The MAP2K2 c.383C>A (p.Pro128Gln, p.P128Q) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as Pathogenic, including review by the ClinGen RASopathy Variant Curation Expert Panel.1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population reference datasets.2 In a published functional study, p.Pro128Gln increased downstream ERK phosphorylation relative to wild type, consistent with an activating effect, and RASopathy VCEP-approved functional assay tables include this variant among pathogenic validation controls for MEK and ERK activation assays.3 Computational evidence supports a damaging effect, with REVEL 0.928 above the MAP2K2 RASopathy PP3 threshold of 0.7 and BayesDel 0.495827 in the damaging direction, while SpliceAI predicts no meaningful splice alteration with a maximum delta score of 0.01.4
Final classification
VUS
PM1PS3PP5PP3PM2
MAP2K2
c.383C>A
p.Pro128Gln
This variant
The MAP2K2 c.383C>A (p.Pro128Gln, p.P128Q) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as Pathogenic, including review by the ClinGen RASopathy Variant Curation Expert Panel.
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MAP2K2 Version 2.3.0 v2.3.0 criteria-combination framework was evaluated deterministically with applied criteria: PM1 moderate, PS3 moderate, PP5 supporting, PP3 supporting, PM2 supporting; no rule matched the adjudicated criteria.
Classification rationale
PM1PS3PP5PP3PM2
VUS
MAP2K2 c.383C>A
PM1 + PS3 + PP5 + PP3 + PM2
→
VUS
3
PMID:20358587 ↗vcep_svi_rasopathy_vcep_v2_approved_functional_studies
4
revelbayesdelspliceai ↗cspec ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_030662.4 · variants mapped to exon structure
MAP2K2
NM_030662.4
Fetching transcript structure from UCSC…
Applied criteria · 5 applied · 13 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 5
Strength
Supporting
Moderate
Strong
Very strong
PS3
moderate
review
Pathogenic
In a published functional study, HEK293T cell assays showed increased downstream ERK phosphorylation for p.Pro128Gln relative to wild type, consistent with an activating effect. The RASopathy VCEP approved functional-study tables also list p.Pro128Gln among pathogenic validation controls for both MEK activation and ERK activation assays, supporting PS3 using two approved assay types.
PMID 20358587 reported increased ERK phosphorylation after transient transfection.VCEP approved assay workbook lists p.Pro128Gln as a pathogenic validation control in MEK and ERK activation assays.
PM1
moderate
Pathogenic
This missense variant affects MAP2K2 codon 128, which falls within the ClinGen RASopathy Expert Panel MAP2K2 critical functional domain spanning amino acids 128-138; this supports PM1 at Moderate strength.
MAP2K2 p.Pro128Gln lies within the VCEP-defined critical region AA128-138.
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and gnomAD v4.1, meeting the RASopathy PM2 criterion at Supporting strength for absence from population controls.
Absent from gnomAD v2.1.Absent from gnomAD v4.1.
PP3
supporting
Pathogenic
For this missense variant, the REVEL score is 0.928, which is above the RASopathy PP3 threshold of 0.7. BayesDel is also positive at 0.495827, supporting a deleterious effect, while SpliceAI predicts no meaningful splice impact with a maximum delta score of 0.01.
REVEL 0.928.BayesDel 0.495827.SpliceAI max delta score 0.01.
Assessed · not applied
· 5 not met · 8 not assessed
Pathogenic
PS1
Available evidence reviewed here does not establish that the same amino acid change, p.Pro128Gln, has been independently reported as a previously established pathogenic variant from a different nucleotide change or validated analogous residue change.
PS2
Available case evidence does not support a confirmed de novo occurrence for this variant.
PS4
This variant has been reported in affected individuals, but the available evidence does not provide enough point-based case data to determine whether the RASopathy PS4 threshold is met.
PM5
Available evidence reviewed here does not establish whether a different pathogenic missense change at the same codon, or a validated analogous pathogenic residue change under the MAP2K1/MAP2K2 paralog rule, is present for this variant.
PM6
Available case evidence does not support a presumed de novo occurrence for this variant.
PP1
This variant has been reported in an affected family, but the available evidence does not provide enough detail to count informative meioses under the RASopathy PP1 point thresholds.
Benign
BA1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0%, which is below the BA1 threshold of 0.05%.
BS1
This variant is absent from gnomAD v2.1 and gnomAD v4.1, so the observed population frequency is 0%, which is below the BS1 threshold of 0.025%.
BS2
No evidence was identified showing this variant in unaffected individuals in a manner that would contribute benign points under the RASopathy BS2 framework.
BS4
No non-segregation data were identified for this variant.
BP2
No evidence was identified for this variant occurring with an alternative molecular cause that would contribute negative points under the RASopathy-specific BP2 framework.
BP4
For this missense variant, the REVEL score is 0.928, which is above the BP4 benign threshold of 0.3, so computational evidence does not support a benign effect.
BP5
No evidence was identified for an alternative molecular explanation that would contribute negative points under the RASopathy-specific BP5 framework.
N/A · 10
PVS1 · PM3 · PM4 · PP2 · PP4 · BS3 · BP1 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.928. BayesDel score = 0.495827.
Functional
Likely Oncogenic
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MAP2K2, an intracellular kinase, is altered by mutation in various cancer types.
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.
Literature · how each cited paper was used
1papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.
Molecular and functional analysis of a novel MEK2 mutation in cardio-facio-cutan
Found
Structured finding pending for this record — see source link.
Applied to
→PS3
moderate
Sources & reference links