About PPP2R1A
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PPP2R1A c.739A>G, p.(Thr247Ala)
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
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Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. 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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0, and present at an extremely low allele frequency in gnomAD v4.1 (1/1,610,866 alleles; AF = 6.21 × 10⁻⁷, 0.00006%), well below the 0.1% PM2 threshold for a rare variant absent from population databases. This constitutes PM2 at supporting strength.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.285 (below commonly used pathogenic threshold of 0.5), BayesDel score is -0.184741 (negative, predicted benign), and SpliceAI predicts no splicing alteration (max delta = 0.00). All three in silico predictors are concordant in not supporting a deleterious effect.
Recorded classification: Uncertain significance
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.
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
1 / 1,610,866 alleles
gnomAD v4.1: 1 / 1,610,866 alleles. Recorded AF 6.20784e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
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. PPP2R1A encodes a serine/threonine phosphatase that regulates cell growth and division. PPP2R1A is frequently mutated in endometrial and ovarian cance
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 22 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_014225.5:c.739A>G (p.Thr247Ala) is a missense variant in exon 6 of PPP2R1A, a gene associated with autosomal dominant Houge-Janssens syndrome type 2 (neurodevelopmental disorder). PVS1 is not applicable as this is a missense variant that does not fall into null-variant categories.
This variant is absent from gnomAD v2.1 and gnomAD-Canada, and is present at an extremely low frequency in gnomAD v4.1 (1/1,610,866 alleles; AF = 6.21 × 10⁻⁷), satisfying PM2 at supporting strength.
Multiple in silico predictors do not support a deleterious effect: REVEL score is 0.285 (below pathogenic threshold of 0.5), BayesDel score is −0.185 (predicted benign), and SpliceAI predicts no splicing impact (max delta = 0.00), satisfying BP4 at supporting strength.
No variant-specific functional studies, de novo reports, case-control data, segregation data, or ClinVar classifications exist for this variant. No pathogenic comparator variant at the same codon or residue has been identified. All remaining criteria are not met or not applicable.
The only applicable criteria are PM2_supporting and BP4_supporting, which carry equal and opposite weight. Under the generic ACMG/AMP 2015 combination rules (PMID:25741868), one supporting pathogenic criterion and one supporting benign criterion cancel each other, resulting in a classification of Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0, and present at an extremely low allele frequency in gnomAD v4.1 (1/1,610,866 alleles; AF = 6.21 × 10⁻⁷, 0.00006%), well below the 0.1% PM2 threshold for a rare variant absent from population databases. This constitutes PM2 at supporting strength. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles).
- gnomAD v4.1: 1/1
- 610
- 866 alleles (AF = 6.21e-07)
- 0 homozygotes.
- Absent from gnomAD-Canada v1.0.
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.285 (below commonly used pathogenic threshold of 0.5), BayesDel score is -0.184741 (negative, predicted benign), and SpliceAI predicts no splicing alteration (max delta = 0.00). All three in silico predictors are concordant in not supporting a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL 0.285 (below 0.5 pathogenic threshold).
- BayesDel -0.184741 (predicted benign).
- SpliceAI max delta 0.00 (no splicing impact).
Sources
Not met · 22 · evaluated, threshold not reached
PS1 No same-amino-acid change (Thr247Ala or T247A) has been reported as pathogenic via a different nucleotide change in ClinVar or the literature. PS1 cannot be applied without an established pathogenic comparator at this position. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no pathogenic comparator at Thr247 identified.
Still missing
- No established pathogenic variant with the same amino acid change exists for comparison.
Sources
PS2 No de novo occurrence with confirmed parentage has been reported for NM_014225.5:c.739A>G. Literature search and ClinVar review did not identify any trio-based de novo observations for this variant. Details ▾Hide ▴
Evidence considered
- Exploratory search of PubMed
- ClinVar
- and DECIPHER found no de novo reports for this exact variant.
Still missing
- No de novo observation with confirmed maternity and paternity.
