Anophthalmia/microphthalmia-esophageal atresia syndrome

Summary

Anophthalmia/microphthalmia-esophageal atresia syndrome (MONDO:0008799) is a disease caused by SOX2 (GenCC Definitive), with 8 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SOX2 (GenCC Definitive)
• Cohort genes: 8
• ClinVar variants: 183
• Phenotypes (HPO): 22

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		30	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0000528	Anophthalmia	Very frequent (80-99%)
HP:0000568	Microphthalmia	Very frequent (80-99%)
HP:0002032	Esophageal atresia	Very frequent (80-99%)
HP:0002575	Tracheoesophageal fistula	Very frequent (80-99%)
HP:0000028	Cryptorchidism	Frequent (30-79%)
HP:0000365	Hearing impairment	Frequent (30-79%)
HP:0000572	Visual loss	Frequent (30-79%)
HP:0001274	Agenesis of corpus callosum	Frequent (30-79%)
HP:0000047	Hypospadias	Occasional (5-29%)
HP:0000238	Hydrocephalus	Occasional (5-29%)
HP:0000612	Iris coloboma	Occasional (5-29%)
HP:0000647	Sclerocornea	Occasional (5-29%)
HP:0000878	11 pairs of ribs	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001360	Holoprosencephaly	Occasional (5-29%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0001629	Ventricular septal defect	Occasional (5-29%)
HP:0001643	Patent ductus arteriosus	Occasional (5-29%)
HP:0002937	Hemivertebrae	Occasional (5-29%)
HP:0003468	Abnormal vertebral morphology	Occasional (5-29%)
HP:0008736	Hypoplasia of penis	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	anophthalmia/microphthalmia-esophageal atresia syndrome
Mondo ID	MONDO:0008799
OMIM	206900
Orphanet	77298
DOID	DOID:0111801
SNOMED CT	698851003
UMLS	C1859773
MedGen	347232
GARD	0001443
Is cancer (heuristic)	no

Also known as: anophthalmia clinical with associated anomalies · anophthalmia esophageal genital syndrome · anophthalmia microphthalmia esophageal atresia · anophthalmia/microphthalmia-esophageal atresia syndrome · MCOPS3 · microphthalmia, syndromic 3 · microphthalmia, syndromic type 3 · SOX2 anophthalmia syndrome · SOX2-related eye disorders · syndromic microphthalmia type 3 · syndromic microphthalmia, type 3

Data availability: 183 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by developmental or physiological process › disorder of development or morphogenesis › developmental defect during embryogenesis › multiple congenital anomalies/dysmorphic syndrome › multiple congenital anomalies/dysmorphic syndrome-variable intellectual disability syndrome › anophthalmia/microphthalmia-esophageal atresia syndrome

