Table 1:

OMIM genes constrained by shet but not by LOEUF.

Gene	$s_{\text{het}}$	LOEUF	Obs.	Exp.	Condition and reference
RPS15A *	0.61	0.56	0	5.4	Diamond-Blackfan anemia: Red blood cell aplasia resulting in growth, craniofacial, and other congenital defects [23]
DCX	0.48	0.62	3	12.6	Lissencephaly: Migrational arrest of neurons resulting in mental re-tardation and seizures [24]
SOX2	0.33	0.57	1	8.3	Syndromic microphthalmia: Missing or small eyes from birth [25]
NDP	0.33	0.88	0	3.4	Norrie disease: Retinal dystrophy resulting in early childhood blindness, mental disorders, and deafness [26]
EIF5A	0.32	0.54	1	8.7	Faundes-Banka syndrome: Developmental delay, microcephaly, and facial dysmorphisms [27]
CDKN1C	0.27	0.53	0	5.7	Beckwith-Wiedemann syndrome: Pediatric overgrowth with predisposition to tumor development [28]
TGIF1	0.25	0.91	5	11.5	Holoprosencephaly: Structural malformation of the forebrain during development [29]
SH2D1A	0.23	0.96	1	4.9	Lymphoproliferative syndrome: Severe immune dysregulation due to improper lymphocyte apoptosis [30]
CEBPA	0.17	1.18	0	2.4	Acute myeloid leukemia: Blood and bone marrow cancer with rapid progression [31]
GATA4	0.15	0.53	3	14.7	Atrial septal defect: Congenital heart defect resulting in a hole between the atria [32]
TIMP3	0.13	0.53	2	11.8	Sorsby fundus dystrophy: Retinal dystrophy that causes loss of vision [33]
FOXC2	0.13	0.79	3	9.8	Lymphedema-distichiasis syndrome: Lymphedema of the limbs and double rows of eyelashes [34]
IGF2	0.12	1.13	3	6.8	Silver-Russell syndrome: Growth retardation, relative macrocephaly, and feeding difficulties [35]
PLN	0.12	1.56	0	1.5	Dilated cardiomyopathy: Enlarged heart chambers, decreased contrac-tile function, and heart failure [20]
TWIST1	0.11	1.06	1	4.5	Saethre-Chotzen syndrome: Craniosynostosis, facial dysmorphism, and hand and foot abnormalities [21] [22]

Mutations that disrupt the functions of these genes are associated with Mendelian diseases in the OMIM database [36]. Genes are ordered by $s_{\text{het}}$ (posterior mean). Obs. and Exp. are the unique number of observed and expected LOFs respectively.

^*RPS15A is associated with Diamond-Blackfan anemia along with nine other genes considered constrained by $s_{\text{het}}$ but not by LOEUF (Supplementary Table 1).