiting — Frequent (79-30%)
- Constipation — Frequent (79-30%)
- Gastrointestinal hemorrhage — Frequent (79-30%)
- Intestinal obstruction — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0008598/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.Val560Ala |
| Coding change (HGVS c.) | c.1679T>C |
| MANE Select transcript | [NM_000222](https://www.ncbi.nlm.nih.gov/nuccore/NM_000222) |
| dbSNP | [rs121913521](https://www.ncbi.nlm.nih.gov/snp/rs121913521/) |
| Variant type | single nucleotide variant |
| Location | chr4:54727447-54727447 (GRCh38) |
| ClinVar | [VCV375915](https://www.ncbi.nlm.nih.gov/clinvar/variation/375915/) |

**All HGVS expressions:** `LRG_307:g.74453T>C`, `LRG_307t1:c.1679T>C`, `NC_000004.11:g.55593613T>C`, `NC_000004.12:g.54727447T>C`, `NG_007456.1:g.74453T>C`, `NM_000222.2:c.1679T>C`, `NM_000222.3:c.1679T>C`, `NM_001093772.2:c.1667T>C`, `NM_001385284.1:c.1682T>C`, `NM_001385285.1:c.1679T>C`, `NM_001385286.1:c.1667T>C`, `NM_001385288.1:c.1670T>C`, `NM_001385290.1:c.1682T>C`, `NM_001385292.1:c.1670T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.8923)
- REVEL 0.716 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -11.451 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 7.878, GERP 2.56, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 27.9**. 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 (54,727,229–54,727,506), spanning 277 bp. Chi-square p 0.96. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (T>G, Δ0.45 donor 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 **8.47e-05%** (nfe) · 1/1,179,980 in the highest group · 1/1,614,118 alleles overall — very rare (popmax 8.47e-05%, 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 3/3, 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):

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

## Protein context {#protein}

Residue **560** lies in a β-strand; a UniProt-annotated variant site (in gist; somatic mutation).

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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-03-02.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2024–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-08-12 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-03-02 |

## Associated conditions {#conditions}

[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):** Gastrointestinal stromal tumor, Hereditary cancer-predisposing syndrome, Gastrointestinal stromal tumor, somatic, Gastrointestinal stroma tumor, Neoplastic Syndromes, Hereditary, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome, Tumor predisposition.

## Same-residue context {#hotspot}

Residue **560** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [KIT p.Val560del](/variant/kit-p-val560del), [KIT p.Val560Asp](/variant/kit-p-val560asp). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related KIT variant pages (same residue, condition, or type): [KIT p.Val560Asp](/variant/kit-p-val560asp), [KIT p.Val560Ile](/variant/kit-p-val560ile), [KIT p.Val560Phe](/variant/kit-p-val560phe), [KIT p.Val560_Leu576del](/variant/kit-p-val560-leu576del), [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).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 2026-10-14); 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 375915). 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.*