NM_000455.5:c.112C>G (p.Pro38Ala) in STK11 is a missense variant with no functional, segregation, or case-control data available. The variant is extremely rare in population databases, absent from gnomAD v2.1 and present in gnomAD v4.1 at AF=5.58e-06 (9/1,613,804 alleles), meeting PM2 at supporting level.1 Multiple in silico tools predict no deleterious effect: SpliceAI max delta=0.0, REVEL=0.328, BayesDel=-0.085, meeting BP4 at supporting benign level.2 ClinVar reports the variant as Uncertain Significance by multiple clinical laboratories (Variation ID 458014) with no expert panel classification.3 The variant does not reside in a known functional domain or mutational hotspot. No same-residue pathogenic comparator (PM5) or de novo evidence (PS2/PM6) was identified. Overall, the available evidence is limited to population frequency data (PM2_supporting) and computational predictions (BP4_supporting_benign), which offset each other. The variant remains a Variant of Uncertain Significance.
STK11
Final classification
VUS
STK11 c.112C>G · p.Pro38Ala
STK11
NM_000455.5:c.112C>G (p.Pro38Ala) in STK11 is a missense variant with no functional, segregation, or case-control data available.
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 benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
STK11 c.112C>G
PM2 + BP4
→
VUS
Gene diagram
· NM_000455.5 · variants mapped to exon structure
STK11
NM_000455.5
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_000455.5:c.112C>G is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF = 5.58e-06; 9/1,613,804 alleles, no homozygotes). This is well below the 0.1% threshold for PM2 in the generic ACMG/AMP framework. The variant is also absent from gnomAD-Canada v1.0.
Absent from gnomAD v2.1gnomAD v4.1 AF=5.58e-06 (9/1613
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact on the gene product. SpliceAI predicts no splice impact (max delta = 0.0). REVEL score is 0.328, below pathogenic thresholds. BayesDel score is -0.085 (negative, favoring a benign interpretation). These findings meet BP4 at supporting benign level.
SpliceAI max delta=0.0REVEL=0.328BayesDel=-0.085 (favoring benign).
Assessed · not applied
Pathogenic
PS1
No evidence of a different pathogenic missense change at the same amino acid residue (Pro38) was identified.
PS2
No de novo reports were identified for NM_000455.5:c.112C>G in the available literature or ClinVar submissions.
PS3
No well-established functional studies demonstrating a damaging effect for NM_000455.5:c.112C>G (p.Pro38Ala) were identified.
PS4
No case-control studies or cohort analyses demonstrate enrichment of NM_000455.5:c.112C>G in affected individuals.
PM1
The variant resides at codon 38 (p.Pro38Ala), which is in the N-terminal region of STK11, upstream of the kinase domain (residues ~49-309).
PM5
No confirmed pathogenic missense variant at the same amino acid residue (Pro38) with a different amino acid substitution was identified.
PM6
No de novo reports were identified for NM_000455.5:c.112C>G.
PP1
No segregation data are available for NM_000455.5:c.112C>G.
PP3
Multiple in silico tools do not support a deleterious effect for NM_000455.5:c.112C>G (p.Pro38Ala).
PP4
No specific phenotypic data are available for individuals carrying NM_000455.5:c.112C>G.
PP5
No reputable source has classified NM_000455.5:c.112C>G as pathogenic.
Benign
BA1
The allele frequency of NM_000455.5:c.112C>G in gnomAD v4.1 is 5.58e-06 (0.00056%), far below the 1% BA1 threshold.
BS1
The allele frequency of NM_000455.5:c.112C>G in gnomAD v4.1 is 5.58e-06 (0.00056%), well below the 0.3% BS1 threshold.
BS2
While 9 alleles are observed in gnomAD v4.1 (no homozygotes), the number is too low to assess whether the variant is observed in healthy adults at a frequency expected for a fully penetrant disorder.
BS3
No well-established functional studies demonstrating no damaging effect for NM_000455.5:c.112C>G (p.Pro38Ala) were identified.
BS4
No segregation data are available to assess lack of segregation with disease.
BP1
BP1 applies to missense variants in genes where primarily truncating variants are known to cause disease.
BP2
No observation of NM_000455.5:c.112C>G in trans with a known pathogenic STK11 variant was identified.
BP5
No cases have been identified where an individual carrying NM_000455.5:c.112C>G has an alternate molecular basis for disease.
BP6
No reputable source has classified NM_000455.5:c.112C>G as benign.
BP7
BP7 applies to synonymous variants with no predicted splice impact.
N/A · 5
PVS1 · PM3 · PM4 · PP2 · BP3
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 5.57689e-06; MAF= 0.00056%, 9/1613804 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 3.12705e-05; MAF= 0.00313%, 2/63958 alleles, homozygotes = 0); grpmax FAF= 2.47e-06.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00056%
· 9 / 1,613,804
0 hom · FAF 0.00025%
0 hom · FAF 0.00025%
European (Finnish) 2 / 63,958 |
0.0031% |
European (non-Finnish) 7 / 1,179,868 |
0.00059% |
+ 8 not observed (Remaining individuals, Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 458014)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.328. BayesDel score = -0.0851511.
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. STK11, a tumor suppressor and intracellular kinase, is frequently 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 not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 9 PMIDs not cited in assessment
25645574 ↗
ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
31672839 ↗
Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium.
CLINVAR
15604628 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
CLINVAR
23788249 ↗
ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.
CLINVAR
25356965 ↗
ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.
CLINVAR
25394175 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR