Is KIT p.Arg740del (c.2217_2219del) pathogenic?

KIT p.Arg740del (c.22172219del) is classified Uncertain significance in KIT (ClinVar, Single submitter, 1 submitter; last evaluated 2026-04-29). Very rare (popmax 0.000558%); Associated with hereditary neoplastic syndrome.

What condition is associated with KIT p.Arg740del (c.2217_2219del)?

KIT p.Arg740del (c.2217_2219del) is associated with hereditary neoplastic syndrome (ClinVar).

How common is KIT p.Arg740del (c.2217_2219del) in the general population?

KIT p.Arg740del (c.2217_2219del) is very rare (popmax 0.000558%) (gnomAD).

KIT p.Arg740del

c.2217_2219del · VCV4858918

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000558%)

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 1.3	GERP -4.5, phastCons 1
Overall
CADD	17.97	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000558%

Overall 0.000558% 9/1,612,842 alleles · very rare exomes 6/1,460,668 · genomes 3/152,174 · joint denominator

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: KIT
Protein: p.Arg740del
Coding: c.2217_2219del
MANE Select: NM_000222
Type: Deletion
Location: chr4:54731401 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.52 · 65 PDB
Residue 740: the protein kinase domain

Full KIT gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary neoplastic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

KIT p.Arg740Thr Uncertain significance ★ ⚠ same residue
KIT p.Asp579del Pathogenic ★★ same condition
KIT p.Asn945fs Uncertain significance ★★ same condition
KIT p.Asp458_Val459del Uncertain significance ★★ same condition
KIT p.Ser688fs Pathogenic ★ same condition
KIT c.1990+1del Conflicting classifications of pathogenicity ★ ⚠ same condition
KIT c.925+5del Uncertain significance ★ same condition
KIT p.Arg740Ile Uncertain significance ★ ⚠ same residue

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/kit-p-arg740del (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown