Hyperopia

Summary

Hyperopia (MONDO:0004891) is a disease whose monogenic forms are linked to MYRF. It is a refractive error in which rays of light entering the eye parallel to the optic axis are brought to a focus behind the retina, as a result of the eyeball being too short from front to back (Mondo). This page aggregates 24 associated genes (282 GWAS associations across 21 studies) and 125 registered clinical trials. Top therapeutic interventions include codeine, levofloxacin anhydrous, and nepafenac.

At a glance

• Causal gene: MYRF (GenCC Strong)
• Cohort genes: 24
• GWAS associations: 282 (top 1% of diseases corpus-wide)
• ClinVar variants: 12
• Clinical trials: 125 (top 3% of diseases corpus-wide)
• Druggability snapshot: 0 of 24 cohort genes are drug-illuminated (an approved/clinical drug with curated evidence); 22 functionally characterized but not yet drugged (MYRF, BMP3, SLC9A6, ZIC2). Atlas-derived.

Clinical features

Clinical description

Mondo: A refractive error in which rays of light entering the eye parallel to the optic axis are brought to a focus behind the retina, as a result of the eyeball being too short from front to back. It is also called farsightedness because the near point is more distant than it is in emmetropia with an equal amplitude of accommodation. (Dorland, 27th ed)

Identifiers

Disease identifiers

Field	Value
Canonical name	hyperopia
Mondo ID	MONDO:0004891
MeSH	D006956
DOID	DOID:9834
ICD-10-CM	H52.0
SNOMED CT	38101003
UMLS	C0020490
MedGen	43780
Is cancer (heuristic)	no

Also known as: hypermetropia

Data availability: 12 ClinVar variants · 282 GWAS associations (21 studies) · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › disorder of orbital region › eye disorder › refractive error › hyperopia

Sibling subtypes (6): presbyopia, myopia, anisometropia, astigmatism, … (+2 more under refractive error)

Genetics & variants

GWAS landscape

282 GWAS associations across 21 studies. Top hits map to 25 distinct genes (as reported by GWAS).

Top associations by p-value

showing 30 of 282 associations by p-value:

rsID	p-value	Gene	Risk allele	Odds ratio
rs12193446	2e-32	LAMA2	?	0.41
rs524952	4e-32	LINC02252 - GJD2	T	0.07
rs7744813	4e-31	KCNQ5	C	0.07
rs3138142	8e-28	RDH5	C	0.08
chr16:7460699	1e-27		A	0.06
rs634990	2e-26	LINC02252 - GJD2	T	0.06
rs7188859	3e-26	RBFOX1	T	0.06
chr8:60179048	1e-23		?	0.22
rs3138141	2e-23	RDH5	C	0.08
rs6929347	7e-23	KCNQ5	?	0.2
chr14:60957171	5e-21		G	0.06
chr3:8191247	3e-18		T	0.05
rs11602008	3e-17	LRRC4C	A	0.06
rs11606250	8e-17	LRRC4C	G	0.06
rs178597	9e-17	LMCD1-AS1	C	0.05
chr1:207444928	1e-16		C	0.05
chr18:42895536	2e-16		C	0.06
rs2093210	3e-16	C14orf39	C	0.05
rs58004513	2e-15	SLC14A2	A	0.06
rs724154	4e-15	LINC00554 - NDUFA12P1	G	0.05
rs112947941	5e-15	SPSB2, LRRC23	?	0.33
rs71640857	5e-15	LYPLAL1-AS1 - ZC3H11B	G	0.04
rs10089517	8e-15	TOX-DT - RNA5SP267	C	0.05
rs1340044	1e-14	ADAMTSL1	T	0.05
chr13:100667862	6e-14		G	0.04
chr6:22079485	1e-13		G	0.04
rs74485555	2e-13	ANKRD34C-AS1	?	0.16
rs1550094	2e-13	PRSS56	G	0.04
rs11594240	2e-13	BICC1	G	0.05
rs869422	2e-13	ZMAT4	A	0.05

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90475882	Verma A	2024	73,817	320,870	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90079387	Backman JD	2021	23,800	3,778	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90083373	Backman JD	2021	23,800	3,778	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90044327	Jiang L	2021	18,730	436,924	A generalized linear mixed model association tool for biobank-scale data.
GCST90477690	Verma A	2024	16,235	90,700	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90480076	Verma A	2024	16,235	90,700	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90044217	Jiang L	2021	16,035	2,695	A generalized linear mixed model association tool for biobank-scale data.
GCST012400	Tideman JWL	2021	11,197	0	Evaluation of Shared Genetic Susceptibility to High and Low Myopia and Hyperopia.
GCST012401	Tideman JWL	2021	10,828	21,416	Evaluation of Shared Genetic Susceptibility to High and Low Myopia and Hyperopia.
GCST90477688	Verma A	2024	8,188	44,636	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	2
Tier 2: splice/UTR	2
Tier 3: regulatory	0
Tier 4: intronic/intergenic	46

MAF distribution

Bucket	Variants
common (>=0.05)	49
low_freq (0.01-0.05)	0
rare (<0.01)	0
unknown	1

Functional consequences

7 consequence types:

Consequence	Count
intron_variant	24
unknown	14
intergenic_variant	6
3_prime_UTR_variant	2
missense_variant	2
synonymous_variant	1
non_coding_transcript_exon_variant	1

Top variants

showing 30 of 50 variants:

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs12193446	6	129498893	A>G	0.05	intron_variant	LAMA2	2e-32	Tier 4: intronic/intergenic
rs524952	15	34713685	T>A,C	0.491	intron_variant	LINC02252 - GJD2	4e-32	Tier 4: intronic/intergenic
rs7744813	6	72933566	C>A,G,T	0.423	intron_variant	KCNQ5	4e-31	Tier 4: intronic/intergenic
rs3138142	12	55721801	C>A,T	0.213	synonymous_variant	RDH5	8e-28	Tier 4: intronic/intergenic
chr16:7460699				0.37			1e-27	Tier 4: intronic/intergenic
rs634990	15	34713872	T>A,C,G	0.479	intron_variant	LINC02252 - GJD2	2e-26	Tier 4: intronic/intergenic
rs7188859	16	7410425	T>C	0.328	intron_variant	RBFOX1	3e-26	Tier 4: intronic/intergenic
chr8:60179048							1e-23	Tier 4: intronic/intergenic
rs3138141	12	55721994	C>A,G,T	0.173	3_prime_UTR_variant	RDH5	2e-23	Tier 2: splice/UTR
rs6929347	6	72919843	A>G	0.05	intron_variant	KCNQ5	7e-23	Tier 4: intronic/intergenic
chr14:60957171				0.451			5e-21	Tier 4: intronic/intergenic
chr3:8191247				0.405			3e-18	Tier 4: intronic/intergenic
rs11602008	11	40127755	A>T	0.167	intron_variant	LRRC4C	3e-17	Tier 4: intronic/intergenic
rs11606250	11	40127750	G>A	0.171	intron_variant	LRRC4C	8e-17	Tier 4: intronic/intergenic
rs178597	3	8155254	C>T	0.472	intron_variant	LMCD1-AS1	9e-17	Tier 4: intronic/intergenic
chr1:207444928				0.327			1e-16	Tier 4: intronic/intergenic
chr18:42895536				0.152			2e-16	Tier 4: intronic/intergenic
rs2093210	14	60490561	C>G,T	0.492	intergenic_variant	C14orf39	3e-16	Tier 4: intronic/intergenic
rs58004513	18	45307920	A>G	0.162	intron_variant	SLC14A2	2e-15	Tier 4: intronic/intergenic
rs724154	13	100021362	G>A,C	0.378	intergenic_variant	LINC00554 - NDUFA12P1	4e-15	Tier 4: intronic/intergenic
rs112947941	12	6888644	A>G	0.05	intron_variant	SPSB2, LRRC23	5e-15	Tier 4: intronic/intergenic
rs71640857	1	219606018	G>A	0.477	intergenic_variant	LYPLAL1-AS1 - ZC3H11B	5e-15	Tier 4: intronic/intergenic
rs10089517	8	59266162	C>A	0.345	intron_variant	TOX-DT - RNA5SP267	8e-15	Tier 4: intronic/intergenic
rs1340044	9	18362107	T>A,G	0.492	non_coding_transcript_exon_variant	ADAMTSL1	1e-14	Tier 4: intronic/intergenic
chr13:100667862				0.416			6e-14	Tier 4: intronic/intergenic
chr6:22079485				0.443			1e-13	Tier 4: intronic/intergenic
rs74485555	15	79161735	C>T	0.05	intron_variant	ANKRD34C-AS1	2e-13	Tier 4: intronic/intergenic
rs1550094	2	232520686	G>A,C,T	0.307	missense_variant	PRSS56	2e-13	Tier 1: coding
rs11594240	10	58525025	G>A,C,T	0.385	intron_variant	BICC1	2e-13	Tier 4: intronic/intergenic
rs869422	8	40866451	A>G	0.216	intron_variant	ZMAT4	2e-13	Tier 4: intronic/intergenic

ClinVar germline variants

12 retrieved; paginated sample, class counts are floors:

5 pathogenic, 4 uncertain significance, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1173069	NM_005916.5(MCM7):c.776G>C (p.Gly259Ala)	MCM7	Pathogenic	criteria provided, multiple submitters, no conflicts
268035	46;XX;t(19;21)(q13.3;q22.3)dn		Pathogenic	criteria provided, single submitter
1804007	NM_005916.5(MCM7):c.133C>T (p.Gln45Ter)	MCM7	Pathogenic	criteria provided, single submitter
1804042	NM_144643.4(SCLT1):c.1043del (p.Ser348fs)	SCLT1	Pathogenic	criteria provided, single submitter
242882	NM_013275.6(ANKRD11):c.5317G>T (p.Glu1773Ter)	ANKRD11	Pathogenic	no assertion criteria provided
1804041	NM_144643.4(SCLT1):c.2060dup (p.Asn687fs)	SCLT1	Likely pathogenic	criteria provided, single submitter
2430245	NM_002235.5(KCNA6):c.1367T>A (p.Val456Asp)	KCNA6	Likely pathogenic	criteria provided, single submitter
183286	NM_172225.2(DMBX1):c.352C>T (p.Arg118Trp)	DMBX1	Likely pathogenic	no assertion criteria provided
523487	NM_005802.5(TOPORS):c.2666A>G (p.His889Arg)	TOPORS	Uncertain significance	criteria provided, multiple submitters, no conflicts
523282	GRCh37/hg19 6p24.1-23(chr6:12536624-13968949)	TBC1D7	Uncertain significance	criteria provided, single submitter
523302	GRCh37/hg19 5p14.3-14.2(chr5:22308420-24492723)	CDH10	Uncertain significance	criteria provided, single submitter
523398	NM_001379110.1(SLC9A6):c.1190C>A (p.Ala397Glu)	SLC9A6	Uncertain significance	criteria provided, single submitter

Pathogenic / likely-pathogenic variants link to their full per-variant reference — ACMG evidence, calibrated predictors, gnomAD frequency — on Sugi Variant.