Related subtypes (68): acromegaloid facial appearance syndrome, Hypoglossia-hypodactyly syndrome, Brachymorphism-onychodysplasia-dysphalangism syndrome, campomelic dysplasia, cerebrocostomandibular syndrome, autosomal dominant popliteal pterygium syndrome, Pallister-Hall syndrome, autosomal dominant primary microcephaly, microgastria-limb reduction defect syndrome, Mobius syndrome, oculodentodigital dysplasia, Char syndrome, Prader-Willi syndrome, Silver-Russell syndrome, ulnar-mammary syndrome, short stature-wormian bones-dextrocardia syndrome, ablepharon macrostomia syndrome, Goodman syndrome, microphthalmia with limb anomalies, Antley-Bixler syndrome, campomelia, Cumming type, CHARGE syndrome, Toriello-Carey syndrome, Donnai-Barrow syndrome, lethal faciocardiomelic dysplasia, hypertrichotic osteochondrodysplasia Cantu type, hypomandibular faciocranial dysostosis, isotretinoin-like syndrome, split hand-foot malformation 3, oculotrichoanal syndrome, Hennekam-Beemer syndrome, Mietens syndrome, Schinzel-Giedion syndrome, SHORT syndrome, moyamoya angiopathy-short stature-facial dysmorphism-hypergonadotropic hypogonadism syndrome, occipital horn syndrome, hydrocephalus-costovertebral dysplasia-Sprengel anomaly syndrome, Potocki-Shaffer syndrome, Marshall-Smith syndrome, PHACE syndrome, Noonan syndrome-like disorder with loose anagen hair, branchiogenic deafness syndrome, combined immunodeficiency with faciooculoskeletal anomalies, chromosome 1p32-p31 deletion syndrome, Malan overgrowth syndrome, dysmorphism-conductive hearing loss-heart defect syndrome, TELO2-related intellectual disability-neurodevelopmental disorder, short stature-heart defect-craniofacial anomalies syndrome, arachnodactyly-intellectual disability-dysmorphism syndrome, polyvalvular heart disease syndrome, Kallmann syndrome-heart disease syndrome, Meier-Gorlin syndrome, symptomatic form of Coffin-Lowry syndrome in female carriers, Prader-Willi-like syndrome, contractures-developmental delay-Pierre Robin syndrome, 22q11.2 deletion syndrome, Noonan syndrome, Carpenter syndrome, Bosley-Salih-Alorainy syndrome, Sotos syndrome, Robinow syndrome, King-Denborough syndrome, Weiss-Kruszka syndrome, retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome, omphalocele-diaphragmatic hernia-cardiovascular anomalies-radial ray defect syndrome, 4q25 proximal deletion syndrome, restrictive dermopathy 1, mosaic SMO syndrome

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

183 retrieved; paginated sample, class counts are floors:

