Table 2 Evidence for CSMD1 variant pathogenicity from in silico tools, deep learning-based protein modeling, and population data. N/A, not applicable.

Variant (NM_033225.6)	VAF^a	ACMG Classification	Chain	CADD Phred score^b	SIFT^b,c	PolyPhen-2 HDIV^b,d	DDmut ΔΔG Stability (kcal/mol)^e	Study
c.412 G > A, p.E138K	0	VUS	A	24.1	0	0.998	-0.25	present
c.559 G > A, p.V187I	<0.0005	VUS	A	17.5	0	0.414	0.03	present
c.563 G > A, p.S188N	<0.001	VUS	A	17.5	0	0.224	-0.09	Costanzo et al., 2022^f
c.638 G > T, p.R213L	0	VUS	A	24.4	0	0.990	0.10	present
c.1507 C > A, p.H503N	<0.0001	VUS	A	24.4	0	0.992	0.81	present
c.4920 C > A, p.N1640K	0	VUS	A	22.6	0.01	0.634	-0.34	present
c.5852 C > T, p.S1951F	0	VUS	A	29.8	0	0.999	-0.04	present
c.5344 C > A, p.Q1782K	<0.005	VUS	A	19.2	0.05	0.227	0.05	Costanzo et al., 2022^f
c.6762 G > C, p.Q2254H	0	VUS	A	19.7	0.37	0.001	0.03	present
c.6886 G > A, p.D2296N	<0.00005	VUS	A	22.8	0.07	0.948	0.14	present
c.7285+2 T > C	0	VUS	N/A	30.0	N/A	N/A	NA	present
c.7322 G > C, p.G2441A	0	VUS	A	23.5	0	1.000	-0.70	present
c.8850 C > G, p.H2950Q	0	VUS	A	22.0	0.07	0.087	-0.53	present
c.9424 G > A, p.V3142M	<0.00005	VUS	A	22.5	0.01	0.730	-0.53	present

^agnomAD v3.1.2 controls
^bGRCh38-v1.6
^cSIFT scores for missense only, ranging from 0 (deleterious) to 1 (tolerated)
^dPolyPhen-2 scores for missense only, ranging from 0 (benign) to 1 (probably damaging)
^eΔΔG = changed in Gibbs free energy; Negative values indicate destabilizing variants
^fCostanzo F, Zanni G, Fucà E, Di Paola M, Barresi S, Travaglini L, et al. Cerebellar Agenesis and Bilateral Polimicrogyria Associated with Rare Variants of CUB and Sushi Multiple Domains 1 Gene (CSMD1): A Longitudinal Neuropsychological and Neuroradiological Case Study. Int J Environ Res Public Health 2022, 19(3).

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