Is KIT p.Met541Leu (c.1621A>C) pathogenic?

KIT p.Met541Leu (c.1621A>C) is classified Benign/Likely benign in KIT (ClinVar, Multiple submitters, 15 submitters; last evaluated 2026-06-04). AlphaMissense: likely benign (0.0833); Common (popmax 10.6%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with hereditary neoplastic syndrome.

What condition is associated with KIT p.Met541Leu (c.1621A>C)?

KIT p.Met541Leu (c.1621A>C) is associated with hereditary neoplastic syndrome, mastocytosis, piebaldism (ClinVar).

What do computational predictors say about KIT p.Met541Leu (c.1621A>C)?

AlphaMissense predicts likely benign (score 0.0833) — an in-silico prediction, not a clinical call.

KIT p.Met541Leu

Q: How common is KIT p.Met541Leu (c.1621A>C) in the general population?

KIT p.Met541Leu (c.1621A>C) is common (popmax 10.6%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1621A>C · rs3822214 · VCV41599

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

AlphaMissense

likely benign

0.0833 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 10.6%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
AlphaMissense	0.0833	likely benign
REVEL	0.419	indeterminate
SaProt	LLR -4.65	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.7	GERP 0.14, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 277 bp · p 0.96 · regional, not allelic
Overall
CADD	15.52	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 10.6% European (non-Finnish) · 124,671/1,179,790 alleles

Filtering AF 10.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 10.5%

Overall 9.53% 153,825/1,613,890 alleles · common

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	10.6%	9
Ashkenazi Jewishnot grpmax-eligible	9.72%	10
Remaining individualsnot grpmax-eligible	9.51%	11
Middle Eastern	7.74%	13
South Asian	7.72%	13
African / African-American	6%	17
Admixed American	5.45%	18
East Asian	4.87%	21
Finnishnot grpmax-eligible	4.44%	23
Amishnot grpmax-eligible	3.51%	29

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.

Cancer therapy — CIViC

Disease	Therapies	Level	Significance
Chronic Leukemia	Imatinib	C	Sensitivity/Response
Chronic Myeloid Leukemia		B	Positive
Colon Signet Ring Adenocarcinoma	Imatinib	E	Sensitivity/Response
Merkel Cell Carcinoma		B	Positive

Variant & gene context

Gene: KIT
Protein: p.Met541Leu
Coding: c.1621A>C
MANE Select: NM_000222
dbSNP: rs3822214
Type: single nucleotide variant
Location: chr4:54727298 (GRCh38)
Gene constraint: LOEUF 0.24 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 78.52 · 65 PDB
Residue 541: a UniProt-annotated variant site (in)

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

Also linked: mastocytosis piebaldism gastrointestinal stromal tumor lip and oral cavity carcinoma

Similar variants

KIT p.Met541Thr 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-met541leu (accessed [today's date]).

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