About MAP2K2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
MAP2K2 c.383C>A, p.(Pro128Gln)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is ClinGen MAP2K2 VCEP v2.3.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 5
Benign evidence criteria: 0
Pathogenic criteria applied · 5
PS3Moderate
PS3 · moderate
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.
PM1Moderate
PM1 · moderate
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.
PM2Supporting
PM2 · supporting
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.
PP3Supporting
PP3 · supporting
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.
PP5Supporting
PP5 · supporting
Expert panel ClinGen RASopathy Variant Curation Expert Panel classified as Pathogenic.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Functional evidence
Statement recorded
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 assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen MAP2K2 VCEP v2.3.0, with the data and sources behind each one.
28 criteria with recorded statuses: 5 met · 5 not met · 8 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
This variant is absent from gnomAD v2.1 and gnomAD v4.1, supporting rarity in population reference datasets.
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.
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.
No criteria match.
Met · 5
PS3 ModerateIn 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. Details ▾Hide ▴
Rule
RASopathy PS3: Moderate for two or more different approved assays; Supporting for one approved assay.
Evidence considered
- 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.
Still missing
- Variant-level confirmation across both approved assays would benefit from direct full-text review of all cited experimental details.
Sources
PM1 ModerateThis 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. Details ▾Hide ▴
Rule
RASopathy MAP2K2 PM1: applicable only to critical and well-established functional domains at AA 47-65 or AA 128-138.
Evidence considered
- MAP2K2 p.Pro128Gln lies within the VCEP-defined critical region AA128-138.
Sources
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD v4.1, meeting the RASopathy PM2 criterion at Supporting strength for absence from population controls. Details ▾Hide ▴
Rule
RASopathy PM2: Supporting when absent from controls (gnomAD).
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
PP3 SupportingFor 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. Details ▾Hide ▴
Rule
RASopathy PP3 for missense variants: REVEL >=0.7; for splicing, predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.928.
- BayesDel 0.495827.
- SpliceAI max delta score 0.01.
Sources
Not met · 5 · evaluated, threshold not reached
PS2 Available case evidence does not support a confirmed de novo occurrence for this variant. Instead, the reported family data describe vertical transmission, so PS2 is not met from the evidence reviewed here. Details ▾Hide ▴
Rule
RASopathy PS2 is point-based for confirmed de novo occurrences.
Evidence considered
- PMID 20358587 describes transmission through four generations.
Still missing
- No confirmed de novo occurrence with parental testing was identified from the available materials.
Sources
PM6 Available case evidence does not support a presumed de novo occurrence for this variant. The reported data instead describe familial transmission, so PM6 is not met from the evidence reviewed here. Details ▾Hide ▴
Rule
RASopathy PM6 is point-based for assumed de novo occurrences.
Evidence considered
- PMID 20358587 describes transmission through four generations.
Still missing
- No presumed de novo occurrence without confirmed parentage was identified from the available materials.
Sources
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%. Details ▾Hide ▴
Rule
RASopathy BA1: gnomAD filtering allele frequency >=0.05%.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
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%. Details ▾Hide ▴
Rule
RASopathy BS1: gnomAD filtering allele frequency >=0.025%.
Evidence considered
- Absent from gnomAD v2.1.
- Absent from gnomAD v4.1.
Sources
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. BayesDel is also positive at 0.495827 rather than benign, and SpliceAI shows no meaningful splice effect with a maximum delta score of 0.01. Details ▾Hide ▴
Rule
RASopathy BP4 for missense variants: REVEL <=0.3.
Evidence considered
- REVEL 0.928 exceeds the benign cutoff <=0.3.
- BayesDel 0.495827 is not benign-supporting.
- SpliceAI max delta score 0.01.
Sources
Not assessed · 8 · no assessment recorded
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. Details ▾Hide ▴
Rule
RASopathy PS1 allows the same amino acid change as a previously established pathogenic variant, including observed analogous residue positions in MAP2K1 and MAP2K2.
