IDH1 c.394C>A (p.Arg132Ser) is absent from population databases (gnomAD v4.1: 0/1,613,196 alleles).1 The variant alters the critical active-site residue Arg132 of IDH1, a well-established mutational hotspot and functional domain essential for substrate binding and catalysis.2 Different missense changes at the same residue (p.Arg132His, p.Arg132Cys) are established pathogenic variants, satisfying PM5.3 Functional studies directly testing the R132S mutant protein demonstrate neomorphic gain-of-function activity: NADPH-dependent reduction of α-ketoglutarate to the oncometabolite (R)-2-hydroxyglutarate.4 Multiple in silico tools support a deleterious effect, including a REVEL score of 0.904 and a SpliceAI max delta of 0.61.5 ClinVar reports this variant as Pathogenic (VariationID 375893) based on a single clinical laboratory submission with criteria provided (1-star). This does not reach the 3-star expert panel threshold required for PP5.6 The variant has been reported in somatic cancers (COSMIC: n=217), primary myelofibrosis (3/301 patients; PMID:21912393), and a case of adult medulloblastoma (PMID:24616312), consistent with oncogenicity but not meeting germline PS4 thresholds.7
IDH1
Final classification
Likely Pathogenic
IDH1 c.394C>A · p.Arg132Ser
IDH1
IDH1 c.394C>A (p.Arg132Ser) is absent from population databases (gnomAD v4.1: 0/1,613,196 alleles).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 moderate, PM1 moderate, PM2 moderate, PM5 moderate, PP3 supporting; combination = 4 moderate + 1 supporting, which maps to Likely Pathogenic.
Classification rationale
PS3PM1PM2PM5PP3
Likely Pathogenic
IDH1 c.394C>A
PS3 + PM1 + PM2 + PM5 + PP3
→
Likely Pathogenic
Gene diagram
· NM_005896.3 · variants mapped to exon structure
IDH1
NM_005896.3
Fetching transcript structure from UCSC…
Applied criteria · 5 applied · 18 assessed
Applied · 5
Strength
Supporting
Moderate
Strong
Very strong
✓
PS3
moderate
Pathogenic
The IDH1 R132S variant was directly tested in recombinant protein functional assays. Dang et al. (2009) generated purified recombinant R132S mutant IDH1 protein and demonstrated that R132S, like other R132 mutations, results in gain-of-function NADPH-dependent reduction of α-ketoglutarate to the oncometabolite (R)-2-hydroxyglutarate. The functional effect is unequivocal: the mutation alters enzymatic activity from oxidative decarboxylation of isocitrate to reductive production of 2-HG. A single study with direct variant-specific testing supports moderate-strength PS3.
R132S mutant IDH1 protein directly tested in recombinant enzyme assaysR132S demonstrated gain-of-function: NADPH-dependent reduction of αKG to (R)-2-hydroxyglutarateFunctional effect unequivocal — loss of normal isocitrate decarboxylation
✓
PM1
moderate
Pathogenic
The variant alters Arg132, the critical active-site residue of IDH1 responsible for isocitrate substrate binding and catalysis. This residue is located in the enzyme's catalytic domain and is a statistically significant mutational hotspot (cancerhotspots.org). All known oncogenic IDH1 mutations occur at this residue. The Arg132 position forms hydrogen bonds with the α- and β-carboxyl groups of isocitrate and is essential for normal enzymatic function.
Arg132 is the enzyme active-site residue critical for isocitrate binding and catalysisResidue-level statistical significance confirmed at cancerhotspots.orgAll known oncogenic IDH1 mutations cluster at Arg132 (R132H
✓
PM2
moderate
Pathogenic
This variant is completely absent from population databases. gnomAD v4.1 reports 0 alleles in 1,613,196 alleles across all populations (AF=0.000%). gnomAD v2.1 and gnomAD-Canada v1.0 also report complete absence. The allele frequency is well below the 0.1% threshold for PM2 under generic ACMG rules.
gnomAD v4.1: 0/1613196 alleles (AF=0.000%)
✓
PM5
moderate
Pathogenic
A different missense change at the same amino acid residue (p.Arg132) has been established as pathogenic. IDH1 p.Arg132His (R132H) is the most common and well-characterized pathogenic IDH1 variant in gliomas and other cancers. p.Arg132Cys (R132C) is also established as pathogenic. Both are listed as pathogenic in ClinVar and extensively characterized in the literature. The current variant, p.Arg132Ser, is a different amino acid change at the same residue.
IDH1 p.Arg132His (R132H) is an established pathogenic variantIDH1 p.Arg132Cys (R132C) is an established pathogenic variantBoth are different amino acid changes at the same residue as p.Arg132Ser
✓
PP3
supporting
Pathogenic
Multiple in silico tools support a deleterious effect. REVEL score is 0.904 (strongly pathogenic prediction). SpliceAI predicts a possible splice impact with a maximum delta score of 0.61 (donor gain delta = 0.61, donor loss delta = 0.48). BayesDel score is 0.419 (moderate). The high REVEL score and moderate SpliceAI signal together provide supporting evidence for a deleterious effect.