Sources
PS3 No variant-specific functional assays (e.g., PP2A phosphatase activity, substrate binding, or HEAT repeat structural integrity) have been performed for p.Thr247Ala. Well-established in vitro or in vivo functional studies supportive of a damaging effect are absent. Details ▾Hide ▴
Evidence considered
- No allelic functional data for p.Thr247Ala
- general PPP2R1A functional studies exist for other residues (e.g.
- p.Arg258Cys) but not for this variant.
Still missing
- No variant-specific functional data available.
PS4 The variant is extremely rare (1/1,610,866 alleles in gnomAD v4.1). No case-control study demonstrates statistically enriched prevalence in affected individuals. The variant is absent from ClinVar, precluding affected case counts. Rarity in the general population does not independently satisfy PS4. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 1 allele in 1
- 610
- 866
- absent from ClinVar
- no case-control enrichment demonstrated.
Still missing
- No affected case counts or case-control data.
Sources
PM1 Residue Thr247 lies within HEAT repeat 6 of the PPP2R1A scaffold domain, a functionally important region for PP2A holoenzyme assembly. However, no statistical hotspot analysis (e.g., Cancer Hotspots) identifies position 247 as a recurrently mutated pathogenic site. Domain membership alone, without evidence of significant mutational clustering of pathogenic variants at this specific residue or immediate vicinity, is insufficient to meet PM1 under generic ACMG/AMP. Details ▾Hide ▴
Evidence considered
- Not in Cancer Hotspots
- exploratory review notes HEAT repeat 6 domain context but lacks residue-level clustering evidence.
Still missing
- No statistical enrichment of pathogenic missense variants at or immediately adjacent to residue 247.
Sources
oncokb ↗40781915
PM5 No pathogenic missense variant at the same amino acid residue (Thr247) has been identified in ClinVar. Automated candidate harvesting found zero same-residue comparator variants. PM5 requires a different pathogenic missense change at the same position, which is not available. Details ▾Hide ▴
Evidence considered
- pm5_candidates.json: zero same-residue candidates
- ClinVar absent for Thr247.
Still missing
- No pathogenic missense comparator at Thr247.
Sources
clinvar ↗pm5_candidates
PM6 No de novo observation (even without confirmed parentage) has been reported for NM_014225.5:c.739A>G. Literature and ClinVar searches did not identify any presumed de novo occurrence. Details ▾Hide ▴
Evidence considered
- No de novo report in ClinVar or literature for this variant.
Still missing
- No reported de novo occurrence
- with or without parental confirmation.
Sources
PP1 No families with multiple affected individuals segregating this variant have been published. No co-segregation data are available. Details ▾Hide ▴
Evidence considered
- No familial segregation data available for c.739A>G.
Still missing
- No co-segregation with disease in multiple affected family members.
PP2 While PPP2R1A is an autosomal dominant neurodevelopmental disorder gene in which missense variants are a known mechanism, PP2 additionally requires demonstration of a low rate of benign missense variation in the gene. REVEL (0.285) and BayesDel (-0.185) scores do not indicate strong constraint at this residue, and no gene-level missense constraint metric (e.g., missense Z-score above 3.09) has been provided. Under generic ACMG/AMP, PP2 is not met without this supporting constraint evidence. Details ▾Hide ▴
Evidence considered
- REVEL 0.285 (below pathogenic threshold)
- BayesDel -0.184741 (predicted benign)
- insufficient constraint evidence.
Still missing
- No gene-level missense constraint metric (e.g.
- gnomAD missense Z-score) demonstrated.
Sources
revelbayesdel
PP3 Multiple in silico prediction tools do not support a deleterious effect. REVEL score is 0.285 (below commonly used pathogenic threshold of 0.5), BayesDel score is -0.184741 (negative, predicting benign), and SpliceAI predicts no splicing impact (max delta = 0.00). No in silico tool predicts a damaging effect. Details ▾Hide ▴
Evidence considered
- REVEL 0.285 (not deleterious).
- BayesDel -0.184741 (predicted benign).
- SpliceAI max delta 0.00 (no splicing impact).
