NM_004168.4:c.163T>C (p.Tyr55His) is classified as Benign based on the ACMG/AMP 2015 framework.

This variant meets BA1 (stand-alone benign): the allele frequency in the East Asian population is 1.96% in gnomAD v2.1 (391/19,954 alleles, 5 homozygotes) and 2.39% in gnomAD v4.1 (1,074/44,890 alleles, 10 homozygotes), with a gnomAD v4.1 grpmax FAF of 2.27%. An allele frequency exceeding 1% in a general population is inconsistent with a role in rare Mendelian disease.

Additional benign evidence includes BS1 (East Asian AF well above 0.3%), BS2 (12 homozygotes observed in gnomAD v4.1 in a gene where biallelic loss-of-function causes severe early-onset recessive disease), BP4 (REVEL = 0.392; BayesDel = 0.00237; SpliceAI max delta = 0.03; all predictors converge on a benign interpretation), and BP6 (ClinVar consensus of Benign/Likely benign from 11 clinical laboratories).

No pathogenic criteria are met. PVS1 is not applicable (missense variant). PP3 is not met (in silico predictors favor benign). PM1 is not met (the variant is common in population databases despite lying in the FAD-binding domain). PS4 is not met (the variant is classified as benign across clinical laboratories and observed at appreciable frequency in unaffected populations).

The classification of Benign is driven by BA1, which alone is sufficient to classify a variant as Benign under the ACMG/AMP 2015 combination rules.