NM_012289.4:c.1222C>A (p.Pro408Thr) in KEAP1 is a rare missense variant present at extremely low frequency in population databases (gnomAD v2.1 AF=0.00337%, v4.1 AF=0.00108%), satisfying PM2 at supporting strength.1 Multiple independent in silico tools (REVEL 0.295, BayesDel -0.344, SpliceAI 0.01) consistently predict no deleterious impact on protein function or splicing, satisfying BP4 at supporting strength.2 The variant is classified as Uncertain significance by a single clinical laboratory in ClinVar (VCV2209515). No expert panel review is available, and no variant-specific publications or functional studies were identified.3 KEAP1 germline mutations cause familial multinodular goiter, with both truncating and missense variants reported as pathogenic (PMID:39373520). Codon 408 falls within the Kelch repeat domain but is not a statistically significant cancer hotspot residue. Under the generic ACMG/AMP 2015 classification framework (PMID:25741868), the tally is PM2 (supporting pathogenic) + BP4 (supporting benign). With one supporting criterion for each direction, the combined evidence is insufficient to classify as either likely benign or likely pathogenic, resulting in a final classification of Uncertain significance.4
KEAP1
Final classification
VUS
KEAP1 c.1222C>A · p.Pro408Thr
KEAP1
NM_012289.4:c.1222C>A (p.Pro408Thr) in KEAP1 is a rare missense variant present at extremely low frequency in population databases (gnomAD v2.1 AF=0.00337%, v4.1 AF=0.00108%), satisfying PM2 at supporting strength.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
KEAP1 c.1222C>A
PM2 + BP4
→
VUS
Gene diagram
· NM_012289.4 · variants mapped to exon structure
KEAP1
NM_012289.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 20 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
This variant is present in gnomAD at extremely low frequency in population databases: v2.1 AF=3.37e-05 (0.00337%, 7/207,868 alleles, 0 homozygotes) and v4.1 AF=1.08e-05 (0.00108%, 17/1,578,050 alleles, 0 homozygotes). The global allele frequency is well below the 0.1% threshold for PM2 under non-VCEP gnomAD rules. No homozygous individuals have been observed.
gnomAD v2.1: AF=0.00337% (7/2078680 homozygotes)
✓
BP4
supporting
Benign
Multiple independent lines of computational evidence consistently predict no deleterious impact: REVEL score 0.295 (below the 0.5 pathogenicity threshold, predicting benign), BayesDel score -0.344 (negative score, predicting benign), and SpliceAI maximum delta 0.01 (no predicted splice-altering effect). This concordance across three in silico tools satisfies BP4 at supporting strength.
REVEL: 0.295 (<0.5predicts benign)BayesDel: -0.344 (negative
Assessed · not applied
Pathogenic
PS1
No alternative nucleotide change at codon 408 resulting in the same Pro408Thr amino acid substitution has been reported as pathogenic.
PS2
No de novo observation has been reported for this variant.
PS3
No variant-specific functional studies have been identified for NM_012289.4:c.1222C>A (p.Pro408Thr).
PS4
No case-control enrichment data are available.
PM1
While codon 408 resides within the Kelch repeat domain of KEAP1 (a well-characterized NRF2-binding domain critical for KEAP1 function), cancerhotspots.org does not identify this residue as a statistically significant hotspot (residue_significant: false).
PM5
No different amino acid change at codon 408 has been identified as pathogenic.
PM6
No de novo observation (confirmed or assumed) has been reported for this variant.
PP1
No co-segregation data are available.
PP2
PP2 requires a low rate of benign missense variation in the gene (e.g., high missense Z-score) and missense variants as a common disease mechanism.
PP3
In silico computational tools do not support a deleterious effect: REVEL score 0.295 (below 0.5 threshold, predicts benign), BayesDel score -0.344 (negative, predicts benign), SpliceAI max delta 0.01 (no predicted splice impact).
PP4
No patient phenotype or family history data are available to evaluate whether the clinical presentation is highly specific for a KEAP1-related disorder with a single genetic etiology.
PP5
ClinVar reports this variant as Uncertain significance (1 submitter, criteria provided, single submitter; not an expert panel).
Benign
BA1
The global population allele frequency in gnomAD v2.1 is 0.00337% (AF=3.37e-05) and in v4.1 is 0.00108% (AF=1.08e-05), both far below the BA1 threshold of 1% (>0.01).
BS1
The global population allele frequency in gnomAD v2.1 is 0.00337% and in v4.1 is 0.00108%, both well below the BS1 threshold of 0.3% under non-VCEP gnomAD rules.
BS2
BS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age.
BS3
No well-established in vitro or in vivo functional studies demonstrating no deleterious effect have been identified for this variant.
BS4
No family segregation data are available.
BP1
BP1 applies to missense variants in genes where primarily truncating variants cause disease.
BP2
No data are available regarding observation of this variant in trans with a pathogenic variant or in cis with a pathogenic variant.
BP6
ClinVar reports this variant as Uncertain significance, not benign.
N/A · 3
PVS1 · BP5 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.07728e-05; MAF= 0.00108%, 17/1578050 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.37558e-05; MAF= 0.00138%, 16/1163148 alleles, homozygotes = 0); grpmax FAF= 8.14e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.36752e-05; MAF= 0.00337%, 7/207868 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 7.40631e-05; MAF= 0.00741%, 7/94514 alleles, homozygotes = 0); grpmax FAF= 3.472e-05.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.00016286644951140066, 3/18420 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0011%
· 17 / 1,578,050
0 hom · FAF 0.00081%
0 hom · FAF 0.00081%
European (non-Finnish) 16 / 1,163,148 |
0.0014% |
African/African American 1 / 73,896 |
0.0014% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0034%
· 7 / 207,868
0 hom · FAF 0.0035%
0 hom · FAF 0.0035%
European (non-Finnish) 7 / 94,514 |
0.0074% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
0.016%
· 3 / 18,420
0 hom · FAF 0.0069%
0 hom · FAF 0.0069%
European (non-Finnish) 3 / 11,740 |
0.026% |
+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 2209515)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.295. BayesDel score = -0.344485.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. KEAP1, a tumor suppressor and adaptor protein, is recurrently mutated in lung cancer.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV105847274, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links