Sources
PP4 No clinical phenotype information for the proband is available for assessment. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology, which cannot be evaluated without clinical data. Details ▾Hide ▴
Evidence considered
- No proband phenotype data available.
Still missing
- Proband clinical phenotype information is unavailable.
PP5 The variant is absent from ClinVar. PP5 requires a reputable source (e.g., clinical diagnostic laboratory) to have classified the variant as pathogenic, which is not available. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no reputable source has classified this variant as pathogenic.
Still missing
- No reputable source classification of pathogenicity.
Sources
BA1 The variant is not a common polymorphism. gnomAD v4.1 allele frequency is 6.21 × 10⁻⁷ (0.00006%), far below the 1% BA1 threshold. The variant is absent from gnomAD v2.1 and gnomAD-Canada. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF = 6.21e-07
- well below 1% BA1 threshold.
Sources
BS1 The variant allele frequency in gnomAD v4.1 (6.21 × 10⁻⁷, 0.00006%) is far below the 0.3% BS1 threshold for a variant too common to cause a dominant fully penetrant disorder. The variant remains exceptionally rare. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF = 6.21e-07
- well below 0.3% BS1 threshold.
Sources
BS2 No homozygous observation of this variant has been reported in any population database. The single heterozygous observation in gnomAD v4.1 does not constitute observation in a healthy adult homozygous state, which is required for BS2. Details ▾Hide ▴
Evidence considered
- 0 homozygotes in gnomAD v4.1
- single heterozygous observation insufficient for BS2.
Still missing
- No homozygous observations in healthy adults.
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrate that p.Thr247Ala does not affect protein function. No functional assays specific to this variant have been performed. Details ▾Hide ▴
Evidence considered
- No variant-specific functional studies showing no damaging effect.
Still missing
- No functional data of any kind for this variant.
BS4 No segregation data are available in affected families. BS4 requires lack of segregation with disease, which cannot be evaluated without family studies. Details ▾Hide ▴
Evidence considered
- No segregation data available for evaluation.
Still missing
- No family segregation data.
BP1 BP1 applies when a missense variant occurs in a gene for which only truncating variants cause disease. PPP2R1A-related neurodevelopmental disorder (Houge-Janssens syndrome type 2) is primarily caused by missense variants, not solely truncating variants. BP1 is not applicable to this gene-disease mechanism. Details ▾Hide ▴
Evidence considered
- PPP2R1A-related NDD is primarily a missense-mediated disorder
- BP1 does not apply.
Sources
3794502440781915
BP2 The variant has not been observed in trans with a known pathogenic PPP2R1A variant. PPP2R1A-associated neurodevelopmental disorder is autosomal dominant, making such an observation unlikely. No observation in cis with a pathogenic variant has been reported either. Details ▾Hide ▴
Evidence considered
- No observation in trans or cis with a pathogenic PPP2R1A variant.
Still missing
- No phase information with pathogenic variants available.
BP5 BP5 requires a reputable source to have classified the variant as benign or to have found an alternative molecular basis for disease in a case. The variant is absent from ClinVar, and no such alternative molecular finding is documented. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no reputable source benign classification available.
Still missing
- No benign classification or alternative molecular finding from a reputable source.
Sources
BP6 The variant is absent from ClinVar. BP6 requires a reputable source to classify the variant as benign, which is not available. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no benign classification from a reputable source.
Still missing
- No reputable source benign classification.
Sources
PS5 No different missense change at the same codon (Thr247) has been established as pathogenic. PS5 requires a previously determined pathogenic variant at the same codon with a different amino acid substitution; no such comparator exists for codon 247. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no pathogenic variant at codon 247 identified with a different amino acid change.
Still missing
- No pathogenic comparator at the same codon.
Sources
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_014225.5:c.739A>G is a missense variant (p.Thr247Ala) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Per ClinGen SVI PVS1 recommendations (PMC6185798), PVS1 is not applicable to this variant class. Details ▾Hide ▴
Evidence considered
- Missense variant
- not a null variant
- apply_generic_pvs1_framework is false per pvs1_variant_assessment.