Evidence considered
- ClinVar confirms pathogenic classification for c.383C>A but does not by itself establish PS1 from a different nucleotide change.
Still missing
- An alternate nucleotide encoding the same amino acid change was not identified from the available materials.
Sources
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. Details ▾Hide ▴
Rule
RASopathy PS4: Supporting for >=1 point, Moderate for >=3 points, Strong for >=5 points.
Evidence considered
- ClinVar includes a Pathogenic expert-panel classification.
- PMID 20358587 reports affected individuals with p.Pro128Gln.
Still missing
- Number of qualifying unrelated probands was not established.
- PS4 point assignment could not be calculated from the available materials.
Sources
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. Details ▾Hide ▴
Rule
RASopathy PM5: Moderate for one pathogenic missense change at the same codon; Strong for >=2 different pathogenic changes at the same codon observed in >=5 probands.
Evidence considered
- RASopathy PM5 allows analogous residue positions in MAP2K1 and MAP2K2.
Still missing
- Same-codon or validated analogous-residue evidence was not directly resolved from the available retrieved materials.
Sources
cspec ↗vcep_map2k_alignment
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. Details ▾Hide ▴
Rule
RASopathy PP1: Supporting for >=3 informative meioses, Moderate for >=5, Strong for >=7.
Evidence considered
- PMID 20358587 describes vertical transmission in an affected family.
Still missing
- Number of informative meioses was not established.
- Segregation details for all tested relatives were not fully available.
Sources
BS2 No evidence was identified showing this variant in unaffected individuals in a manner that would contribute benign points under the RASopathy BS2 framework. Details ▾Hide ▴
Rule
RASopathy BS2 is point-based for observations in unaffected individuals.
Still missing
- Unaffected carrier data were not available.
Sources
BS4 No non-segregation data were identified for this variant. Available evidence does not show the variant tracking away from disease in informative meioses. Details ▾Hide ▴
Rule
RASopathy BS4 requires at least one informative meiosis showing lack of segregation.
Evidence considered
- Published evidence describes affected familial transmission rather than non-segregation.
Still missing
- Informative non-segregation data were not available.
Sources
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. Details ▾Hide ▴
Rule
RASopathy BP2 is point-based for alternative molecular causes/phase context.
Still missing
- Phase and alternate molecular diagnosis data were not available.
BP5 No evidence was identified for an alternative molecular explanation that would contribute negative points under the RASopathy-specific BP5 framework. Details ▾Hide ▴
Rule
RASopathy BP5 is point-based for alternative molecular causes.
Still missing
- Alternative molecular diagnosis data were not available.
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis variant is a missense substitution and does not fall into the null-variant categories used for PVS1 assessment. The MAP2K2 RASopathy specification also marks PVS1 as not applicable. Details ▾Hide ▴
Rule
PVS1 not applicable in the MAP2K2 RASopathy specification for this missense variant.
Evidence considered
- Variant is p.Pro128Gln missense.
- PVS1 variant assessment did not place this variant in a PVS1 null-variant bucket.
Sources
cspec ↗pvs1_variant_assessment
PM3 N/AThe ClinGen RASopathy Expert Panel marks PM3 as not applicable for MAP2K2 in this framework. Details ▾Hide ▴
Rule
PM3 not applicable in the MAP2K2 RASopathy specification.
Evidence considered
- CSPEC lists PM3 as not applicable.
Sources
PM4 N/APM4 addresses protein length changes such as in-frame insertions or deletions and stop-loss variants. This variant is a missense substitution, so PM4 does not apply. Details ▾Hide ▴
Rule
PM4 applies to protein length changes, not missense substitutions.
Evidence considered
- Variant is a missense substitution.
Sources
PP2 N/AThe ClinGen RASopathy Expert Panel marks PP2 as not applicable for MAP2K2 in this framework. Details ▾Hide ▴
Rule
PP2 not applicable in the MAP2K2 RASopathy specification.