REVEL score: 0.904 (strongly pathogenic)SpliceAI max delta: 0.61 (DG=0.61DL=0.48)
Assessed · not applied
Pathogenic
PS1
No evidence of a different nucleotide change at this codon producing the same amino acid substitution (p.Arg132Ser) that has been previously classified as pathogenic.
PS2
No de novo data available for this variant.
PS4
No case-control comparison data available to demonstrate statistically significant increased prevalence of this variant in affected individuals versus controls.
PM6
No de novo data available.
PP1
No co-segregation data available.
PP2
Insufficient data to assess the missense constraint profile of IDH1 for germline disease.
PP4
No specific patient phenotype or clinical information was provided for this case.
PP5
ClinVar reports this variant as Pathogenic with review status 'criteria provided, single submitter' (1 star).
Benign
BA1
This variant is absent from gnomAD v4.1 (0/1,613,196 alleles, AF=0.000%), well below the BA1 threshold of >1% allele frequency.
BS1
This variant is absent from gnomAD v4.1 (0/1,613,196 alleles, AF=0.000%), well below the BS1 threshold of >0.3% allele frequency.
BS2
This variant has not been observed in healthy adult individuals.
BS3
Well-established functional studies demonstrate a damaging gain-of-function effect, not a benign effect.
BS4
No segregation data available.
BP1
IDH1 disease mechanism in cancer is primarily gain-of-function via missense mutations at Arg132.
BP2
No data available regarding observation of this variant in trans with a pathogenic variant.
BP4
Multiple in silico tools predict a deleterious effect, not a benign effect.
BP5
ClinVar classifies this variant as Pathogenic, not benign.
BP6
ClinVar classifies this variant as Pathogenic, not benign.
N/A · 5
PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1613196 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74792 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / 1,613,196
0 hom
0 hom
Not observed in any ancestry group.
+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
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 Pathogenic (1 clinical laboratory). (ClinVarID = 375893)
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.61). REVEL score = 0.904. BayesDel score = 0.419369.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Hotspot
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV61615649, n = 217 times).
Hotspots
This variant lies in a statistically significant hotspot.
Literature · how each cited paper was used
2papers cited
Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 6 further PMIDs triaged but not cited — see Sources & References.
Cancer-associated IDH1 mutations produce 2-hydroxyglutarate.
Searched
R132SR132.SArg132Serc.394394C>ACGT>AGT
Found
IDH1 R132S was directly tested in recombinant protein functional assays. R132S mutant IDH1 demonstrated gain-of-function neomorphic activity: NADPH-dependent reduction of α-ketoglutarate to the oncometabolite (R)-2-hydroxyglutarate (2-HG), while losing normal isocitrate decarboxylation activity. This functional effect was shared with R132H, R132C, and R132L mutations.
Variant
✓ Names this variant — characterised directly
Applied to
→PM1 supports · met
→PM5 supports · met
→PS3 supports · met
Why
Variant-specific functional data confirmed; directly supports PS3 (moderate) and informs PM1/PM5/BS3 adjudication.
Similar to R132H mutant protein, R132C, R132L, and R132S mutations all result in a gain-of-function for NADPH-dependent reduction of αKG.
Location Results section; Supplementary Figure 4; Methods Summary · Context Recombinant protein purification from E. coli; stopped-flow spectrophotometry enzyme assays; LC-MS metabolite detection; U87MG and LN-18 glioblastoma cell lines · full text
What a difference a hydroxyl makes: mutant IDH, (R)-2-hydroxyglutarate, and cancer.
Searched
R132SR132.SArg132Ser
Found
This is a comprehensive review of IDH mutations in cancer. R132S is listed among the known IDH1 mutant alleles in tabular summaries of mutation frequencies across tumor types. The review summarizes the gain-of-function mechanism by which mutant IDH enzymes (including R132S) produce (R)-2-hydroxyglutarate, promoting tumorigenesis through epigenetic dysregulation.
Variant
✓ Names this variant — characterised directly
Applied to
→PM1 supports · met
→PM5 supports · met
Why
Review confirms R132S is a recognized IDH1 mutant allele in the established spectrum of oncogenic R132 mutations; supports PM1 and PM5 but is not primary evidence.
IDH1 R132C/S/L/G/V 5%-8%
Location Table 1 (allele frequencies); text describing IDH1 R132C/S/L/G/V mutant alleles · Context Review article; no primary experimental data · full text
Sources & reference links
Triaged references · 6 PMIDs not cited in assessment
21760534 ↗
Value and limitations of immunohistochemistry and gene sequencing for detection of the IDH1-R132H mutation in diffuse glioma biopsy specimens.
ONCOKB
21912393 ↗
IDH mutations in primary myelofibrosis predict leukemic transformation and shortened survival: clinical evidence for leukemogenic collaboration with JAK2V617F.
ONCOKB
22033490 ↗
Differential prognostic effect of IDH1 versus IDH2 mutations in myelodysplastic syndromes: a Mayo Clinic study of 277 patients.
ONCOKB
22918138 ↗
Opportunities and challenges associated with clinical diagnostic genome sequencing: a report of the Association for Molecular Pathology.
CLINVAR
23619274 ↗
American College of Medical Genetics and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in neoplastic disorders.
CLINVAR