Sources
PM3 N/APPP2R1A-associated neurodevelopmental disorder is autosomal dominant. PM3 applies exclusively to recessive disorders (detected in trans with a pathogenic variant). Details ▾Hide ▴
Evidence considered
- Autosomal dominant inheritance
- PM3 is a recessive-only criterion.
PM4 N/AThis variant is a substitution, not a protein-length-altering change (in-frame deletion/insertion, stop-loss, or initiation codon variant). PM4 is trivially not applicable. Details ▾Hide ▴
Evidence considered
- Substitution variant
- no protein length alteration.
BP3 N/AThis variant is a substitution, not an in-frame insertion/deletion in a repetitive region. BP3 is trivially not applicable. Details ▾Hide ▴
Evidence considered
- Substitution variant in non-repetitive region.
BP7 N/ABP7 applies specifically to synonymous (silent) variants for which splicing prediction algorithms predict no impact and the nucleotide is not highly conserved. NM_014225.5:c.739A>G is a missense variant (p.Thr247Ala), not a synonymous variant. BP7 is not applicable to missense variants per ACMG/AMP framework. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is defined for synonymous variants only.
Identifiers
- Gene
- PPP2R1A
- Transcript
- NM_014225.5
- Coding (HGVS c.)
- NM_014225.5:c.739A>G
- Protein (HGVS p.)
- NP_055040.2:p.(Thr247Ala)
- GRCh38
- chr19:52213042 A>G
- GRCh37
- chr19:52716295 A>G
Gene diagram
Every interpreted variant in PPP2R1A, mapped onto the exon structure of NM_014225.5. Select a row to find it on the plot.
PPP2R1ANM_014225.5
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 PPP2R1A
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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
1 / 1,610,866 alleles
AF 6.21e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,610,866 alleles · 0 hom
| European (non-Finnish)1 / 1,179,334 | 8.5e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.20784e-07; MAF= 0.00006%, 1/1610866 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47936e-07; MAF= 0.00008%, 1/1179334 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.285
- BayesDel
- -0.185
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.285 (below commonly used pathogenic threshold of 0.5), BayesDel score is -0.184741 (negative, predicted benign), and SpliceAI predicts no splicing alteration (max delta = 0.00). All three in silico predictors are concordant in not supporting a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL 0.285 (below 0.5 pathogenic threshold).
- BayesDel -0.184741 (predicted benign).
- SpliceAI max delta 0.00 (no splicing impact).
Sources
PP3 Multiple in silico prediction tools do not support a deleterious effect. REVEL score is 0.285 (below commonly used pathogenic threshold of 0.5), BayesDel score is -0.184741 (negative, predicting benign), and SpliceAI predicts no splicing impact (max delta = 0.00). No in silico tool predicts a damaging effect. Details ▾Hide ▴
Evidence considered
- REVEL 0.285 (not deleterious).
- BayesDel -0.184741 (predicted benign).
- SpliceAI max delta 0.00 (no splicing impact).
Sources
BP7 N/ABP7 applies specifically to synonymous (silent) variants for which splicing prediction algorithms predict no impact and the nucleotide is not highly conserved. NM_014225.5:c.739A>G is a missense variant (p.Thr247Ala), not a synonymous variant. BP7 is not applicable to missense variants per ACMG/AMP framework. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is defined for synonymous variants only.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.285. BayesDel score = -0.184741.
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
1 / 1,610,866 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
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 ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_014225.5%3Ac.739A%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/19-52716295-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr19-52213042-A-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/19-52213042-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_014225.5%3Ac.739A…
- OncoKB ↗www.oncokb.org/gene/PPP2R1A/T247A
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PPP2R1A+c.739A%3EG
- 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
This variant is present in gnomAD v4.1 (AF= 6.20784e-07; MAF= 0.00006%, 1/1610866 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47936e-07; MAF= 0.00008%, 1/1179334 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.285. BayesDel score = -0.184741.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. PPP2R1A encodes a serine/threonine phosphatase that regulates cell growth and division. PPP2R1A is frequently mutated in endometrial and ovarian cance
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.