Evidence considered
- CSPEC lists PP2 as not applicable.
Sources
PP4 N/AThe ClinGen RASopathy Expert Panel marks PP4 as not applicable for MAP2K2 in this framework. Details ▾Hide ▴
Rule
PP4 not applicable in the MAP2K2 RASopathy specification.
Evidence considered
- CSPEC lists PP4 as not applicable.
Sources
BS3 N/AThe ClinGen RASopathy Expert Panel marks BS3 as not applicable for MAP2K2 in this framework. Details ▾Hide ▴
Rule
BS3 not applicable in the MAP2K2 RASopathy specification.
Evidence considered
- CSPEC lists BS3 as not applicable.
Sources
BP1 N/ABP1 in this specification is intended for truncating variants in genes without an established loss-of-function disease mechanism. This variant is missense, so BP1 does not apply. Details ▾Hide ▴
Rule
RASopathy BP1 is used for truncating variants under specified contraindications, not missense variants.
Evidence considered
- Variant is missense
- not truncating.
Sources
BP3 N/AThe ClinGen RASopathy Expert Panel marks BP3 as not applicable for MAP2K2 in this framework. Details ▾Hide ▴
Rule
BP3 not applicable in the MAP2K2 RASopathy specification.
Evidence considered
- CSPEC lists BP3 as not applicable.
Sources
BP6 N/AThe ClinGen RASopathy Expert Panel marks BP6 as not applicable for MAP2K2 in this framework. Details ▾Hide ▴
Rule
BP6 not applicable in the MAP2K2 RASopathy specification.
Evidence considered
- CSPEC lists BP6 as not applicable.
Sources
BP7 N/ABP7 is for synonymous or certain noncoding variants without predicted splice impact. This variant is a missense change, so BP7 does not apply. Details ▾Hide ▴
Rule
BP7 applies to synonymous/intronic/noncoding variants, not missense variants.
Evidence considered
- Variant is missense p.Pro128Gln.
- SpliceAI max delta score is 0.01.
Sources
Identifiers
- Gene
- MAP2K2
- Transcript
- NM_030662.4
- Coding (HGVS c.)
- NM_030662.4:c.383C>A
- Protein (HGVS p.)
- NP_109587.1:p.(Pro128Gln)
- GRCh38
- chr19:4110576 G>T
- GRCh37
- chr19:4110574 G>T
Gene diagram
Every interpreted variant in MAP2K2, mapped onto the exon structure of NM_030662.4. Select a row to find it on the plot.
MAP2K2NM_030662.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in MAP2K2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingFor 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. Details ▾Hide ▴
Rule
RASopathy PP3 for missense variants: REVEL >=0.7; for splicing, predicted outcome must match disease mechanism.
Evidence considered
- REVEL 0.928.
- BayesDel 0.495827.
- SpliceAI max delta score 0.01.
Sources
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. BayesDel is also positive at 0.495827 rather than benign, and SpliceAI shows no meaningful splice effect with a maximum delta score of 0.01. Details ▾Hide ▴
Rule
RASopathy BP4 for missense variants: REVEL <=0.3.
Evidence considered
- REVEL 0.928 exceeds the benign cutoff <=0.3.
- BayesDel 0.495827 is not benign-supporting.
- SpliceAI max delta score 0.01.
Sources
BP7 N/ABP7 is for synonymous or certain noncoding variants without predicted splice impact. This variant is a missense change, so BP7 does not apply. Details ▾Hide ▴
Rule
BP7 applies to synonymous/intronic/noncoding variants, not missense variants.
Evidence considered
- Variant is missense p.Pro128Gln.
- SpliceAI max delta score is 0.01.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.928. BayesDel score = 0.495827.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/643243118
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/8275/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/19-4110574-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr19-4110576-G-T?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_030662.4%3Ac.383C…
- OncoKB ↗www.oncokb.org/gene/MAP2K2/P128Q
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=MAP2K2+c.383C%3EA
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
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
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.