Multiple congenital anomalies-hypotonia-seizures syndrome 2

Summary

Multiple congenital anomalies-hypotonia-seizures syndrome 2 (MONDO:0010466) is a disease caused by PIGA (GenCC Definitive), with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PIGA (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 281

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		24	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	multiple congenital anomalies-hypotonia-seizures syndrome 2
Mondo ID	MONDO:0010466
OMIM	300868
Orphanet	300496
DOID	DOID:0080139
UMLS	C3275508
MedGen	477139
GARD	0012777
Is cancer (heuristic)	no

Also known as: DEE20 · developmental and epileptic encephalopathy 20 · epileptic encephalopathy, early infantile, 20 · glycosylphosphatidylinositol biosynthesis defect 4 · GPIBD4 · MCAHS type 2 · MCAHS2 · multiple congenital anomalies-hypotonia-seizures syndrome 2 · multiple congenital anomalies-hypotonia-seizures syndrome 2, X-linked recessive · multiple congenital anomalies-hypotonia-seizures syndrome type 2 · multiple congenital anomalies/dysmorphic syndrome-intellectual disability caused by mutation in PIGA · PIGA multiple congenital anomalies/dysmorphic syndrome-intellectual disability

Data availability: 281 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › multiple congenital anomalies-hypotonia-seizures syndrome 2

Related subtypes (216): polymicrogyria, congenital myasthenic syndrome with tubular aggregates, prenatal-onset spinal muscular atrophy with congenital bone fractures, anencephaly, cerebral cavernous malformation, meningocele, progressive external ophthalmoplegia, congenital nystagmus, congenital toxoplasmosis, congenital contractural arachnodactyly, congenital trigeminal anesthesia, familial congenital palsy of trochlear nerve, Myhre syndrome, Aase-Smith syndrome, KBG syndrome, autosomal dominant primary microcephaly, Mobius syndrome, MYH7-related skeletal myopathy, congenital stationary night blindness autosomal dominant 2, Prader-Willi syndrome, congenital myopathy 7A, myosin storage, autosomal dominant, Smith-Magenis syndrome, spina bifida, Freeman-Sheldon syndrome, isolated cerebellar hypoplasia/agenesis, Chediak-Higashi syndrome, Cohen syndrome, multiple pterygium-malignant hyperthermia syndrome, corpus callosum, agenesis of, congenital lactic acidosis, Saguenay-Lac-Saint-Jean type, facial dysmorphism-macrocephaly-myopia-Dandy-Walker malformation syndrome, diastematomyelia, EEM syndrome, Mowat-Wilson syndrome, Johanson-Blizzard syndrome, intellectual disability, Buenos-Aires type, myasthenia, congenital, refractory to acetylcholinesterase inhibitors, congenital myasthenic syndrome 6, Bailey-Bloch congenital myopathy, congenital stationary night blindness 1B, radioulnar synostosis-developmental delay-hypotonia syndrome, Schinzel-Giedion syndrome, schizencephaly, intellectual disability, Wolff type, X-linked intellectual disability-plagiocephaly syndrome, X-linked adrenal hypoplasia congenita, syndromic X-linked intellectual disability 7, syndromic X-linked intellectual disability Shashi type, syndromic X-linked intellectual disability Lubs type, syndromic X-linked intellectual disability Abidi type, syndromic X-linked intellectual disability Siderius type, X-linked intellectual disability, Cabezas type, X-linked intellectual disability-cubitus valgus-dysmorphism syndrome, syndromic X-linked intellectual disability Claes-Jensen type, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, developmental and epileptic encephalopathy, 36, blepharophimosis - intellectual disability syndrome, MKB type, X-linked intellectual disability-short stature-overweight syndrome, intellectual disability, X-linked, syndromic 33, syndromic X-linked intellectual disability 34, infantile-onset X-linked spinal muscular atrophy, syndromic X-linked intellectual disability 5, holoprosencephaly-hypokinesia-congenital contractures syndrome, X-linked intellectual disability with marfanoid habitus, Wieacker-Wolff syndrome, MERRF syndrome, macrocephaly-spastic paraplegia-dysmorphism syndrome, intellectual disability-sparse hair-brachydactyly syndrome, myofibrillar myopathy 1, isolated hereditary congenital facial paralysis, fibrosis of extraocular muscles, congenital, 2, Pierpont syndrome, congenital cataracts-facial dysmorphism-neuropathy syndrome, Bohring-Opitz syndrome, PHACE syndrome, B4GALT1-congenital disorder of glycosylation, developmental malformations-deafness-dystonia syndrome, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, AICA-ribosiduria, myofibrillar myopathy 3, fibrosis of extraocular muscles, congenital, 3c, myofibrillar myopathy 4, myofibrillar myopathy 5, cone-rod synaptic disorder, congenital nonprogressive, congenital stationary night blindness autosomal dominant 3, congenital stationary night blindness autosomal dominant 1, intellectual disability, autosomal recessive 12, progressive myoclonic epilepsy type 3, chromosome 15q13.3 microdeletion syndrome, combined pituitary hormone deficiencies, genetic form, congenital stationary night blindness 1D, DYRK1A-related intellectual disability syndrome, Pitt-Hopkins-like syndrome 2, developmental and epileptic encephalopathy, 15, Schuurs-Hoeijmakers syndrome, severe intellectual disability-poor language-strabismus-grimacing face-long fingers syndrome, severe intellectual disability-progressive spastic diplegia syndrome, hypotonia, infantile, with psychomotor retardation and characteristic facies, developmental and epileptic encephalopathy, 18, CTCF-related neurodevelopmental disorder, autism spectrum disorder due to AUTS2 deficiency, developmental and epileptic encephalopathy, 23, ADNP-related multiple congenital anomalies - intellectual disability - autism spectrum disorder, Bardet-Biedl syndrome 11, cerebellar-facial-dental syndrome, fibrosis of extraocular muscles, congenital, 5, congenital myasthenic syndrome 15, lethal fetal cerebrorenogenitourinary agenesis/hypoplasia syndrome, autosomal dominant intellectual disability-craniofacial anomalies-cardiac defects syndrome, congenital myasthenic syndrome 18, autosomal recessive spinocerebellar ataxia 20, Houge-Janssens syndrome 1, intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, congenital stationary night blindness 1G, hypomyelinating leukodystrophy 10, developmental and epileptic encephalopathy, 50, congenital insensitivity to pain-hypohidrosis syndrome, macrocephaly-intellectual disability-neurodevelopmental disorder-small thorax syndrome, SLC39A8-CDG, spastic paraplegia-severe developmental delay-epilepsy syndrome, cardiac anomalies - developmental delay - facial dysmorphism syndrome, severe intellectual disability-corpus callosum agenesis-facial dysmorphism-cerebellar ataxia syndrome, intellectual disability, autosomal recessive 53, TELO2-related intellectual disability-neurodevelopmental disorder, micrognathia-recurrent infections-behavioral abnormalities-mild intellectual disability syndrome, autosomal recessive limb-girdle muscular dystrophy type 2Y, myofibrillar myopathy 7, short stature-brachydactyly-obesity-global developmental delay syndrome, autosomal recessive limb-girdle muscular dystrophy type 2R1, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, congenital laryngeal palsy, congenital or early infantile CACH syndrome, congenital epulis, severe congenital nemaline myopathy, intermediate nemaline myopathy, typical nemaline myopathy, childhood-onset nemaline myopathy, adult-onset nemaline myopathy, qualitative or quantitative defects of protein involved in O-glycosylation of alpha-dystroglycan, holoprosencephaly, congenital insensitivity to pain with hyperhidrosis, congenital hydrocephalus, familial congenital mirror movements, macrocephaly-short stature-paraplegia syndrome, cephalocele, mitochondrial neurogastrointestinal encephalomyopathy, X-linked intellectual disability-hypogonadism-ichthyosis-obesity-short stature syndrome, 7p22.1 microduplication syndrome, congenital achiasma, congenital retinal arteriovenous communication, 3q27.3 microdeletion syndrome, Prader-Willi-like syndrome, 9q31.1q31.3 microdeletion syndrome, congenital oculomotor nerve palsy, congenital abducens nerve palsy, neurodevelopmental disorder-craniofacial dysmorphism-cardiac defect-hip dysplasia syndrome, congenital insensitivity to pain with severe intellectual disability, X-linked intellectual disability-cerebellar hypoplasia-spondylo-epiphyseal dysplasia syndrome, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, lissencephaly spectrum disorders, hyaline body myopathy, 22q11.2 deletion syndrome, craniorachischisis, Leber congenital amaurosis, Ritscher-Schinzel syndrome, Rubinstein-Taybi syndrome, X-linked intellectual disability-hypogammaglobulinemia-progressive neurological deterioration syndrome, X-linked intellectual disability-epilepsy-progressive joint contractures-dysmorphism syndrome, X-linked intellectual disability, Pai type, X-linked intellectual disability, Stevenson type, X-linked intellectual disability, Stoll type, congenital muscular dystrophy, congenital vitreoretinal dysplasia, periventricular nodular heterotopia, postsynaptic congenital myasthenic syndrome, subcortical band heterotopia, congenital fibrosis of extraocular muscles type 1, Al Gazali Khidr Prem Chandran syndrome, distal arthrogryposis Moore weaver type, congenital myotonic dystrophy, myasthenic syndrome, congenital, 7B, presynaptic, autosomal recessive, intellectual disability, autosomal dominant 47, intellectual disability, autosomal dominant 48, spondyloepiphyseal dysplasia, sensorineural hearing loss, impaired intellectual development, and leber congenital amaurosis, myasthenic syndrome, congenital, 23, presynaptic, myasthenic syndrome, congenital, 24, presynaptic, myasthenic syndrome, congenital, 25, presynaptic, developmental and epileptic encephalopathy, 77, night blindness, congenital stationary, type1i, neuropathy, congenital hypomelinating, congenital axonal neuropathy with encephalopathy, developmental and epileptic encephalopathy, 73, PHIP-related behavioral problems-intellectual disability-obesity-dysmorphic features syndrome, isolated exencephaly, myasthenic syndrome, congenital, 22, intellectual developmental disorder with gastrointestinal difficulties and high pain threshold, intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies, 9q33.3q34.11 microdeletion syndrome, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome, SIN3A-related intellectual disability syndrome, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, X-linked congenital stationary night blindness, neurodevelopmental disorder with progressive microcephaly, spasticity, and brain anomalies, FOXG1 disorder, alpha-actinopathy, TPM3-related myopathy, X-linked recessive mitochondrial myopathy, RYR1-related myopathy, TTN-related myopathy, TPM2-related myopathy, myopathy caused by variation in POMGNT1, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, segmental spinal dysgenesis, myopathy, myofibrillar, 13, with rimmed vacuoles, congenital neuronal ceroid lipofuscinosis 10

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

281 retrieved; paginated sample, class counts are floors:

131 uncertain significance, 71 likely benign, 29 conflicting classifications of pathogenicity, 15 benign/likely benign, 12 benign, 10 likely pathogenic, 10 pathogenic, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
2424508	NC_000023.10:g.(?14861689)(15870650_?)del	ACE2	Pathogenic	criteria provided, single submitter
132814	NM_002641.4(PIGA):c.355C>T (p.Arg119Trp)	PIGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
132815	NM_002641.4(PIGA):c.76dup (p.Tyr26fs)	PIGA	Pathogenic	no assertion criteria provided
132816	NM_002641.4(PIGA):c.230G>T (p.Arg77Leu)	PIGA	Pathogenic	no assertion criteria provided
132817	NM_002641.4(PIGA):c.616A>T (p.Ile206Phe)	PIGA	Pathogenic	no assertion criteria provided
132818	NM_002641.4(PIGA):c.1030_1032del (p.Leu344del)	PIGA	Pathogenic	criteria provided, single submitter
132819	NM_002641.4(PIGA):c.278C>T (p.Pro93Leu)	PIGA	Pathogenic	no assertion criteria provided
1686067	NM_002641.4(PIGA):c.350T>C (p.Phe117Ser)	PIGA	Pathogenic	criteria provided, single submitter
2863441	NM_002641.4(PIGA):c.1028del (p.Asn343fs)	PIGA	Pathogenic	criteria provided, single submitter
29988	NM_002641.4(PIGA):c.1234C>T (p.Arg412Ter)	PIGA	Pathogenic	criteria provided, multiple submitters, no conflicts
623369	NM_002641.4(PIGA):c.145G>A (p.Val49Met)	PIGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
813740	NM_002641.4(PIGA):c.356G>A (p.Arg119Gln)	PIGA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
860851	NM_002641.4(PIGA):c.1354G>A (p.Asp452Asn)	PIGA	Pathogenic	criteria provided, single submitter
1029466	NM_002641.4(PIGA):c.1A>G (p.Met1Val)	PIGA	Likely pathogenic	criteria provided, single submitter
1033523	NM_002641.4(PIGA):c.986T>C (p.Val329Ala)	PIGA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1704280	NM_002641.4(PIGA):c.268T>C (p.Tyr90His)	PIGA	Likely pathogenic	no assertion criteria provided
2844498	NM_002641.4(PIGA):c.188G>C (p.Arg63Thr)	PIGA	Likely pathogenic	criteria provided, single submitter
393551	NM_002641.4(PIGA):c.395C>G (p.Ser132Cys)	PIGA	Likely pathogenic	criteria provided, single submitter
4686666	NM_002641.4(PIGA):c.751T>C (p.Cys251Arg)	PIGA	Likely pathogenic	criteria provided, single submitter
656542	NM_002641.4(PIGA):c.193C>T (p.His65Tyr)	PIGA	Likely pathogenic	criteria provided, single submitter
803711	NM_002641.4(PIGA):c.1386_1393dup (p.Thr465fs)	PIGA	Likely pathogenic	criteria provided, single submitter
850786	NM_002641.4(PIGA):c.242G>A (p.Arg81His)	PIGA	Likely pathogenic	criteria provided, multiple submitters, no conflicts
973228	NM_002641.4(PIGA):c.1355A>T (p.Asp452Val)	PIGA	Likely pathogenic	criteria provided, single submitter
1034888	NM_002641.4(PIGA):c.35G>A (p.Arg12His)	PIGA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1038996	NM_002641.4(PIGA):c.43G>A (p.Ala15Thr)	PIGA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1064449	NM_002641.4(PIGA):c.1352T>C (p.Ile451Thr)	PIGA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1161748	NM_002641.4(PIGA):c.420C>T (p.Phe140=)	PIGA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1517329	NM_002641.4(PIGA):c.236G>A (p.Gly79Asp)	PIGA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1549539	NM_002641.4(PIGA):c.849-19C>T	PIGA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1998032	NM_002641.4(PIGA):c.154C>T (p.His52Tyr)	PIGA	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 5 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
PIGA	Definitive	X-linked	multiple congenital anomalies-hypotonia-seizures syndrome 2	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PIGA	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
PIGA	Orphanet:300496	Multiple congenital anomalies-hypotonia-seizures syndrome type 2
PIGA	Orphanet:397922	Ferro-cerebro-cutaneous syndrome
PIGA	Orphanet:447	Paroxysmal nocturnal hemoglobinuria
PIGA	Orphanet:697160	Infantile epileptic spasms syndrome

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
PIGA	HGNC:8957	ENSG00000165195	P37287	Phosphatidylinositol N-acetylglucosaminyltransferase subunit A	gencc,clinvar
ACE2	HGNC:13557	ENSG00000130234	Q9BYF1	Angiotensin-converting enzyme 2	clinvar
ZRSR2	HGNC:23019	ENSG00000169249	Q15696	U2 small nuclear ribonucleoprotein auxiliary factor 35 kDa subunit-related protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PIGA	Phosphatidylinositol N-acetylglucosaminyltransferase subunit A	Catalytic subunit of the glycosylphosphatidylinositol-N-acetylglucosaminyltransferase (GPI-GnT) complex that catalyzes the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine to phosphatidylinositol and participates in the first s…
ACE2	Angiotensin-converting enzyme 2	Essential counter-regulatory carboxypeptidase of the renin-angiotensin hormone system that is a critical regulator of blood volume, systemic vascular resistance, and thus cardiovascular homeostasis.
ZRSR2	U2 small nuclear ribonucleoprotein auxiliary factor 35 kDa subunit-related protein 2	Pre-mRNA-binding protein required for splicing of both U2- and U12-type introns.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Protease	1	12.2×	0.239
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PIGA	Other/Unknown	no		Glyco_trans_1, PIGA_GPI_anchor_biosynthesis, PIG-A/GPI3
ACE2	Protease	yes	3.4.15.1	Peptidase_M2, Collectrin_dom
ZRSR2	Transcription factor	no		RRM_dom, Znf_CCCH, RRM_euk-type

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
endometrium epithelium	1
mucosa of stomach	1
secondary oocyte	1
gall bladder	1
ileal mucosa	1
ileum	1
granulocyte	1
monocyte	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PIGA	266	ubiquitous	marker	secondary oocyte, mucosa of stomach, endometrium epithelium
ACE2	152	tissue_specific	marker	ileal mucosa, ileum, gall bladder
ZRSR2	284	ubiquitous	marker	sural nerve, granulocyte, monocyte

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACE2	5,940
PIGA	2,324
ZRSR2	1,350

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACE2	Q9BYF1	345

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PIGA	P37287	86.22
ZRSR2	Q15696	69.72

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 3 evidence-associated genes (3 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Attachment and Entry	1	951.7×	0.014	ACE2
Early SARS-CoV-2 Infection Events	1	346.1×	0.014	ACE2
Induction of Cell-Cell Fusion	1	292.8×	0.014	ACE2
Synthesis of glycosylphosphatidylinositol (GPI)	1	211.5×	0.014	PIGA
Metabolism of Angiotensinogen to Angiotensins	1	211.5×	0.014	ACE2
Attachment and Entry	1	200.3×	0.014	ACE2
Late SARS-CoV-2 Infection Events	1	97.6×	0.023	ACE2
Peptide hormone metabolism	1	90.6×	0.023	ACE2
mRNA Splicing - Minor Pathway	1	74.6×	0.025	ZRSR2
SARS-CoV-1 Infection	1	47.6×	0.035	ACE2
Potential therapeutics for SARS	1	38.1×	0.040	ACE2
SARS-CoV-2 Infection	1	26.8×	0.052	ACE2
SARS-CoV Infections	1	18.5×	0.070	ACE2
Viral Infection Pathways	1	10.3×	0.115	ACE2
Infectious disease	1	8.3×	0.132	ACE2
Disease	1	4.4×	0.223	ACE2
Metabolism of proteins	1	4.1×	0.223	ACE2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
positive regulation of amino acid transport	1	2808.7×	0.004	ACE2
entry receptor-mediated virion attachment to host cell	1	2808.7×	0.004	ACE2
positive regulation of L-proline import across plasma membrane	1	2808.7×	0.004	ACE2
angiotensin-mediated drinking behavior	1	1872.4×	0.004	ACE2
viral life cycle	1	1404.3×	0.004	ACE2
regulation of systemic arterial blood pressure by renin-angiotensin	1	1123.5×	0.004	ACE2
receptor-mediated virion attachment to host cell	1	936.2×	0.004	ACE2
tryptophan transport	1	802.5×	0.004	ACE2
positive regulation of gap junction assembly	1	802.5×	0.004	ACE2
positive regulation of cardiac muscle contraction	1	702.2×	0.004	ACE2
receptor-mediated endocytosis of virus by host cell	1	510.7×	0.005	ACE2
angiotensin maturation	1	432.1×	0.006	ACE2
maternal process involved in female pregnancy	1	312.1×	0.007	ACE2
regulation of cardiac conduction	1	280.9×	0.007	ACE2
regulation of vasoconstriction	1	267.5×	0.007	ACE2
negative regulation of smooth muscle cell proliferation	1	208.1×	0.008	ACE2
membrane fusion	1	208.1×	0.008	ACE2
blood vessel diameter maintenance	1	208.1×	0.008	ACE2
spliceosomal complex assembly	1	200.6×	0.008	ZRSR2
positive regulation of reactive oxygen species metabolic process	1	170.2×	0.009	ACE2
GPI anchor biosynthetic process	1	165.2×	0.009	PIGA
symbiont entry into host cell	1	133.8×	0.010	ACE2
regulation of cytokine production	1	82.6×	0.016	ACE2
negative regulation of ERK1 and ERK2 cascade	1	72.0×	0.017	ACE2
regulation of inflammatory response	1	56.2×	0.021	ACE2
cellular response to leukemia inhibitory factor	1	53.0×	0.022	PIGA
regulation of cell population proliferation	1	38.5×	0.029	ACE2
mRNA splicing, via spliceosome	1	30.5×	0.035	ZRSR2
RNA splicing	1	29.4×	0.035	ZRSR2
negative regulation of transcription by RNA polymerase II	1	5.9×	0.160	ACE2

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 2

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
ACE2	CAPTOPRIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ACE2	8	4
PIGA	0	0
ZRSR2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CAPTOPRIL	4	ACE2
FLUORESCEIN	4	ACE2
CINACALCET	4	ACE2
HYDROXYCHLOROQUINE	4	ACE2
CHLOROQUINE	4	ACE2
DIMINAZENE	2	ACE2
CEPHARANTHINE	2	ACE2
ORE-1001	1	ACE2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
ACE2	107	Binding:98, Functional:6, ADMET:3

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ACE2	3.4.15.1, 3.4.17.23	peptidyl-dipeptidase A, angiotensin-converting enzyme 2

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
ACE2	107

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

8 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
CAPTOPRIL	4	ACE2
FLUORESCEIN	4	ACE2
CINACALCET	4	ACE2
HYDROXYCHLOROQUINE	4	ACE2
CHLOROQUINE	4	ACE2
DIMINAZENE	2	ACE2
CEPHARANTHINE	2	ACE2
ORE-1001	1	ACE2

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ACE2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	PIGA, ZRSR2

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
PIGA	0	—
ZRSR2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.