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.

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.

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).

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).