71 pathogenic, 45 uncertain significance, 28 likely benign, 13 likely pathogenic, 12 conflicting classifications of pathogenicity, 9 benign, 3 benign/likely benign, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
986755	t(3;11)(q27;p11.2)		Pathogenic	no assertion criteria provided
986754	GRCh37/hg19 3q26.33(chr3:180102701-181991155)x1	FXR1	Pathogenic	no assertion criteria provided
986756	GRCh37/hg19 3q26.33-27.2(chr3:181171210-184706091)x1	HTR3C	Pathogenic	no assertion criteria provided
1065422	NM_003106.4(SOX2):c.498G>A (p.Trp166Ter)	LOC108281177	Pathogenic	criteria provided, multiple submitters, no conflicts
1075154	NM_003106.4(SOX2):c.175del (p.Met59fs)	LOC108281177	Pathogenic	criteria provided, single submitter
12816	NM_003106.4(SOX2):c.248C>A (p.Ser83Ter)	LOC108281177	Pathogenic	no assertion criteria provided
12820	NM_003106.4(SOX2):c.163C>T (p.Gln55Ter)	LOC108281177	Pathogenic	no assertion criteria provided
12821	NM_003106.4(SOX2):c.221G>C (p.Arg74Pro)	LOC108281177	Pathogenic	no assertion criteria provided
12822	NM_003106.4(SOX2):c.138T>G (p.Asn46Lys)	LOC108281177	Pathogenic	no assertion criteria provided
12828	NM_003106.4(SOX2):c.551del (p.Pro184fs)	LOC108281177	Pathogenic	no assertion criteria provided
2098215	NM_003106.4(SOX2):c.384del (p.Gly129fs)	LOC108281177	Pathogenic	criteria provided, single submitter
279895	NM_003106.4(SOX2):c.59dup (p.Gly21fs)	LOC108281177	Pathogenic	criteria provided, multiple submitters, no conflicts
29891	NM_003106.4(SOX2):c.245T>A (p.Leu82Ter)	LOC108281177	Pathogenic	no assertion criteria provided
3242251	NM_003106.4(SOX2):c.67_89del (p.Gly23fs)	LOC108281177	Pathogenic	criteria provided, single submitter
3722712	NM_003106.4(SOX2):c.513_514dup (p.Ser172fs)	LOC108281177	Pathogenic	criteria provided, single submitter
39804	NM_003106.4(SOX2):c.143_144delinsAA (p.Phe48Ter)	LOC108281177	Pathogenic	no assertion criteria provided
521127	NM_003106.4(SOX2):c.70_86del (p.Asn24fs)	LOC108281177	Pathogenic	criteria provided, multiple submitters, no conflicts
535836	NM_003106.4(SOX2):c.540C>G (p.Tyr180Ter)	LOC108281177	Pathogenic	criteria provided, multiple submitters, no conflicts
599276	NM_003106.4(SOX2):c.385_386del (p.Gly129fs)	LOC108281177	Pathogenic	criteria provided, single submitter
94104	NM_003106.4(SOX2):c.70_89del (p.Asn24fs)	LOC108281177	Pathogenic	criteria provided, multiple submitters, no conflicts
986768	NM_003106.4(SOX2):c.486_487dup (p.Met163fs)	LOC108281177	Pathogenic	no assertion criteria provided
12819	NC_000003.12:g.(179547548_181649736)_(181808821_182152788)del	LOC123256955	Pathogenic	no assertion criteria provided
467820	NC_000003.12:g.(?181712341)(181874887_?)del	LOC123256955	Pathogenic	criteria provided, single submitter
986761	GRCh37/hg19 3q26.33-27.1(chr3:180834336-183551661)x1	MAP6D1	Pathogenic	no assertion criteria provided
986757	GRCh37/hg19 3q27.1(chr3:182902731-182945128)x1	MCF2L2	Pathogenic	no assertion criteria provided
986758	GRCh37/hg19 3q27.1(chr3:182871341-182987855)x1	MCF2L2	Pathogenic	no assertion criteria provided
12814	NM_003106.4(SOX2):c.529C>T (p.Gln177Ter)	SOX2	Pathogenic	criteria provided, single submitter
1387489	NM_003106.4(SOX2):c.497G>A (p.Trp166Ter)	SOX2	Pathogenic	criteria provided, single submitter
1700169	NM_003106.4(SOX2):c.329A>C (p.Tyr110Ser)	SOX2	Pathogenic	criteria provided, single submitter
2582377	NM_003106.4(SOX2):c.621C>A (p.Tyr207Ter)	SOX2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 8 · Orphanet: 8 · 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
SOX2	Definitive	Autosomal dominant	anophthalmia/microphthalmia-esophageal atresia syndrome	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SOX2	Orphanet:3157	Septo-optic dysplasia spectrum
SOX2	Orphanet:35612	Nanophthalmos
SOX2	Orphanet:77298	Anophthalmia/microphthalmia-esophageal atresia syndrome
SOX2	Orphanet:98938	Colobomatous microphthalmia
SIX6	Orphanet:35612	Nanophthalmos
SIX6	Orphanet:435930	Colobomatous optic disc-macular atrophy-chorioretinopathy syndrome
SIX6	Orphanet:98938	Colobomatous microphthalmia
C14orf39	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation

Cohort genes → proteins

8 cohort genes, 7 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	8

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SOX2	HGNC:11195	ENSG00000181449	P48431	Transcription factor SOX-2	gencc,clinvar
SIX6	HGNC:10892	ENSG00000184302	O95475	Homeobox protein SIX6	clinvar
C14orf39	HGNC:19849	ENSG00000179008	Q8N1H7	Protein SIX6OS1	clinvar
SOX2-OT	HGNC:20209	ENSG00000242808		SOX2 overlapping transcript	clinvar
HTR3C	HGNC:24003	ENSG00000178084	Q8WXA8	5-hydroxytryptamine receptor 3C	clinvar
MAP6D1	HGNC:25753	ENSG00000180834	Q9H9H5	MAP6 domain-containing protein 1	clinvar
MCF2L2	HGNC:30319	ENSG00000053524	Q86YR7	Probable guanine nucleotide exchange factor MCF2L2	clinvar
FXR1	HGNC:4023	ENSG00000114416	P51114	RNA-binding protein FXR1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SOX2	Transcription factor SOX-2	Transcription factor that forms a trimeric complex with OCT4 on DNA and controls the expression of a number of genes involved in embryonic development such as YES1, FGF4, UTF1 and ZFP206.
SIX6	Homeobox protein SIX6	May be involved in eye development.
C14orf39	Protein SIX6OS1	Meiotic protein that localizes to the central element of the synaptonemal complex and is required for chromosome synapsis during meiotic recombination.
HTR3C	5-hydroxytryptamine receptor 3C	Forms serotonin (5-hydroxytryptamine/5-HT3)-activated cation-selective channel complexes, which when activated cause fast, depolarizing responses in neurons.
MAP6D1	MAP6 domain-containing protein 1	May have microtubule-stabilizing activity.
MCF2L2	Probable guanine nucleotide exchange factor MCF2L2	Probably functions as a guanine nucleotide exchange factor.
FXR1	RNA-binding protein FXR1	mRNA-binding protein that acts as a regulator of mRNAs translation and/or stability, and which is required for various processes, such as neurogenesis, muscle development and spermatogenesis.

Protein-family classification

Druggable: 1 · Difficult: 3 · Unknown: 4 · Druggable fraction: 0.12

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
Complement	1	33.5×	0.118
Transcription factor	2	2.1×	0.503
Scaffold/PPI	1	2.2×	0.506
Other/Unknown	4	0.9×	0.755

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SOX2	Transcription factor	no		HMG_box_dom, SOX_fam, HMG_box_dom_sf
SIX6	Transcription factor	no		HD, Homeodomain-like_sf, SIX1_SD
C14orf39	Other/Unknown	no		SIX6OS1
SOX2-OT	Other/Unknown	no
HTR3C	Other/Unknown	no		Neurotrans-gated_channel_TM, Neur_channel, Neur_chan_lig-bd
MAP6D1	Other/Unknown	no		MAP6
MCF2L2	Scaffold/PPI	no		DH_dom, CRAL-TRIO_dom, PH_domain
FXR1	Complement	yes		KH_dom, KH_dom_type_1, Agenet-like_dom

Expression context

Cohort genes with no expression data: 0.

7 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)	1
broad (>20)	7
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adenohypophysis	2
male germ line stem cell (sensu Vertebrata) in testis	2
bronchial epithelial cell	1
ganglionic eminence	1
ventricular zone	1
cranial nerve II	1
pituitary gland	1
primordial germ cell in gonad	1
corpus callosum	1
inferior vagus X ganglion	1
subthalamic nucleus	1
mucosa of transverse colon	1
right lung	1
C1 segment of cervical spinal cord	1
cerebellar cortex	1
cerebellar hemisphere	1
anterior cingulate cortex	1
cingulate cortex	1
right frontal lobe	1
gastrocnemius	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SOX2	203	broad	marker	ventricular zone, bronchial epithelial cell, ganglionic eminence
SIX6	34	tissue_specific	marker	adenohypophysis, pituitary gland, cranial nerve II
C14orf39	129	broad	marker	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, adenohypophysis
SOX2-OT	186	broad	marker	corpus callosum, subthalamic nucleus, inferior vagus X ganglion
HTR3C	20		marker	male germ line stem cell (sensu Vertebrata) in testis, right lung, mucosa of transverse colon
MAP6D1	131	broad	yes	C1 segment of cervical spinal cord, cerebellar cortex, cerebellar hemisphere
MCF2L2	167	broad	marker	right frontal lobe, cingulate cortex, anterior cingulate cortex
FXR1	299	ubiquitous	marker	sperm, hindlimb stylopod muscle, gastrocnemius

