Table 1.

Overview of proteins analyzed in depth, including UniProt name, protein functional class, protein length, and number of amino acids within the TM region, number of group A (=pathogenic), group B (=benign and/or nonrare gnomAD) and benign variants before and after filtering, the sequence depth of the MSA used by GEMME, the Nf (neff/$\sqrt{\text{len}}$) of the MSA, the AUC for our two predictors ($\Delta \Delta$G and $\Delta \Delta$E) and the MIM disease phenotype

Protein information		Length		Before filtering			After filtering			GEMME		AUC		MIM
Name	Class	All	TM	Group A	Group B	Benign	Group A	Group B	Benign	MSA depth	Nf (neff/$\sqrt{\text{len}}$)	$\Delta \Delta$G	$\Delta \Delta$E	Phenotype
NPC1	transporter	1278	277	60	36	13	44	12	5	1486	31.43	0.69	0.84	Niemann-Pick disease
OPSD	GPCR	348	161	67	10	2	41	6	2	1183	49.16	0.79	0.69	night blindness; retinitis punctata albescens; retinitis pigmentosa
GTR1	transporter	492	261	56	9	4	42	7	2	1772	65.62	0.65	0.92	dystonia; GLUT1 deficiency syndrome; epilepsy
AT2A2	transporter	1042	204	12	9	7	8	5	4	1924	44.33	0.85	1	acrokeratosis verruciformis; Darier disease
ACHB2	ion channel	502	86	3	16	12	1	5	3	1789	57.23	0.8	1	epilepsy
CXB2	cell junction	226	83	60	23	8	33	16	5	1351	82.1	0.42	0.84	deafness; Bart-Pumphrey syndrome; Vohwinkel syndrome; etc.
S5A2	enzyme	254	84	21	11	5	18	8	5	1177	60.18	0.63	0.9	pseudovaginal perineoscrotal hypospadias
MC4R	GPCR	332	165	12	11	2	10	8	1	1265	54.02	0.66	0.9	obesity
AQP2	ion channel	271	124	10	2	1	7	1	1	1326	62.36	1	0.86	diabetes insipidus
ACHA4	ion channel	627	85	3	47	32	3	6	4	1107	27.84	0.33	0.94	epilepsy; nicotine addiction
JAGN1	transporter	183	84	5	4	3	4	3	3	196	13.45	0.42	0.92	neutropenia
SMO	GPCR	787	147	1	25	6	1	7	1	823	17.7	1	0.86	Curry-Jones syndrome; Pallister-Hall-like syndrome; basal cell carcinoma
ABCG8	transporter	673	126	1	35	11	0	15	3	86	2.14	–	–	gallbladder disease; sitosterolemia
ABCG5	transporter	651	127	1	27	9	0	0	0	31	0.81	–	–	sitosterolemia
GPT	enzyme	408	228	7	5	1	6	2	1	1812	64.45	0.5	0.92	congenital disorder of glycosylation; myasthenic syndrome
FZD4	GPCR	537	206	5	13	6	2	3	2	1055	37.22	0.83	1	exudative vitreoretinopathy; retinopathy of prematurity
Total				324	283	122	220	104	42			0.64	0.82

MSA, multiple sequence alignment; TM, transmembrane.