Genes & proteins

Molecular basis

The molecular function of this disease’s causal gene(s), from UniProt. Attributed to the gene/protein — reporting UniProt’s curation, not an assertion about this disease’s clinical phenotype.

MYRF — Myelin regulatory factor (Q9Y2G1) · GenCC Strong · Belongs to the MRF family. Function: Constitutes a precursor of the transcription factor. Localization / cofactor: Endoplasmic reticulum membrane Nucleus UniProt gene–disease: Encephalitis/encephalopathy, mild, with reversible myelin vacuolization (MMERV) [MIM:618113] An autosomal dominant disease characterized by episodes of acute encephalitis associated with impaired consciousness, delirious behavior, seizures, and reversible …

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 18 · 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.

1 cohort genes:

Gene	Classification	Inheritance	Disease	Records
MYRF	Strong	Autosomal dominant	hyperopia	7

Orphanet rare-disease linkage (cohort genes)

18 cohort genes:

Gene	Orphanet ID	Rare disease
MYRF	Orphanet:647811	Cardiac-urogenital syndrome
SLC9A6	Orphanet:85278	Christianson syndrome
ZIC2	Orphanet:220386	Semilobar holoprosencephaly
ZIC2	Orphanet:280195	Septopreoptic holoprosencephaly
ZIC2	Orphanet:280200	Microform holoprosencephaly
ZIC2	Orphanet:93924	Lobar holoprosencephaly
ZIC2	Orphanet:93925	Alobar holoprosencephaly
ZIC2	Orphanet:93926	Midline interhemispheric variant of holoprosencephaly
TBC1D7	Orphanet:2477	Isolated megalencephaly
ANKRD11	Orphanet:2332	KBG syndrome
ANKRD11	Orphanet:261250	16q24.3 microdeletion syndrome
TOPORS	Orphanet:2754	Orofaciodigital syndrome type 6
TOPORS	Orphanet:791	Retinitis pigmentosa
SCLT1	Orphanet:110	Bardet-Biedl syndrome
PRSS56	Orphanet:35612	Nanophthalmos
LAMA2	Orphanet:258	Laminin subunit alpha 2-related congenital muscular dystrophy
LAMA2	Orphanet:565837	Laminin subunit alpha 2-related limb-girdle muscular dystrophy R23
MCM7	Orphanet:2512	Autosomal recessive primary microcephaly

Cohort genes → proteins

24 cohort genes, 23 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	14
multi_evidence	10

Cohort genes

24 cohort genes:

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MYRF	HGNC:1181	ENSG00000124920	Q9Y2G1	Myelin regulatory factor	gencc
RNU6-1	HGNC:10227	ENSG00000206625		RNA, U6 small nuclear 1	gwas
RORB	HGNC:10259	ENSG00000198963	Q92753	Nuclear receptor ROR-beta	gwas
BMP3	HGNC:1070	ENSG00000152785	P12645	Bone morphogenetic protein 3	gwas
SLC9A6	HGNC:11079	ENSG00000198689	Q92581	Sodium/hydrogen exchanger 6	clinvar
ZIC2	HGNC:12873	ENSG00000043355	O95409	Zinc finger protein ZIC 2	gwas
CDH10	HGNC:1749	ENSG00000040731	Q9Y6N8	Cadherin-10	clinvar
RBFOX1	HGNC:18222	ENSG00000078328	Q9NWB1	RNA binding protein fox-1 homolog 1	gwas
TOX	HGNC:18988	ENSG00000198846	O94900	Thymocyte selection-associated high mobility group box protein TOX	gwas
DMBX1	HGNC:19026	ENSG00000197587	Q8NFW5	Diencephalon/mesencephalon homeobox protein 1	clinvar
GJD2	HGNC:19154	ENSG00000159248	Q9UKL4	Gap junction delta-2 protein	gwas
ZIC5	HGNC:20322	ENSG00000139800	Q96T25	Zinc finger protein ZIC 5	gwas
TBC1D7	HGNC:21066	ENSG00000145979	Q9P0N9	TBC1 domain family member 7	clinvar
ANKRD11	HGNC:21316	ENSG00000167522	Q6UB99	Ankyrin repeat domain-containing protein 11	clinvar
TOPORS	HGNC:21653	ENSG00000197579	Q9NS56	E3 ubiquitin-protein ligase Topors	clinvar
RASGEF1B	HGNC:24881	ENSG00000138670	Q0VAM2	Ras-GEF domain-containing family member 1B	gwas
KAZALD1	HGNC:25460	ENSG00000107821	Q96I82	Kazal-type serine protease inhibitor domain-containing protein 1	gwas
SCLT1	HGNC:26406	ENSG00000151466	Q96NL6	Sodium channel and clathrin linker 1	clinvar
LRRC4C	HGNC:29317	ENSG00000148948	Q9HCJ2	Leucine-rich repeat-containing protein 4C	gwas
GOLGA8B	HGNC:31973	ENSG00000215252	A8MQT2	Golgin subfamily A member 8B	gwas
PRSS56	HGNC:39433	ENSG00000237412	P0CW18	Serine protease 56	gwas
KCNA6	HGNC:6225	ENSG00000151079	P17658	Potassium voltage-gated channel subfamily A member 6	clinvar
LAMA2	HGNC:6482	ENSG00000196569	P24043	Laminin subunit alpha-2	gwas
MCM7	HGNC:6950	ENSG00000166508	P33993	DNA replication licensing factor MCM7	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

23 cohort genes:

Symbol	Protein name	Function (lead sentence)
MYRF	Myelin regulatory factor	Constitutes a precursor of the transcription factor.
RORB	Nuclear receptor ROR-beta	Nuclear receptor that binds DNA as a monomer to ROR response elements (RORE) containing a single core motif half-site 5’-AGGTCA-3’ preceded by a short A-T-rich sequence.
BMP3	Bone morphogenetic protein 3	Growth factor of the TGF-beta superfamily that plays an essential role in developmental process by inducing and patterning early skeletal formation and by negatively regulating bone density.
SLC9A6	Sodium/hydrogen exchanger 6	Endosomal Na(+), K(+)/H(+) antiporter.
ZIC2	Zinc finger protein ZIC 2	Acts as a transcriptional activator or repressor.
CDH10	Cadherin-10	Cadherins are calcium-dependent cell adhesion proteins.
RBFOX1	RNA binding protein fox-1 homolog 1	RNA-binding protein that regulates alternative splicing events by binding to 5’-UGCAUGU-3’ elements.
TOX	Thymocyte selection-associated high mobility group box protein TOX	Transcriptional regulator with a major role in neural stem cell commitment and corticogenesis as well as in lymphoid cell development and lymphoid tissue organogenesis.
DMBX1	Diencephalon/mesencephalon homeobox protein 1	Functions as a transcriptional repressor.
GJD2	Gap junction delta-2 protein	One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.
ZIC5	Zinc finger protein ZIC 5	Essential for neural crest development, converting cells from an epidermal fate to a neural crest cell fate.
TBC1D7	TBC1 domain family member 7	Non-catalytic component of the TSC-TBC complex, a multiprotein complex that acts as a negative regulator of the canonical mTORC1 complex, an evolutionarily conserved central nutrient sensor that stimulates anabolic reactions and macromolec…
ANKRD11	Ankyrin repeat domain-containing protein 11	Chromatin regulator which modulates histone acetylation and gene expression in neural precursor cells.
TOPORS	E3 ubiquitin-protein ligase Topors	Functions as an E3 ubiquitin-protein ligase and as an E3 SUMO1-protein ligase.
RASGEF1B	Ras-GEF domain-containing family member 1B	Guanine nucleotide exchange factor (GEF) with specificity for RAP2A, it doesn’t seems to activate other Ras family proteins (in vitro).
KAZALD1	Kazal-type serine protease inhibitor domain-containing protein 1	Involved in the proliferation of osteoblasts during bone formation and bone regeneration.
SCLT1	Sodium channel and clathrin linker 1	Adapter protein that links SCN10A to clathrin.
LRRC4C	Leucine-rich repeat-containing protein 4C	May promote neurite outgrowth of developing thalamic neurons.
GOLGA8B	Golgin subfamily A member 8B	May be involved in maintaining Golgi structure.
PRSS56	Serine protease 56	Serine protease required during eye development.
KCNA6	Potassium voltage-gated channel subfamily A member 6	Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes.
LAMA2	Laminin subunit alpha-2	Binding to cells via a high affinity receptor, laminin is thought to mediate the attachment, migration and organization of cells into tissues during embryonic development by interacting with other extracellular matrix components.
MCM7	DNA replication licensing factor MCM7	Acts as a component of the MCM2-7 complex (MCM complex) which is the replicative helicase essential for ‘once per cell cycle’ DNA replication initiation and elongation in eukaryotic cells.

Protein-family classification

Druggable: 5 · Difficult: 6 · Unknown: 13 · Druggable fraction: 0.21

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
Nuclear receptor	1	16.1×	0.346
Ion channel	1	4.7×	0.346
Antibody/Immunoglobulin	2	2.4×	0.346
Transcription factor	5	1.7×	0.346
Protease	1	1.5×	0.680
Other/Unknown	13	1.0×	0.754
Scaffold/PPI	1	0.7×	0.761

Per-gene assignment

24 cohort genes:

Symbol	Family	Druggable?	EC	InterPro (top 3)
MYRF	Transcription factor	no		p53-like_TF_DNA-bd_sf, NDT80_DNA-bd_dom, MYRF_C2
RNU6-1	Other/Unknown	no
RORB	Nuclear receptor	yes		Nucl_hrmn_rcpt_lig-bd, Znf_hrmn_rcpt, Nuclear_hrmn_rcpt
BMP3	Other/Unknown	no		TGF-b_C, TGF-beta-like, BMP3/BMP3B
SLC9A6	Other/Unknown	no		NHE-6/7/9, NaH_exchanger, Cation/H_exchanger_TM
ZIC2	Transcription factor	no		Zf-C2H2_type, Znf_C2H2_sf, Znf_ZIC
CDH10	Other/Unknown	no		Cadherin_Y-type_LIR, Cadherin-like_dom, Cadherin-like_sf
RBFOX1	Other/Unknown	no		RRM_dom, Nucleotide-bd_a/b_plait_sf, RBFOX1-3
TOX	Other/Unknown	no		HMG_box_dom, HMG_box_dom_sf, TOX_protein
DMBX1	Transcription factor	no		HD, OAR_dom, Homeodomain-like_sf
GJD2	Other/Unknown	no		Connexin, Connexin36, Connexin_N
ZIC5	Transcription factor	no		Zf-C2H2_type, Znf_C2H2_sf, Znf_ZIC
TBC1D7	Other/Unknown	no		Rab-GAP-TBC_dom, Rab-GAP_TBC_sf, TBC1D7
ANKRD11	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, ANKRD11
TOPORS	Transcription factor	no		Znf_RING, Znf_RING/FYVE/PHD, Znf_RING_CS
RASGEF1B	Other/Unknown	no		Ras-like_Gua-exchang_fac_N, RASGEF_cat_dom, Ras-like_GEF
KAZALD1	Antibody/Immunoglobulin	yes		IGFBP-like, Kazal_dom, Ig_sub2
SCLT1	Other/Unknown	no		SCLT1
LRRC4C	Antibody/Immunoglobulin	yes		LRRNT, Leu-rich_rpt, Leu-rich_rpt_typical-subtyp
GOLGA8B	Other/Unknown	no		GOLGA, GOLGA_C, GOLGA_cons_dom
PRSS56	Protease	yes		Trypsin_dom, Peptidase_S1A, Peptidase_S1_PA
KCNA6	Ion channel	yes		BTB/POZ_dom, T1-type_BTB, K_chnl_volt-dep_Kv
LAMA2	Other/Unknown	no		Laminin_IV, EGF, Laminin_G
MCM7	Other/Unknown	no		MCM_dom, AAA+_ATPase, MCM7

Expression context

Cohort genes with no expression data: 0.

18 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)	24
unknown	0

Top tissues across cohort

20 tissues:

Tissue	Cohort genes
middle temporal gyrus	5
Brodmann (1909) area 23	4
cortical plate	4
male germ line stem cell (sensu Vertebrata) in testis	3
primordial germ cell in gonad	3
ganglionic eminence	3
sural nerve	2
endothelial cell	2
cerebellar cortex	2
cerebellar hemisphere	2
ventricular zone	2
calcaneal tendon	2
monocyte	2
buccal mucosa cell	2
C1 segment of cervical spinal cord	1
inferior vagus X ganglion	1
middle frontal gyrus	1
adrenal tissue	1
corpus callosum	1
muscle layer of sigmoid colon	1

Per-gene tissue summary

24 cohort genes:

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MYRF	223	ubiquitous	marker	middle frontal gyrus, C1 segment of cervical spinal cord, inferior vagus X ganglion
RNU6-1	117	broad	yes	sural nerve, adrenal tissue, corpus callosum
RORB	196	broad	marker	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus
BMP3	126	tissue_specific	marker	muscle layer of sigmoid colon, male germ line stem cell (sensu Vertebrata) in testis, rectum
SLC9A6	286	ubiquitous	yes	lateral nuclear group of thalamus, middle temporal gyrus, pons
ZIC2	139	broad	marker	cerebellar cortex, cerebellar hemisphere, cerebellum
CDH10	172	broad	marker	Brodmann (1909) area 23, middle temporal gyrus, Brodmann (1909) area 46
RBFOX1	220	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, cortical plate
TOX	231	ubiquitous	marker	cortical plate, endothelial cell, ventricular zone
DMBX1	33	broad	yes	male germ line stem cell (sensu Vertebrata) in testis, upper arm skin, primordial germ cell in gonad
GJD2	70	tissue_specific	marker	islet of Langerhans, primordial germ cell in gonad, tongue squamous epithelium
ZIC5	57	tissue_specific	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
TBC1D7	242	ubiquitous	marker	cortical plate, oocyte, ganglionic eminence
ANKRD11	278	ubiquitous	marker	tendon of biceps brachii, sural nerve, stromal cell of endometrium
TOPORS	285	ubiquitous	marker	secondary oocyte, calcaneal tendon, sperm
RASGEF1B	164	ubiquitous	marker	ganglionic eminence, right lobe of liver, monocyte
KAZALD1	176	ubiquitous	yes	primordial germ cell in gonad, spleen, mucosa of transverse colon
SCLT1	217	ubiquitous	marker	buccal mucosa cell, monocyte, leukocyte
LRRC4C	206	broad	marker	middle temporal gyrus, buccal mucosa cell, Brodmann (1909) area 23
GOLGA8B	134	broad	marker	body of pancreas, left lobe of thyroid gland, right lobe of thyroid gland
PRSS56	47	tissue_specific	yes	hindlimb stylopod muscle, gastrocnemius, muscle of leg
KCNA6	123	tissue_specific	yes	cortical plate, male germ line stem cell (sensu Vertebrata) in testis, prefrontal cortex
LAMA2	272	ubiquitous	marker	mucosa of stomach, calcaneal tendon, right ovary
MCM7	143	ubiquitous	marker	embryo, ganglionic eminence, ventricular zone

Protein interactions among cohort

Intra-cohort edges: 6.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MCM7	4,341
RBFOX1	2,500
LAMA2	2,020
ANKRD11	1,694
TOPORS	1,420
LRRC4C	1,363
SLC9A6	1,323
RORB	1,322
TOX	1,208
ZIC2	1,166

Intra-cohort edges

6 intra-cohort edges:

A	B	Sources
GJD2	GOLGA8B	string_interaction
GJD2	PRSS56	string_interaction
KAZALD1	PRSS56	string_interaction
LAMA2	PRSS56	string_interaction
LRRC4C	RBFOX1	string_interaction
ZIC2	ZIC5	string_interaction

Structural data

PDB: 9 · AlphaFold-only: 14 · No structure: 1

Cohort genes with PDB structures

9 cohort genes:

Symbol	UniProt	PDB entries
MCM7	P33993	28
GJD2	Q9UKL4	24
TBC1D7	Q9P0N9	6
SLC9A6	Q92581	5
RBFOX1	Q9NWB1	4
MYRF	Q9Y2G1	2
LAMA2	P24043	2
BMP3	P12645	1
LRRC4C	Q9HCJ2	1

AlphaFold-only cohort genes (by pLDDT)

14 cohort genes:

Symbol	UniProt	pLDDT
RASGEF1B	Q0VAM2	87.31
KAZALD1	Q96I82	82.85
SCLT1	Q96NL6	82.44
RORB	Q92753	79.48
CDH10	Q9Y6N8	78.29
KCNA6	P17658	75.42
PRSS56	P0CW18	74.35
GOLGA8B	A8MQT2	70.37
DMBX1	Q8NFW5	63.71
TOX	O94900	54.57
ZIC5	Q96T25	52.58
ZIC2	O95409	51.36
TOPORS	Q9NS56	49.39
ANKRD11	Q6UB99	39.44

Alliance gene associations

Curated gene–disease associations from the Alliance of Genome Resources (Disease Ontology) — distinct from the cohort above: implicated (causal/mechanistic) vs biomarker (a marker for the disease).

Implicated genes (2): MYRF, NOG

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 83. Enrichment computed across 24 evidence-associated genes (12 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 12 annotated cohort genes). Counts and members are kept as ground-truth.

30 pathways by enrichment:

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective SLC9A6 causes X-linked, syndromic mental retardation,, Christianson type (MRXSCH)	1	951.7×	0.081	SLC9A6
MECP2 regulates transcription factors	1	190.3×	0.098	RBFOX1
Electric Transmission Across Gap Junctions	1	158.6×	0.098	GJD2
Sodium/Proton exchangers	1	105.7×	0.098	SLC9A6
DNA strand elongation	1	95.2×	0.098	MCM7
Formation of the anterior neural plate	1	86.5×	0.098	ZIC2
SUMOylation of immune response proteins	1	79.3×	0.098	TOPORS
Unwinding of DNA	1	73.2×	0.098	MCM7
MET promotes cell motility	1	50.1×	0.098	LAMA2
Attachment of bacteria to epithelial cells	1	41.4×	0.098	LAMA2
Gap junction trafficking and regulation	1	39.6×	0.098	GJD2
Gap junction trafficking	1	39.6×	0.098	GJD2
Laminin interactions	1	31.7×	0.098	LAMA2
MET activates PTK2 signaling	1	31.7×	0.098	LAMA2
Rab regulation of trafficking	1	30.7×	0.098	TBC1D7
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	30.7×	0.098	LAMA2
Bacterial Infection Pathways	1	28.0×	0.098	LAMA2
SUMOylation of SUMOylation proteins	1	27.2×	0.098	TOPORS
Activation of the pre-replicative complex	1	27.2×	0.098	MCM7
Signaling by MET	1	26.4×	0.098	LAMA2
DNA Replication Pre-Initiation	1	26.4×	0.098	MCM7
Transcriptional Regulation by MECP2	1	26.4×	0.098	RBFOX1
Formation of the dystrophin-glycoprotein complex (DGC)	1	25.7×	0.098	LAMA2
Activation of ATR in response to replication stress	1	25.0×	0.098	MCM7
Switching of origins to a post-replicative state	1	25.0×	0.098	MCM7
Synthesis of DNA	1	25.0×	0.098	MCM7
Gap junction assembly	1	24.4×	0.098	GJD2
Expression of BMAL (ARNTL), CLOCK, and NPAS2	1	24.4×	0.098	RORB
TBC/RABGAPs	1	21.6×	0.098	TBC1D7
Gastrulation	1	21.6×	0.098	ZIC2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 23 annotated cohort genes). Counts and members are kept as ground-truth.

30 GO terms by enrichment:

GO term	Cohort genes	Fold	FDR	Sample cohort genes
DNA-templated transcription	6	58.6×	8e-08	RORB, MYRF, ZIC2, TOX, DMBX1, TOPORS
synaptic membrane adhesion	2	50.5×	0.041	CDH10, LRRC4C
central nervous system development	3	15.1×	0.041	ZIC2, DMBX1, ZIC5
NK T cell lineage commitment	1	732.7×	0.043	TOX
CD4-positive, CD25-positive, alpha-beta regulatory T cell lineage commitment	1	366.4×	0.043	TOX
CD4-positive, alpha-beta T cell lineage commitment	1	366.4×	0.043	TOX
CD8-positive, alpha-beta T cell lineage commitment	1	366.4×	0.043	TOX
regulation of positive thymic T cell selection	1	366.4×	0.043	TOX
leukocyte differentiation	1	146.5×	0.085	TOX
central nervous system myelin maintenance	1	122.1×	0.085	MYRF
regulation of phosphorylation	1	122.1×	0.085	MCM7
regulation of basement membrane organization	1	122.1×	0.085	LAMA2
clustering of voltage-gated sodium channels	1	104.7×	0.092	SCLT1
DNA strand elongation involved in DNA replication	1	81.4×	0.094	MCM7
retinal rod cell development	1	73.3×	0.094	RORB
dendrite extension	1	73.3×	0.094	SLC9A6
amacrine cell differentiation	1	66.6×	0.094	RORB
RNA transport	1	66.6×	0.094	RBFOX1
retinal cone cell development	1	61.1×	0.094	RORB
response to growth factor	1	61.1×	0.094	TBC1D7
double-strand break repair via break-induced replication	1	56.4×	0.094	MCM7
positive regulation of integrin-mediated signaling pathway	1	56.4×	0.094	LAMA2
cerebral cortex neuron differentiation	1	52.3×	0.094	TOX
positive regulation of muscle cell differentiation	1	48.9×	0.094	LAMA2
maintenance of protein location in nucleus	1	48.9×	0.094	TOPORS
regulation of DNA-templated DNA replication initiation	1	45.8×	0.094	MCM7
photoreceptor cell outer segment organization	1	45.8×	0.094	TOPORS
central nervous system myelination	1	43.1×	0.094	MYRF
natural killer cell differentiation	1	38.6×	0.094	TOX
regulation of axonogenesis	1	38.6×	0.094	LRRC4C

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 23

Druggability breadth: 4 of 24 evidence-associated genes (17%) 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
RORB	Tretinoin

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RORB	2	4
MYRF	0	0
RNU6-1	0	0
BMP3	0	0
SLC9A6	0	0
ZIC2	0	0
CDH10	0	0
RBFOX1	0	0
TOX	0	0
DMBX1	0	0

Drugs targeting cohort genes

2 drugs:

Molecule	Max phase	Targets in cohort
Tretinoin	4	RORB
Cintirorgon	1	RORB

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity

3 cohort genes by assay count:

Symbol	Assays	Type breakdown
RORB	90	Binding:87, Functional:3
KCNA6	29	Binding:24, Functional:3, Toxicity:1, ADMET:1
MCM7	9	Binding:9

Pharmacogenomics

Cohort genes with a PharmGKB record: 24; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

2 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.

2 compounds:

Compound	Max phase	Cohort target (bioactivity)
Tretinoin	4	RORB
Cintirorgon	1	RORB

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	RORB
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	LRRC4C
D	Druggable family + AlphaFold only, no drug	3	KAZALD1, PRSS56, KCNA6
E	Difficult family or no structure, no drug	19	MYRF, RNU6-1, BMP3, SLC9A6, ZIC2, CDH10, RBFOX1, TOX, DMBX1, GJD2 (+9 more)

Undrugged target profiles

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

23 cohort genes:

Symbol	ChEMBL assays	Drugged partners (top 3)
MYRF	0	—
RNU6-1	0	—
BMP3	0	—
SLC9A6	0	—
ZIC2	0	—
CDH10	0	—
RBFOX1	0	—
TOX	0	—
DMBX1	0	—
GJD2	0	—
ZIC5	0	—
TBC1D7	0	—
ANKRD11	0	—
TOPORS	0	—
RASGEF1B	0	—
KAZALD1	0	—
SCLT1	0	—
LRRC4C	0	—
GOLGA8B	0	—
PRSS56	0	—
KCNA6	29	—
LAMA2	0	—
MCM7	9	—

Clinical trials & evidence

Clinical trials

Clinical trials: 125.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	101
Phase 4	10
Phase 3	6
Phase 1/2	5
Phase 2	1
Phase 1	1
Early Phase 1	1

Top trials by phase / activity

showing 40 of 125 trials:

NCT	Phase	Status	Sponsor	Title
NCT00347204	Phase 4	COMPLETED	Center For Excellence In Eye Care	Comparison of Acular LS Versus Nevanac for Pain Control in Eyes Undergoing PRK
NCT00455455	Phase 4	COMPLETED	University of Waterloo	Corneal and Conjunctival Sensitivity and Staining Study
NCT00937105	Phase 4	COMPLETED	University Hospitals Cleveland Medical Center	Daily Wear Corneal Infiltrative Event Study
NCT01387360	Phase 4	COMPLETED	Technolas Perfect Vision GmbH	Presbyopic Supracor Treatment for Near Myopic/Hyperopic Pseudophakic Eyes
NCT01977807	Phase 4	UNKNOWN	Technolas Perfect Vision GmbH	A Prospective Safety and Effectiveness Study of the 500 Hz Technolas Perfect Vision Excimer Laser in Asian Eyes Using LASIK
NCT02071576	Phase 4	UNKNOWN	Technolas Perfect Vision GmbH	A Prospective Safety and Effectiveness Study of the 500 Hz Technolas Perfect Vision Excimer Laser Using LASIK
NCT02112968	Phase 4	UNKNOWN	Technolas Perfect Vision GmbH	A Prospective Safety and Effectiveness Study of a New High Repetition Rate Excimer Laser Using LASIK for the Correction of Ammetropia and Presbyopia
NCT03881670	Phase 4	COMPLETED	Indiana University	On-Eye Optical Quality of Lotrafilcon B Lenses Over 12 Hours
NCT04208750	Phase 4	COMPLETED	Pete Kollbaum, OD, PhD	Clinical Investigation of the Vision-R800 Device.
NCT04283331	Phase 4	UNKNOWN	Beeran Meghpara, MD	Anesthetic Impregnated Bandage Soft Contact Lens (BSCL) in Pain Management After Photorefractive Keratectomy (PRK)
NCT00520689	Phase 3	COMPLETED	University of Waterloo	Multipurpose Disinfecting Solution Compatibility With a Silicone Hydrogel Contact Lens
NCT00910403	Phase 3	COMPLETED	Technolas Perfect Vision GmbH	Multicenter Evaluation of Safety and Effectiveness of Presbyopic LASIK for Hyperopes
NCT00928122	Phase 3	UNKNOWN	20/10 Perfect Vision	Intrastromal Correction of Ametropia by a Femtosecond Laser
NCT01028378	Phase 3	COMPLETED	Clinical Research Consultants, Inc.	Safety and Efficacy Study of Topography-Guided LASIK to Treat Myopia and Hyperopia
NCT01322919	Phase 3	COMPLETED	Technolas Perfect Vision GmbH	Safety and Efficacy Study to Evaluate the Treatment of Both Near and Distance Vision in a Simultaneous Laser Procedure
NCT05247658	Phase 3	TERMINATED	TBF Genie Tissulaire	Use of a Disk of Amniotic Membrane (Visio-AMTRIX) in Postoperative Care After PKR
NCT00574717	Phase 1/2	TERMINATED	Ohio State University	Enhancement of Emmetropization in Hyperopic Infants
NCT01024855	Phase 1/2	COMPLETED	Abbott Medical Optics	Comparative Evaluation of Corneal Staining With Balafilcon A Lenses and Two Multi-Purpose Solutions
NCT01893359	Phase 1/2	TERMINATED	Glaukos Corporation	Safety and Efficacy of Corneal Collagen Cross-linking Following LASIK for Treatment of Hyperopia and Hyperopic Astigmatism
NCT02148016	Phase 1/2	UNKNOWN	Sun Yat-sen University	Corneal Epithelium Repair and Therapy Using Autologous Limbal Stem Cell Transplantation
NCT04883996	Phase 1/2	UNKNOWN	Canyon City Eyecare	A Phase 1/2 Crossover Study to Assess EXP039 for Myopia or Hyperopia
NCT05477875	Phase 2	COMPLETED	University of Florida	Cannabinoid vs Opioid for Photorefractive Keratectomy Pain Control
NCT01556893	Phase 1	COMPLETED	Alcon LenSx, Inc.	Creating LASIK Flaps With the LenSx Femtosecond Laser
NCT06742541	Early Phase 1	COMPLETED	McGill University	ICL and LASIK for Hyperopic Astigmatism
NCT04616144	Not specified	ACTIVE_NOT_RECRUITING	Eye Hospital Pristina Kosovo	Fresh Corneal Lenticule Implantation in Hyperopic Patients With High Astigmatism
NCT04632784	Not specified	ACTIVE_NOT_RECRUITING	Ophtec BV	Clinical Trial With Artiflex Presbyopic (Artiplus)
NCT04692012	Not specified	ACTIVE_NOT_RECRUITING	Eye Hospital Pristina Kosovo	Treatment of Residual Hypermetropic Refraction on Pseudophakic Patients Using Allogenic Fresh Myopic Lenticule
NCT04712318	Not specified	ENROLLING_BY_INVITATION	Eye Hospital Pristina Kosovo	Treatment of Residual Refraction Errors 6 Months After Trifocal IOL Implantation With Relex-Smile
NCT05264623	Not specified	ACTIVE_NOT_RECRUITING	Bausch & Lomb Incorporated	Safety and Effectiveness of the TENEO 317 Model 2 (1.28 US) Excimer Laser for Laser In Situ Keratomileusis (LASIK) Surgery to Treat Hyperopia With or Without Astigmatism
NCT05689567	Not specified	ACTIVE_NOT_RECRUITING	Children’s Hospital of Fudan University	Focus-out Glasses on Emmetropization in Chinese Children
NCT06597292	Not specified	NOT_YET_RECRUITING	VIS, Inc.	The VIS Opti-K Low Vision Aid Device Provides Vision Improvement.
NCT07133737	Not specified	ENROLLING_BY_INVITATION	Gemini Eye Clinic	5 Year Follow up of SMILE® Procedure for the Correction of Hyperopia
NCT07135570	Not specified	RECRUITING	Data Yakka, Inc.	My Eyes, My Light: Amar Chokh, Amar Alo
NCT07142915	Not specified	NOT_YET_RECRUITING	Zhongshan Ophthalmic Center, Sun Yat-sen University	Effect of Light-Blocking Lenses on Pediatric Hyperopia
NCT07142928	Not specified	NOT_YET_RECRUITING	Zhongshan Ophthalmic Center, Sun Yat-sen University	Effect of Light-Blocking Lenses on Hyperopic Anisometropic Children
NCT07240480	Not specified	NOT_YET_RECRUITING	Trakya University	Assessing the Turkish DDIVAT for Visual Acuity Measurement
NCT07401511	Not specified	NOT_YET_RECRUITING	Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine	Efficacy of S.T.O.P®KIT in Retarding Axial Length Growth in Children With Low Hyperopia
NCT07647146	Not specified	NOT_YET_RECRUITING	Sohag University	Corneal Epithelial Thickness Mapping by Anterior Segment Optical Coherence Tomography in Patients With Refractive Errors
NCT07746752	Not specified	RECRUITING	Shanghai Eye Disease Prevention and Treatment Center	School-based Myopia Prevention Trial for Children With Adequate Hyperopic Reserve
NCT07746804	Not specified	RECRUITING	Shanghai Eye Disease Prevention and Treatment Center	School-based Myopia Prevention Trial for Children With Insufficient Hyperopic Reserve

Drugs tested across these trials

9 drugs:

Molecule	Max phase	Trials referencing
Codeine	4	1
Levofloxacin Anhydrous	4	1
Nepafenac	4	1
Proparacaine	4	1
Lotrafilcon B	3	3
Enfilcon A	3	1
Etafilcon A	3	1
Ocufilcon D	3	1
Senofilcon A	3	1

Other drugs named in trials

Drugs named in these trials’ interventions but not in the ChEMBL table above — includes investigational drugs not yet in ChEMBL. Linked where an Atlas drug page exists.

11 drugs named in trials:

Drug	Max trial phase
Ketorolac (Acular LS)	Phase 4
Nepafenac (Nevanac)	Phase 4
Optifree RepleniSH Multipurpose Disinfecting Solution	Phase 4
Proparacaine Ophthalmic	Phase 4
ReNu Multiplus Multipurpose Solution	Phase 4
1% Exp039	Phase 1/2
Betamethasone	Phase 1/2
Levofloxacin	Phase 1/2
Limbal stem cells (LSCs)	Phase 1/2
Oral cannabinoid	Phase 2
Riboflavin ophthalmic solution, 0% dextran	Phase 1/2