PM1 (moderate): Pro95 is located within the RRM domain of SRSF2, a well-established functional domain and mutational hotspot where other pathogenic missense changes (P95H, P95L, P95R) have been documented in COSMIC. Cancer Hotspots confirms the residue as statistically significant.1 PM2 (supporting): This variant is present at extremely low frequency in gnomAD (v2.1: 2/239,628 alleles, AF=8.35e-06; v4.1: 11/1,611,376 alleles, AF=6.83e-06), well below the 0.1% PM2 threshold. No homozygotes observed. Absent from gnomAD-Canada.2 BP4 (supporting): Multiple lines of computational evidence suggest no significant impact: REVEL score 0.444, BayesDel score -0.15213 (benign), and SpliceAI max delta score 0.00 (no predicted splicing effect).3 Overall assessment: 1 moderate pathogenic criterion (PM1) + 1 supporting pathogenic criterion (PM2) + 1 supporting benign criterion (BP4). Using generic ACMG/AMP 2015 combination rules (PMID:25741868), this combination of criteria is insufficient to reach Likely Pathogenic (requires ≥2 moderate or 1 moderate + ≥4 supporting), Likely Benign (requires ≥1 strong benign + 1 supporting benign, or ≥2 supporting benign), or Benign. The variant is classified as a Variant of Uncertain Significance (VUS).4
SRSF2
Final classification
VUS
SRSF2 c.283C>A · p.Pro95Thr
SRSF2
PM1 (moderate): Pro95 is located within the RRM domain of SRSF2, a well-established functional domain and mutational hotspot where other pathogenic missense changes (P95H, P95L, P95R) have been documented in COSMIC. Cancer Hotspots confirms the residue as statistically significant.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 supporting, BP4 supporting; combination = 1 moderate + 1 supporting + 1 supporting benign, which maps to VUS because the evidence is conflicting.
Classification rationale
PM1PM2
BP4
VUS
SRSF2 c.283C>A
PM1 + PM2 + BP4
→
VUS
Gene diagram
· NM_003016.4 · variants mapped to exon structure
SRSF2
NM_003016.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 16 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PM1
moderate
Pathogenic
Pro95 is located within the RNA recognition motif (RRM) domain of SRSF2, a well-established functional domain critical for RNA binding and splicing. This codon is a known mutational hotspot in hematologic malignancies, with recurrent pathogenic missense changes (P95H, P95L, P95R) documented in COSMIC. Cancer Hotspots analysis confirms the residue is statistically significant.
Pro95 in RRM domainstatistically significant cancer hotspotrecurrent somatic mutations at same residue (P95H/L/R in COSMIC
✓
PM2
supporting
Pathogenic
This variant is present at extremely low frequency in population databases: gnomAD v2.1 exomes AF=8.35e-06 (2/239,628 alleles, 0 homozygotes) and gnomAD v4.1 AF=6.83e-06 (11/1,611,376 alleles, 0 homozygotes). Both are well below the 0.1% threshold for PM2. Absent from gnomAD-Canada.
gnomAD v2.1: 2/239628 alleles (AF=0.00083%)gnomAD v4.1: 11/1
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no significant impact on the gene product: REVEL score 0.444 (below pathogenic threshold), BayesDel score -0.15213 (predicts benign), and SpliceAI predicts no splicing alteration (max delta score 0.00).
REVEL=0.444BayesDel=-0.15213SpliceAI max delta=0.00
Assessed · not applied
Pathogenic
PS2
No reports of de novo occurrence of SRSF2 p.Pro95Thr in a patient with a matching phenotype and confirmed parentage were identified in the literature or databases.
PS3
No well-established in vitro or in vivo functional studies specifically assessing the functional impact of p.Pro95Thr were identified.
PS4
No case-control studies demonstrating statistically significant enrichment of p.Pro95Thr in affected individuals versus controls were identified.
PM5
While other missense changes at Pro95 (P95H, P95L, P95R) are well-established somatic driver mutations in hematologic malignancies, no germline pathogenic or likely pathogenic classification exists in ClinVar for a different missense substitution at this residue.
PM6
No reports of presumed de novo occurrence (without confirmation of parentage) were identified for this variant.
PP1
No family segregation data are available for this variant.
PP2
Insufficient data to determine whether SRSF2 has a low rate of benign missense variation (e.g., high missense Z-score from gnomAD constraint metrics).
PP3
Multiple in silico predictors do not support a damaging effect: REVEL score 0.444 (below the typical pathogenic threshold of 0.5), BayesDel score -0.152 (negative score indicates benign), and SpliceAI predicts no splicing impact (max delta score 0.00).
PP4
No specific patient phenotype or clinical information was provided with this case.
PP5
This variant is absent from ClinVar.
Benign
BA1
The allele frequency in gnomAD is far below the 1% BA1 threshold: v2.1 AF=0.00083%, v4.1 AF=0.00068%.
BS1
The allele frequency in gnomAD is below the 0.3% BS1 threshold: v2.1 AF=0.00083%, v4.1 AF=0.00068%.
BS3
No well-established in vitro or in vivo functional studies demonstrate that p.Pro95Thr has no damaging effect on protein function or splicing.
BS4
No family studies are available to assess lack of segregation of this variant with disease in affected family members.
BP5
No evidence is available that this variant has been observed in a case with an alternate molecular basis for disease.
BP6
This variant is absent from ClinVar.
N/A · 6
PVS1 · PS1 · BS2 · BP1 · BP2 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.82646e-06; MAF= 0.00068%, 11/1611376 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09878e-05; MAF= 0.00110%, 1/91010 alleles, homozygotes = 0); grpmax FAF= 4.29e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 8.34627e-06; MAF= 0.00083%, 2/239628 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.87716e-05; MAF= 0.00188%, 2/106544 alleles, homozygotes = 0); grpmax FAF= 3.12e-06.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00068%
· 11 / 1,611,376
0 hom · FAF 0.00043%
0 hom · FAF 0.00043%
South Asian 1 / 91,010 |
0.0011% |
European (non-Finnish) 10 / 1,179,354 |
0.00085% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.00083%
· 2 / 239,628
0 hom · FAF 0.00031%
0 hom · FAF 0.00031%
European (non-Finnish) 2 / 106,544 |
0.0019% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.444. BayesDel score = -0.15213.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; 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; COSV57970203, n = 11 times).
Hotspots
This variant lies in a statistically significant hotspot.
Sources & reference links