NM_000545.6:c.341G>A (p.Arg114His) is a missense variant in HNF1A, a gene in which loss-of-function variants cause autosomal dominant monogenic diabetes (MODY3). This variant is present in gnomAD v2.1 at a grpmax filtering allele frequency of 9.374e-05 (14/282,682 alleles) and in gnomAD v4.1 at 4.428e-05 (78/1,614,100 alleles), exceeding the CSPEC BS1_Strong threshold of 1:30,000 (0.000033).¹ Functional characterization by Najmi et al. (2017) demonstrated that p.Arg114His retains 83% of wild-type transactivation activity in a luciferase reporter assay and shows normal nuclear localization (81%), meeting the CSPEC BS3_Supporting threshold of ≥75% activity.² The variant is located at codon 114, which lies within the CSPEC-defined DNA binding domain subset (codons 107-174), supporting application of PM1_Supporting. However, Arg114 is not among the directly DNA-binding residues specified for PM1_Moderate.³ In silico predictions are indeterminate: REVEL score is 0.58 (below the CSPEC PP3 threshold of 0.70; above the BP4 threshold of 0.15); SpliceAI predicts no splicing impact (max delta 0.01).⁴ The variant has been reported in ClinVar as Uncertain significance by 5 clinical laboratories and Likely benign by 1 laboratory (VariationID: 134508). No expert panel classification is available.⁵ Applying the CSPEC v3.1.0 combination rules: BS1 (Strong Benign) and BS3 (Supporting Benign) are met on the benign side, while PM1 (Supporting Pathogenic) is met on the pathogenic side. Per Rule 24 (≥1 Benign Strong + ≥1 Pathogenic Supporting), the evidence is conflicting, resulting in a classification of Uncertain Significance.⁶