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SOX2	9,645
FXR1	4,128
SIX6	1,309
MAP6D1	708
HTR3C	609
MCF2L2	567
C14orf39	478
SOX2-OT	0

Intra-cohort edges

A	B	Sources
MAP6D1	MCF2L2	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 5 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SOX2	P48431	13
FXR1	P51114	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SIX6	O95475	81.68
HTR3C	Q8WXA8	81.38
MCF2L2	Q86YR7	73.88
C14orf39	Q8N1H7	58.97
MAP6D1	Q9H9H5	57.09

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 29. Enrichment computed across 8 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
POU5F1 (OCT4), SOX2, NANOG repress genes related to differentiation	1	380.7×	0.020	SOX2
Formation of the posterior neural plate	1	380.7×	0.020	SOX2
Formation of the anterior neural plate	1	346.1×	0.020	SOX2
POU5F1 (OCT4), SOX2, NANOG activate genes related to proliferation	1	292.8×	0.020	SOX2
Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition	1	292.8×	0.020	SOX2
Germ layer formation at gastrulation	1	223.9×	0.020	SOX2
Specification of the neural plate border	1	211.5×	0.020	SOX2
Transcriptional regulation of pluripotent stem cells	1	181.3×	0.020	SOX2
Transcriptional Regulation by MECP2	1	105.7×	0.030	SOX2
Gastrulation	1	86.5×	0.033	SOX2
Deactivation of the beta-catenin transactivating complex	1	77.7×	0.034	SOX2
MITF-M-dependent gene expression	1	60.4×	0.036	SOX2
Transcriptional and post-translational regulation of MITF-M expression and activity	1	59.5×	0.036	SOX2
Signaling by BRAF and RAF1 fusions	1	56.8×	0.036	FXR1
TCF dependent signaling in response to WNT	1	39.2×	0.045	SOX2
MITF-M-regulated melanocyte development	1	38.1×	0.045	SOX2
Signaling by WNT	1	37.3×	0.045	SOX2
Interleukin-4 and Interleukin-13 signaling	1	34.3×	0.045	SOX2
Neurotransmitter receptors and postsynaptic signal transmission	1	33.4×	0.045	HTR3C
Transmission across Chemical Synapses	1	25.4×	0.056	HTR3C
Signaling by Interleukins	1	21.4×	0.064	SOX2
Neuronal System	1	14.8×	0.087	HTR3C
Cytokine Signaling in Immune system	1	13.6×	0.090	SOX2
RNA Polymerase II Transcription	1	7.5×	0.154	SOX2
Gene expression (Transcription)	1	6.0×	0.184	SOX2
Generic Transcription Pathway	1	5.0×	0.207	SOX2
Developmental Biology	1	4.8×	0.208	SOX2
Immune System	1	4.3×	0.222	SOX2
Signal Transduction	1	3.4×	0.267	SOX2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
eye development	2	117.0×	0.009	SOX2, SIX6
regulation of myofibroblast cell apoptotic process	1	1404.3×	0.014	SOX2
meiotic DNA double-strand break processing involved in reciprocal meiotic recombination	1	936.2×	0.014	C14orf39
regulation of translation at presynapse, modulating synaptic transmission	1	936.2×	0.014	FXR1
negative regulation of mRNA catabolic process	1	936.2×	0.014	FXR1
glial cell fate commitment	1	702.2×	0.014	SOX2
nuclear pore localization	1	561.7×	0.014	FXR1
serotonin-gated cation-selective signaling pathway	1	561.7×	0.014	HTR3C
endodermal cell fate specification	1	468.1×	0.014	SOX2
adenohypophysis development	1	401.2×	0.014	SOX2
regulation of circadian sleep/wake cycle, sleep	1	401.2×	0.014	FXR1
negative regulation of cell cycle G1/S phase transition	1	401.2×	0.014	SOX2
positive regulation of miRNA-mediated gene silencing	1	401.2×	0.014	FXR1
skeletal muscle organ development	1	351.1×	0.014	FXR1
response to oxygen-glucose deprivation	1	351.1×	0.014	SOX2
serotonin receptor signaling pathway	1	312.1×	0.014	HTR3C
positive regulation of long-term neuronal synaptic plasticity	1	312.1×	0.014	FXR1
nuclear pore complex assembly	1	280.9×	0.015	FXR1
obsolete regulation of DNA-binding transcription factor activity	1	255.3×	0.015	C14orf39
response to growth factor	1	234.1×	0.016	SOX2
negative regulation of long-term synaptic potentiation	1	216.1×	0.017	FXR1
membraneless organelle assembly	1	187.2×	0.018	FXR1
cytoskeleton-dependent intracellular transport	1	156.0×	0.020	MAP6D1
obsolete inorganic cation transmembrane transport	1	156.0×	0.020	HTR3C
positive regulation of cell-cell adhesion	1	127.7×	0.022	SOX2
tissue regeneration	1	127.7×	0.022	SOX2
animal organ development	1	122.1×	0.022	FXR1
mRNA destabilization	1	112.3×	0.022	FXR1
neuronal stem cell population maintenance	1	112.3×	0.022	SOX2
synaptonemal complex assembly	1	108.0×	0.022	C14orf39

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 7

Druggability breadth: 2 of 8 evidence-associated genes (25%) 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
HTR3C	ARIPIPRAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
HTR3C	19	4
SOX2	0	0
SIX6	0	0
C14orf39	0	0
SOX2-OT	0	0
MAP6D1	0	0
MCF2L2	0	0
FXR1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
ARIPIPRAZOLE	4	HTR3C
CISAPRIDE	4	HTR3C
GRANISETRON	4	HTR3C
NICOTINE	4	HTR3C
CLOZAPINE	4	HTR3C
ONDANSETRON	4	HTR3C
TROPISETRON	4	HTR3C
MIANSERIN	4	HTR3C
ZIPRASIDONE	4	HTR3C
OLANZAPINE	4	HTR3C
METOCLOPRAMIDE	4	HTR3C
IMIPRAMINE	4	HTR3C
SEROTONIN	3	HTR3C
ZACOPRIDE	2	HTR3C
QUIPAZINE	2	HTR3C
BEMESETRON	2	HTR3C
CHLOROPHENYLPIPERAZINE	2	HTR3C
MEBUFOTENIN	2	HTR3C
PHA-543613	1	HTR3C

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
HTR3C	184	Binding:119, Functional:64, ADMET:1
FXR1	6	Binding:6

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
HTR3C	184

Pharmacogenomics

Cohort genes with a PharmGKB record: 8; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

19 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)
ARIPIPRAZOLE	4	HTR3C
CISAPRIDE	4	HTR3C
GRANISETRON	4	HTR3C
NICOTINE	4	HTR3C
CLOZAPINE	4	HTR3C
ONDANSETRON	4	HTR3C
TROPISETRON	4	HTR3C
MIANSERIN	4	HTR3C
ZIPRASIDONE	4	HTR3C
OLANZAPINE	4	HTR3C
METOCLOPRAMIDE	4	HTR3C
IMIPRAMINE	4	HTR3C
SEROTONIN	3	HTR3C
ZACOPRIDE	2	HTR3C
QUIPAZINE	2	HTR3C
BEMESETRON	2	HTR3C
CHLOROPHENYLPIPERAZINE	2	HTR3C
MEBUFOTENIN	2	HTR3C
PHA-543613	1	HTR3C

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	HTR3C
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	FXR1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	6	SOX2, SIX6, C14orf39, SOX2-OT, MAP6D1, MCF2L2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
SOX2	0	—
SIX6	0	—
C14orf39	0	—
SOX2-OT	0	—
MAP6D1	0	—
MCF2L2	0	—
FXR1	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.