Is KIT p.Lys558= (c.1674G>A) pathogenic?

KIT p.Lys558= (c.1674G>A) is classified Conflicting classifications of pathogenicity in KIT (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2026-06-04). Ultra-rare (popmax 0.0187%, afr); Associated with mastocytosis.

What condition is associated with KIT p.Lys558= (c.1674G>A)?

KIT p.Lys558= (c.1674G>A) is associated with mastocytosis, piebaldism, gastrointestinal stromal tumor (ClinVar).

How common is KIT p.Lys558= (c.1674G>A) in the general population?

KIT p.Lys558= (c.1674G>A) is ultra-rare (popmax 0.0187%, afr) (gnomAD).

KIT p.Lys558=

c.1674G>A · rs200375589 · VCV220634

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 8 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0187%, afr)

Conditions

mastocytosis

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP -0.42, phastCons 1
Overall
CADD	8.36	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0187% African / African-American · 14/75,042 alleles

Filtering AF 0.0116% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0109%

Overall 0.0109% 176/1,614,126 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0187%	5,360
European (non-Finnish)	0.0133%	7,516
Remaining individualsnot grpmax-eligible	0.0064%	15,626
Finnishnot grpmax-eligible	0.00156%	64,026

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.Lys558=
Coding: c.1674G>A
MANE Select: NM_000222
dbSNP: rs200375589
Type: single nucleotide variant
Location: chr4:54727442 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.52 · 65 PDB
Residue 558: a β-strand; a UniProt-annotated variant site (in gist; somatic mutation)

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

Disease context

mastocytosis — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: piebaldism gastrointestinal stromal tumor hereditary neoplastic syndrome

Similar variants

KIT p.Lys558Asn Uncertain significance ★★ ⚠ same residue
KIT p.Ala621Thr Pathogenic/Likely pathogenic ★★ same condition
KIT p.Asp820Tyr Pathogenic ★★ same condition
KIT p.Gln190Ter Pathogenic ★★ same condition
KIT p.Leu576Pro Pathogenic/Likely pathogenic ★★ same condition
KIT p.Lys642Glu Pathogenic ★★ same condition
KIT p.Trp557Arg Pathogenic/Likely pathogenic ★★ same condition
KIT p.Val559Ala Pathogenic/Likely pathogenic ★★ same condition

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-lys558 (accessed [today's date]).

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