Ptosis

Summary

Ptosis (MONDO:0000728) is a disease with 20 cohort genes (4 GWAS associations across 10 studies) and 44 clinical trials. Top therapeutic interventions include oxymetazoline, brimonidine, and epinephrine.

At a glance

• Cohort genes: 20
• GWAS associations: 4
• ClinVar variants: 21
• Clinical trials: 44

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	ptosis
Mondo ID	MONDO:0000728
MeSH	D001763
DOID	DOID:0060260
ICD-11	1361674069
NCIT	C27298
SNOMED CT	11934000
UMLS	C0005745
MedGen	2287
Is cancer (heuristic)	no

Also known as: blepharoptosis · drooping eyelid · eyelid ptosis · ptosis · ptosis (disease)

Data availability: 21 ClinVar variants · 4 GWAS associations (10 studies) · 1 HPO phenotype.

Disease family

An umbrella term covering 3 Mondo subtypes.

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

Related subtypes (119): eye accommodation disease, corneal disorder, asthenopia, lens disorder, keratomalacia, scleral disorder, ocular siderosis, coloboma, luxation of globe, mucopolysaccharidosis type 1, lacrimal apparatus disorder, Foster-Kennedy syndrome, anterior dislocation of lens, uveal disorder, eyelid disorder, ocular hypotension, scotoma, exophthalmos, ophthalmia nodosa, eye degenerative disorder, refractive error, glaucoma, retinal disorder, eye allergy, ocular vascular disorder, optic neuritis, conjunctival disorder, ocular hypertension, Tietz syndrome, Alagille syndrome, glaucoma-sleep apnea syndrome, Marshall syndrome, microcornea-glaucoma-absent frontal sinuses syndrome, nail-patella syndrome, oculodentodigital dysplasia, piebaldism, Sturge-Weber syndrome, cerebrotendinous xanthomatosis, ocular cystinosis, alpha-mannosidosis, megalocornea-intellectual disability syndrome, mucolipidosis type IV, mucopolysaccharidosis type 6, Netherton syndrome, galactosialidosis, Niemann-Pick disease type A, ocular motor apraxia, Cogan type, Peters plus syndrome, isolated Pierre-Robin syndrome, ectodermal dysplasia-blindness syndrome, Sandhoff disease, SHORT syndrome, Sjogren-Larsson syndrome, Smith-Lemli-Opitz syndrome, Tay-Sachs disease, tyrosinemia type II, Ito hypomelanosis, X-linked cone dysfunction syndrome with myopia, red color blindness, oculocerebrorenal syndrome, Lowry-MacLean syndrome, pigment dispersion syndrome, hereditary hyperferritinemia with congenital cataracts, dyssegmental dysplasia-glaucoma syndrome, mevalonic aciduria, familial cavitary optic disk anomaly, blindness - scoliosis - arachnodactyly syndrome, fatty acyl-CoA reductase 1 deficiency, microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome, neurotrophic keratopathy, Cogan syndrome, atopic keratoconjunctivitis, rhizomelic chondrodysplasia punctata, Ehlers-Danlos syndrome, kyphoscoliotic type 1, IRVAN syndrome, Rothmund-Thomson syndrome type 2, microcornea-corectopia-macular hypoplasia syndrome, isolated anophthalmia-microphthalmia syndrome, Spasmus nutans, toxic maculopathy due to antimalarial drugs, syndromic recessive X-linked ichthyosis, acute zonal occult outer retinopathy, acute annular outer retinopathy, phakomatosis pigmentovascularis, lamellar ichthyosis, idiopathic linear interstitial keratitis, chondroectodermal dysplasia with night blindness, galactosemia, GM1 gangliosidosis, Gaucher disease, visual snow syndrome, extensive peripapillary myelinated nerve fibers, IgG4-related ophthalmic disorder, global developmental delay-visual anomalies-progressive cerebellar atrophy-truncal hypotonia syndrome, vernal keratoconjunctivitis, Gardner syndrome, anterior segment dysgenesis, isolated ankyloblepharon filiforme adnatum, hereditary optic neuropathy, essential strabismus, Axenfeld anomaly, eye neoplasm, isolated blepharochalasis, punctate inner choroidopathy, eye infectious disorder, vitreous body disorder, 9q33.3q34.11 microdeletion syndrome, autoimmune/inflammatory optic neuropathy, LTBP2-related ocular dysgenesis, ocular growth disorder, ocular dysgenesis caused by defects in PAX6 regulation, choroidal neovascularization, anterior segment developmental abnormality with extraocular manifestations, congenital optic disk excavation, neuroocular syndrome, isolated angioid streaks, multiple evanescent white dot syndrome, stellate multiform amelanotic choroidopathy, macular telangiectasia

Subtypes (3): congenital ptosis, mcpherson robertson cammarano syndrome, mehta lewis patton syndrome

Genetics & variants

GWAS landscape

4 GWAS associations across 10 studies. Top hits map to 1 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
chr14:23993761	2e-19		T	3.93
rs10886198	1e-17	CASC2	A	0.14
rs144066900	1e-07	RPL21P41 - KBTBD8	?

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST90475893	Verma A	2024	11,068	432,448	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90477749	Verma A	2024	1,871	118,684	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90480089	Verma A	2024	1,871	118,684	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90436011	Zhou W	2018	1,834	399,306	Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies.
GCST90043796	Jiang L	2021	1,797	454,551	A generalized linear mixed model association tool for biobank-scale data.
GCST90079871	Backman JD	2021	1,655	386,181	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90083857	Backman JD	2021	1,655	386,181	Exome sequencing and analysis of 454,787 UK Biobank participants.
GCST90475892	Verma A	2024	1,297	57,881	Diversity and scale: Genetic architecture of 2068 traits in the VA Million Veteran Program.
GCST90651864	Liu TY	2025	430	217,632	Diversity and longitudinal records: Genetic architecture of disease associations and polygenic risk in the Taiwanese Han population.
GCST90727258	Kim HI	2026	152	43,874	Exome sequencing and analysis of 44,028 British South Asians enriched for high autozygosity.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

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

MAF distribution

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

Functional consequences

Consequence	Count
unknown	1
intron_variant	1
intergenic_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
chr14:23993761				0			2e-19	Tier 4: intronic/intergenic
rs10886198	10	118063926	A>G	0.244	intron_variant	CASC2	1e-17	Tier 4: intronic/intergenic
rs144066900	3	66981600	C>T		intergenic_variant	RPL21P41 - KBTBD8	1e-07	Tier 4: intronic/intergenic

ClinVar germline variants

21 retrieved; paginated sample, class counts are floors:

7 pathogenic, 5 uncertain significance, 3 conflicting classifications of pathogenicity, 3 likely pathogenic, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
268035	46;XX;t(19;21)(q13.3;q22.3)dn		Pathogenic	criteria provided, single submitter
279678	NM_013275.6(ANKRD11):c.1903_1907del (p.Lys635fs)	ANKRD11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523250	GRCh37/hg19 15q13.2-13.3(chr15:30366065-32899558)	ARHGAP11B	Pathogenic	criteria provided, single submitter
242499	NM_002180.3(IGHMBP2):c.92G>A (p.Trp31Ter)	IGHMBP2	Pathogenic	criteria provided, multiple submitters, no conflicts
40513	NM_002834.5(PTPN11):c.417G>C (p.Glu139Asp)	PTPN11	Pathogenic	reviewed by expert panel
12977	NM_000540.3(RYR1):c.6617C>T (p.Thr2206Met)	RYR1	Pathogenic	reviewed by expert panel
812923	NC_000005.10:g.139189727_139201554del	SIL1	Pathogenic	no assertion criteria provided
40672	NM_005633.4(SOS1):c.1300G>A (p.Gly434Arg)	SOS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
411584	NM_006772.3(SYNGAP1):c.2059C>T (p.Arg687Ter)	SYNGAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
590777	NM_001378418.1(TCF20):c.3605dup (p.Pro1203fs)	TCF20	Pathogenic	criteria provided, single submitter
374185	NM_000751.3(CHRND):c.1385G>T (p.Trp462Leu)	CHRND	Likely pathogenic	criteria provided, single submitter
374186	NM_000751.3(CHRND):c.822del (p.Ser274fs)	CHRND	Likely pathogenic	criteria provided, single submitter
2580154	NM_032525.3(TUBB6):c.1153T>A (p.Phe385Ile)	TUBB6	Likely pathogenic	criteria provided, single submitter
374132	NM_004006.3(DMD):c.10247G>A (p.Trp3416Ter)	DMD	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
627565	NM_000168.6(GLI3):c.1622C>T (p.Thr541Met)	GLI3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214916	NM_130837.3(OPA1):c.113_130del (p.Arg38_Ser43del)	OPA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
635772	GRCh37/hg19 14q24.1(chr14:68126321-68269053)x3	ARG2	Uncertain significance	no assertion criteria provided
3769602	NM_000080.4(CHRNE):c.1340G>C (p.Trp447Ser)	CHRNE	Uncertain significance	criteria provided, multiple submitters, no conflicts
692386	NC_012920.1(MT-ND1):m.3670G>A	MT-ND1	Uncertain significance	criteria provided, multiple submitters, no conflicts
812543	NC_012920.1(MT-TN):m.5702A>G	MT-TN	Uncertain significance	reviewed by expert panel
3061822	NM_006000.3(TUBA4A):c.3+290C>G	TUBA4A	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 55 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RYR1	Orphanet:169186	Autosomal recessive centronuclear myopathy
RYR1	Orphanet:169189	Autosomal dominant centronuclear myopathy
RYR1	Orphanet:178145	Moderate multiminicore disease with hand involvement
RYR1	Orphanet:324581	Benign Samaritan congenital myopathy
RYR1	Orphanet:33108	Lethal multiple pterygium syndrome
RYR1	Orphanet:423	Malignant hyperthermia of anesthesia
RYR1	Orphanet:424107	Congenital myopathy with myasthenic-like onset
RYR1	Orphanet:466650	Exercise-induced malignant hyperthermia
RYR1	Orphanet:597	Central core disease
RYR1	Orphanet:700188	Calf-predominant weakness-gastrocnemius medialis atrophy-distal myopathy
RYR1	Orphanet:98905	Congenital multicore myopathy with external ophthalmoplegia
RYR1	Orphanet:99741	King-Denborough syndrome
SOS1	Orphanet:2024	Hereditary gingival fibromatosis
SOS1	Orphanet:648	Noonan syndrome
SYNGAP1	Orphanet:1942	Epilepsy with myoclonic-atonic seizures
SYNGAP1	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
SYNGAP1	Orphanet:544254	SYNGAP1-related developmental and epileptic encephalopathy
TCF20	Orphanet:528084	Non-specific syndromic intellectual disability
MED12	Orphanet:1415	Hardikar syndrome
MED12	Orphanet:293707	Blepharophimosis-intellectual disability syndrome, MKB type
MED12	Orphanet:776	Lujan-Fryns syndrome
MED12	Orphanet:777	X-linked non-syndromic intellectual disability
MED12	Orphanet:93932	FG syndrome type 1
CHRND	Orphanet:33108	Lethal multiple pterygium syndrome
CHRND	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
CHRNE	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
ANKRD11	Orphanet:2332	KBG syndrome
ANKRD11	Orphanet:261250	16q24.3 microdeletion syndrome
SIL1	Orphanet:559	Marinesco-Sjögren syndrome
DMD	Orphanet:154	Familial isolated dilated cardiomyopathy
DMD	Orphanet:206546	Symptomatic form of muscular dystrophy of Duchenne and Becker in female carriers
DMD	Orphanet:777	X-linked non-syndromic intellectual disability
DMD	Orphanet:98895	Becker muscular dystrophy
DMD	Orphanet:98896	Duchenne muscular dystrophy
GLI3	Orphanet:36	Acrocallosal syndrome
GLI3	Orphanet:380	Greig cephalopolysyndactyly syndrome
GLI3	Orphanet:672	Pallister-Hall syndrome
GLI3	Orphanet:93322	Isolated tibial hemimelia
GLI3	Orphanet:93334	Postaxial polydactyly type A
GLI3	Orphanet:93335	Postaxial polydactyly type B
GLI3	Orphanet:93338	Polysyndactyly
IGHMBP2	Orphanet:443073	Charcot-Marie-Tooth disease type 2S
IGHMBP2	Orphanet:98920	Spinal muscular atrophy with respiratory distress type 1
MT-ND1	Orphanet:104	Leber hereditary optic neuropathy
MT-ND1	Orphanet:255210	Mitochondrial DNA-associated Leigh syndrome
MT-ND1	Orphanet:2609	Isolated complex I deficiency
MT-ND1	Orphanet:550	MELAS
MT-TN	Orphanet:663	Mitochondrial DNA-related progressive external ophthalmoplegia
OPA1	Orphanet:1215	Autosomal dominant optic atrophy plus syndrome
OPA1	Orphanet:1239	Behr syndrome

Cohort genes → proteins

20 cohort genes, 19 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	20

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RYR1	HGNC:10483	ENSG00000196218	P21817	Ryanodine receptor 1	clinvar
SOS1	HGNC:11187	ENSG00000115904	Q07889	Son of sevenless homolog 1	clinvar
SYNGAP1	HGNC:11497	ENSG00000197283	Q96PV0	Ras/Rap GTPase-activating protein SynGAP	clinvar
TCF20	HGNC:11631	ENSG00000100207	Q9UGU0	Transcription factor 20	clinvar
MED12	HGNC:11957	ENSG00000184634	Q93074	Mediator of RNA polymerase II transcription subunit 12	clinvar
TUBA4A	HGNC:12407	ENSG00000127824	P68366	Tubulin alpha-4A chain	clinvar
ARHGAP11B	HGNC:15782	ENSG00000285077	Q3KRB8	Inactive Rho GTPase-activating protein 11B	clinvar
CHRND	HGNC:1965	ENSG00000135902	Q07001	Acetylcholine receptor subunit delta	clinvar
CHRNE	HGNC:1966	ENSG00000108556	Q04844	Acetylcholine receptor subunit epsilon	clinvar
TUBB6	HGNC:20776	ENSG00000176014	Q9BUF5	Tubulin beta-6 chain	clinvar
ANKRD11	HGNC:21316	ENSG00000167522	Q6UB99	Ankyrin repeat domain-containing protein 11	clinvar
SIL1	HGNC:24624	ENSG00000120725	Q9H173	Nucleotide exchange factor SIL1	clinvar
DMD	HGNC:2928	ENSG00000198947	P11532	Dystrophin	clinvar
GLI3	HGNC:4319	ENSG00000106571	P10071	Transcriptional activator GLI3	clinvar
IGHMBP2	HGNC:5542	ENSG00000132740	P38935	DNA-binding protein SMUBP-2	clinvar
ARG2	HGNC:664	ENSG00000081181	P78540	Arginase-2, mitochondrial	clinvar
MT-ND1	HGNC:7455	ENSG00000198888	P03886	NADH-ubiquinone oxidoreductase chain 1	clinvar
MT-TN	HGNC:7493	ENSG00000210135		mitochondrially encoded tRNA-Asn (AAU/C)	clinvar
OPA1	HGNC:8140	ENSG00000198836	O60313	Dynamin-like GTPase OPA1, mitochondrial	clinvar
PTPN11	HGNC:9644	ENSG00000179295	Q06124	Tyrosine-protein phosphatase non-receptor type 11	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RYR1	Ryanodine receptor 1	Cytosolic calcium-activated calcium channel that mediates the release of Ca(2+) from the sarcoplasmic reticulum into the cytosol and thereby plays a key role in triggering muscle contraction following depolarization of T-tubules.
SOS1	Son of sevenless homolog 1	Promotes the exchange of Ras-bound GDP by GTP.
SYNGAP1	Ras/Rap GTPase-activating protein SynGAP	Major constituent of the PSD essential for postsynaptic signaling.
TCF20	Transcription factor 20	Transcriptional activator that binds to the regulatory region of MMP3 and thereby controls stromelysin expression.
MED12	Mediator of RNA polymerase II transcription subunit 12	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
TUBA4A	Tubulin alpha-4A chain	Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.
ARHGAP11B	Inactive Rho GTPase-activating protein 11B	Hominin-specific protein that promotes development and evolutionary expansion of the brain neocortex.
CHRND	Acetylcholine receptor subunit delta	After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.
CHRNE	Acetylcholine receptor subunit epsilon	After binding acetylcholine, the AChR responds by an extensive change in conformation that affects all subunits and leads to opening of an ion-conducting channel across the plasma membrane.
TUBB6	Tubulin beta-6 chain	Tubulin is the major constituent of microtubules, a cylinder consisting of laterally associated linear protofilaments composed of alpha- and beta-tubulin heterodimers.
ANKRD11	Ankyrin repeat domain-containing protein 11	Chromatin regulator which modulates histone acetylation and gene expression in neural precursor cells.
SIL1	Nucleotide exchange factor SIL1	Required for protein translocation and folding in the endoplasmic reticulum (ER).
DMD	Dystrophin	Anchors the extracellular matrix to the cytoskeleton via F-actin.
GLI3	Transcriptional activator GLI3	Has a dual function as a transcriptional activator and a repressor of the sonic hedgehog (Shh) pathway, and plays a role in limb development.
IGHMBP2	DNA-binding protein SMUBP-2	5’ to 3’ helicase that unwinds RNA and DNA duplexes in an ATP-dependent reaction.
ARG2	Arginase-2, mitochondrial	May play a role in the regulation of extra-urea cycle arginine metabolism and also in down-regulation of nitric oxide synthesis.
MT-ND1	NADH-ubiquinone oxidoreductase chain 1	Core subunit of the mitochondrial membrane respiratory chain NADH dehydrogenase (Complex I) which catalyzes electron transfer from NADH through the respiratory chain, using ubiquinone as an electron acceptor.
OPA1	Dynamin-like GTPase OPA1, mitochondrial	Dynamin-related GTPase that is essential for normal mitochondrial morphology by mediating fusion of the mitochondrial inner membranes, regulating cristae morphology and maintaining respiratory chain function.
PTPN11	Tyrosine-protein phosphatase non-receptor type 11	Acts downstream of various receptor and cytoplasmic protein tyrosine kinases to participate in the signal transduction from the cell surface to the nucleus.

Protein-family classification

Druggable: 4 · Difficult: 7 · Unknown: 9 · Druggable fraction: 0.2

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
Ion channel	1	5.6×	0.326
Phosphatase	1	4.2×	0.326
Scaffold/PPI	3	2.6×	0.326
Transcription factor	4	1.6×	0.326
Enzyme (other)	2	1.2×	0.607
Other/Unknown	9	0.8×	0.885

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RYR1	Ion channel	yes		RIH_dom, B30.2/SPRY, Ryanodine_rcpt
SOS1	Scaffold/PPI	no		DH_dom, Ras-like_Gua-exchang_fac_N, PH_domain
SYNGAP1	Scaffold/PPI	no		C2_dom, PH_domain, RasGAP_dom
TCF20	Transcription factor	no		Znf_PHD, Znf_RING/FYVE/PHD, EPHD
MED12	Other/Unknown	no		Mediator_Med12, Mediator_Med12_catenin-bd, Mediator_Med12_LCEWAV
TUBA4A	Other/Unknown	no		Tubulin, Alpha_tubulin, Tubulin_FtsZ_GTPase
ARHGAP11B	Other/Unknown	no		RhoGAP_dom, Rho_GTPase_activation_prot, ARHGAP11A/B
CHRND	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
CHRNE	Other/Unknown	no		Nicotinic_acetylcholine_rcpt, Neurotrans-gated_channel_TM, Neur_channel
TUBB6	Other/Unknown	no		Tubulin, Beta_tubulin, Tubulin_FtsZ_GTPase
ANKRD11	Scaffold/PPI	no		Ankyrin_rpt, Ankyrin_rpt-contain_sf, ANKRD11
SIL1	Other/Unknown	no		ARM-like, Nucleotide_exch_fac_Fes1, ARM-type_fold
DMD	Transcription factor	no		Znf_ZZ, WW_dom, Actinin_actin-bd_CS
GLI3	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, GLI-like
IGHMBP2	Transcription factor	no	3.6.4.12	Znf_AN1, R3H_dom, AAA+_ATPase
ARG2	Enzyme (other)	yes	3.5.3.1	Ureohydrolase, Arginase, Ureohydrolase_Mn_BS
MT-ND1	Other/Unknown	no		NADH_UbQ_OxRdtase_su1/FPO, NADH_UbQ_OxRdtase_su1_CS
MT-TN	Other/Unknown	no
OPA1	Enzyme (other)	yes	3.6.5.5	Dynamin_GTPase, Dynamin, P-loop_NTPase
PTPN11	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, SH2

Expression context

Cohort genes with no expression data: 0.

14 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)	20
unknown	0

Top tissues across cohort

Tissue	Cohort genes
tendon of biceps brachii	4
gastrocnemius	3
hindlimb stylopod muscle	2
adenohypophysis	2
cortical plate	2
lower esophagus muscularis layer	2
gluteal muscle	1
colonic epithelium	1
jejunal mucosa	1
pituitary gland	1
right uterine tube	1
ganglionic eminence	1
tonsil	1
left ovary	1
right adrenal gland	1
right adrenal gland cortex	1
frontal pole	1
gingiva	1
gingival epithelium	1
bone marrow	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RYR1	214	broad	marker	gluteal muscle, gastrocnemius, hindlimb stylopod muscle
SOS1	289	ubiquitous	marker	colonic epithelium, jejunal mucosa, tendon of biceps brachii
SYNGAP1	137	ubiquitous	marker	pituitary gland, right uterine tube, adenohypophysis
TCF20	134	ubiquitous	yes	cortical plate, ganglionic eminence, tonsil
MED12	281	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, left ovary
TUBA4A	299	ubiquitous	marker	gingival epithelium, frontal pole, gingiva
ARHGAP11B	134	ubiquitous	yes	male germ line stem cell (sensu Vertebrata) in testis, bone marrow, bone marrow cell
CHRND	86	tissue_specific	yes	gastrocnemius, muscle of leg, hindlimb stylopod muscle
CHRNE	162	broad	yes	right atrium auricular region, cardiac atrium, adenohypophysis
TUBB6	279	ubiquitous	marker	lower esophagus, lower esophagus muscularis layer, saphenous vein
ANKRD11	278	ubiquitous	marker	tendon of biceps brachii, sural nerve, stromal cell of endometrium
SIL1	251	ubiquitous	marker	islet of Langerhans, body of pancreas, left testis
DMD	295	ubiquitous	marker	trigeminal ganglion, skeletal muscle tissue of rectus abdominis, dorsal root ganglion
GLI3	263	ubiquitous	marker	ventricular zone, olfactory bulb, tendon of biceps brachii
IGHMBP2	189	ubiquitous	yes	mucosa of stomach, esophagogastric junction muscularis propria, lower esophagus muscularis layer
ARG2	269	ubiquitous	marker	tendon of biceps brachii, oocyte, cortical plate
MT-ND1	134	ubiquitous	marker	adipose tissue, gastrocnemius, frontal cortex
MT-TN	118	tissue_specific	yes	duodenum, skeletal muscle tissue, vermiform appendix
OPA1	288	ubiquitous	marker	adrenal tissue, calcaneal tendon, endothelial cell
PTPN11	295	ubiquitous	marker	medial globus pallidus, dorsal motor nucleus of vagus nerve, globus pallidus

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PTPN11	6,009
TUBB6	4,838
SIL1	4,196
ARG2	3,757
SOS1	3,625
MT-ND1	3,537
MED12	3,322
GLI3	2,825
OPA1	2,630
TCF20	2,572

Intra-cohort edges

A	B	Sources
PTPN11	SOS1	biogrid_interaction, string_interaction

Structural data

PDB: 13 · AlphaFold-only: 6 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PTPN11	Q06124	115
SOS1	Q07889	91
ARG2	P78540	18
CHRND	Q07001	13
CHRNE	Q04844	13
OPA1	O60313	11
DMD	P11532	6
MT-ND1	P03886	5
SIL1	Q9H173	4
IGHMBP2	P38935	4
MED12	Q93074	3
RYR1	P21817	2
GLI3	P10071	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TUBB6	Q9BUF5	92.77
TUBA4A	P68366	92.02
ARHGAP11B	Q3KRB8	77.88
SYNGAP1	Q96PV0	60.43
ANKRD11	Q6UB99	39.44
TCF20	Q9UGU0	39.03

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 297. Enrichment computed across 20 evidence-associated genes (15 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 15 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Highly sodium permeable postsynaptic acetylcholine nicotinic receptors	2	217.5×	0.003	CHRND, CHRNE
Neurotransmitter receptors and postsynaptic signal transmission	4	26.7×	0.003	TUBA4A, CHRND, CHRNE, TUBB6
Transmission across Chemical Synapses	4	20.3×	0.003	TUBA4A, CHRND, CHRNE, TUBB6
Presynaptic nicotinic acetylcholine receptors	2	126.9×	0.005	CHRND, CHRNE
Activated NTRK2 signals through FRS2 and FRS3	2	126.9×	0.005	SOS1, PTPN11
Hedgehog ‘off’ state	3	35.7×	0.005	TUBA4A, TUBB6, GLI3
Acetylcholine binding and downstream events	2	108.8×	0.005	CHRND, CHRNE
Postsynaptic nicotinic acetylcholine receptors	2	108.8×	0.005	CHRND, CHRNE
Signaling by FLT3 ITD and TKD mutants	2	101.5×	0.006	SOS1, PTPN11
Tie2 Signaling	2	80.1×	0.007	SOS1, PTPN11
Microtubule-dependent trafficking of connexons from Golgi to the plasma membrane	2	72.5×	0.007	TUBA4A, TUBB6
Transport of connexons to the plasma membrane	2	72.5×	0.007	TUBA4A, TUBB6
FRS-mediated FGFR3 signaling	2	72.5×	0.007	SOS1, PTPN11
Mitochondrial protein degradation	3	22.8×	0.007	ARG2, MT-ND1, OPA1
Neuronal System	4	11.8×	0.007	TUBA4A, CHRND, CHRNE, TUBB6
FRS-mediated FGFR4 signaling	2	66.2×	0.007	SOS1, PTPN11
Gap junction trafficking and regulation	2	63.4×	0.007	TUBA4A, TUBB6
Gap junction trafficking	2	63.4×	0.007	TUBA4A, TUBB6
Post-chaperonin tubulin folding pathway	2	63.4×	0.007	TUBA4A, TUBB6
FRS-mediated FGFR1 signaling	2	60.9×	0.007	SOS1, PTPN11
FRS-mediated FGFR2 signaling	2	58.6×	0.007	SOS1, PTPN11
Formation of tubulin folding intermediates by CCT/TriC	2	56.4×	0.007	TUBA4A, TUBB6
Cooperation of Prefoldin and TriC/CCT in actin and tubulin folding	2	54.4×	0.008	TUBA4A, TUBB6
Prefoldin mediated transfer of substrate to CCT/TriC	2	52.5×	0.008	TUBA4A, TUBB6
Downstream signal transduction	2	50.8×	0.008	SOS1, PTPN11
Activation of AMPK downstream of NMDARs	2	50.8×	0.008	TUBA4A, TUBB6
RHO GTPases activate IQGAPs	2	46.1×	0.008	TUBA4A, TUBB6
FLT3 Signaling	2	46.1×	0.008	SOS1, PTPN11
Sealing of the nuclear envelope (NE) by ESCRT-III	2	46.1×	0.008	TUBA4A, TUBB6
Signaling by CSF1 (M-CSF) in myeloid cells	2	46.1×	0.008	SOS1, PTPN11

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 18 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
embryonic neurocranium morphogenesis	2	208.1×	0.009	MED12, GLI3
Schwann cell development	2	117.0×	0.009	SOS1, MED12
neurotrophin TRK receptor signaling pathway	2	117.0×	0.009	SOS1, PTPN11
muscle contraction	3	34.7×	0.009	RYR1, CHRND, CHRNE
striated muscle contraction	2	93.6×	0.011	RYR1, ARG2
lateral ganglionic eminence cell proliferation	1	936.2×	0.014	GLI3
negative regulation of cortisol secretion	1	936.2×	0.014	PTPN11
negative regulation of growth hormone secretion	1	936.2×	0.014	PTPN11
lambdoid suture morphogenesis	1	936.2×	0.014	GLI3
sagittal suture morphogenesis	1	936.2×	0.014	GLI3
mammary gland specification	1	936.2×	0.014	GLI3
anterior semicircular canal development	1	936.2×	0.014	GLI3
lateral semicircular canal development	1	936.2×	0.014	GLI3
negative regulation of chemokine (C-C motif) ligand 4 production	1	936.2×	0.014	ARG2
regulation of muscle system process	1	936.2×	0.014	DMD
regulation of cellular response to growth factor stimulus	1	936.2×	0.014	DMD
mitochondrial inner membrane fusion	1	936.2×	0.014	OPA1
negative regulation of chondrocyte differentiation	2	74.9×	0.014	GLI3, PTPN11
acetylcholine receptor signaling pathway	2	69.3×	0.014	CHRND, CHRNE
skeletal muscle contraction	2	56.7×	0.014	CHRND, CHRNE
membrane depolarization	2	56.7×	0.014	CHRND, CHRNE
face morphogenesis	2	55.1×	0.014	ANKRD11, PTPN11
heart development	3	13.1×	0.017	MED12, GLI3, PTPN11
smoothened signaling pathway involved in ventral spinal cord interneuron specification	1	468.1×	0.018	GLI3
smoothened signaling pathway involved in spinal cord motor neuron cell fate specification	1	468.1×	0.018	GLI3
microvillus organization	1	468.1×	0.018	PTPN11
negative regulation of mitochondrial membrane permeability	1	468.1×	0.018	ARHGAP11B
intestinal epithelial cell migration	1	468.1×	0.018	PTPN11
cardiac muscle cell action potential	1	468.1×	0.018	DMD
larynx morphogenesis	1	468.1×	0.018	GLI3

Therapeutics

Drugs indicated for this disease

No approved or late-stage (phase ≥3) drug is indicated for this disease; the following are in earlier-phase trials only.

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Bupivacaine.

Drug target analysis

Approved (phase 4): 7 · Phase ≥3: 7 · Phased (≥1): 9 · Undrugged: 11

Druggability breadth: 12 of 20 evidence-associated genes (60%) 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
SOS1	IDARUBICIN
TUBA4A	COLCHICINE
CHRND	VARENICLINE
CHRNE	MECAMYLAMINE
TUBB6	COLCHICINE
OPA1	MOMELOTINIB
PTPN11	ESTRAMUSTINE PHOSPHATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TUBA4A	22	4
TUBB6	21	4
CHRND	10	4
PTPN11	8	4
SOS1	5	4
CHRNE	4	4
ARG2	2	2
OPA1	2	4
MED12	1	2
RYR1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
IDARUBICIN	4	SOS1
DOXORUBICIN	4	SOS1
SOTORASIB	4	SOS1
ADAGRASIB	4	SOS1
COLCHICINE	4	TUBA4A, TUBB6
VINBLASTINE	4	TUBA4A, TUBB6
LEVOFLOXACIN ANHYDROUS	4	TUBA4A, TUBB6
DOCETAXEL	4	TUBA4A, TUBB6
NOSCAPINE	4	TUBA4A, TUBB6
VINBLASTINE SULFATE	4	TUBA4A, TUBB6
PACLITAXEL	4	TUBA4A, TUBB6
LEVOFLOXACIN	4	TUBA4A, TUBB6
VINORELBINE	4	TUBA4A, TUBB6
TIRBANIBULIN	4	TUBA4A, TUBB6
PODOFILOX	4	TUBA4A, TUBB6
VINCRISTINE	4	TUBA4A, TUBB6
DOCETAXEL ANHYDROUS	4	TUBA4A, TUBB6
VARENICLINE	4	CHRND
NICOTINE	4	CHRND, CHRNE
TROPISETRON	4	CHRND
BUPROPION	4	CHRND
MECAMYLAMINE	4	CHRND, CHRNE
DONEPEZIL	4	CHRNE
TACRINE	4	CHRNE
MOMELOTINIB	4	OPA1
ESTRAMUSTINE PHOSPHATE	4	PTPN11
PATUPILONE	3	TUBA4A, TUBB6
DEXMECAMYLAMINE	3	CHRND
CYTISINICLINE	3	CHRND
TIVANTINIB	3	OPA1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
TUBB6	1,757	Binding:1717, Functional:34, ADMET:6
TUBA4A	1,695	Binding:1654, Functional:35, ADMET:6
PTPN11	588	Binding:585, Functional:2, ADMET:1
SOS1	421	Binding:409, Functional:12
CHRND	75	Binding:44, Functional:31
ARG2	37	Binding:34, Functional:3
CHRNE	28	Binding:26, Functional:2
RYR1	16	Binding:13, Functional:3
MED12	6	Binding:6
MT-ND1	5	Binding:5
OPA1	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
IGHMBP2	3.6.4.12	DNA helicase
ARG2	3.5.3.1	arginase
OPA1	3.6.5.5	dynamin GTPase
PTPN11	3.1.3.48	protein-tyrosine-phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SOS1	421
TUBA4A	1,695
TUBB6	1,757
PTPN11	588

Pharmacogenomics

Cohort genes with a PharmGKB record: 20; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
RYR1	1

Chemical tractability of cohort targets

30 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)
IDARUBICIN	4	SOS1
DOXORUBICIN	4	SOS1
SOTORASIB	4	SOS1
ADAGRASIB	4	SOS1
COLCHICINE	4	TUBA4A, TUBB6
VINBLASTINE	4	TUBA4A, TUBB6
LEVOFLOXACIN ANHYDROUS	4	TUBA4A, TUBB6
DOCETAXEL	4	TUBA4A, TUBB6
NOSCAPINE	4	TUBA4A, TUBB6
VINBLASTINE SULFATE	4	TUBA4A, TUBB6
PACLITAXEL	4	TUBA4A, TUBB6
LEVOFLOXACIN	4	TUBA4A, TUBB6
VINORELBINE	4	TUBA4A, TUBB6
TIRBANIBULIN	4	TUBA4A, TUBB6
PODOFILOX	4	TUBA4A, TUBB6
VINCRISTINE	4	TUBA4A, TUBB6
DOCETAXEL ANHYDROUS	4	TUBA4A, TUBB6
VARENICLINE	4	CHRND
NICOTINE	4	CHRND, CHRNE
TROPISETRON	4	CHRND
BUPROPION	4	CHRND
MECAMYLAMINE	4	CHRND, CHRNE
DONEPEZIL	4	CHRNE
TACRINE	4	CHRNE
MOMELOTINIB	4	OPA1
ESTRAMUSTINE PHOSPHATE	4	PTPN11
PATUPILONE	3	TUBA4A, TUBB6
DEXMECAMYLAMINE	3	CHRND
CYTISINICLINE	3	CHRND
TIVANTINIB	3	OPA1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	7	SOS1, TUBA4A, CHRND, CHRNE, TUBB6, OPA1, PTPN11
B	Phased (≥1) drug, not yet approved	2	MED12, ARG2
C	Druggable family + PDB, no drug	1	RYR1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	10	SYNGAP1, TCF20, ARHGAP11B, ANKRD11, SIL1, DMD, GLI3, IGHMBP2, MT-ND1, MT-TN

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
RYR1	16	—
SYNGAP1	0	—
TCF20	0	—
ARHGAP11B	0	—
ANKRD11	0	—
SIL1	0	—
DMD	0	—
GLI3	0	—
IGHMBP2	0	—
MT-ND1	5	—
MT-TN	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 44.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	27
PHASE4	5
PHASE3	5
PHASE2/PHASE3	2
PHASE1/PHASE2	2
EARLY_PHASE1	2
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT04007276	PHASE4	NOT_YET_RECRUITING	The Effect of Lumify™ on Ocular Redness, Intraocular Pressure, and Eyelid Position in Glaucoma Patients
NCT07390578	PHASE4	NOT_YET_RECRUITING	Upneeq vs. Lumify Ptosis
NCT00793988	PHASE4	COMPLETED	Vibration-Assisted Anaesthesia
NCT01239498	PHASE4	UNKNOWN	Saline Injection - Assisted Anesthesia in Eyelid Surgery
NCT02761083	PHASE4	WITHDRAWN	PMCF-study Using Novosyn® Quick Suture Material in Ophthalmic Surgery
NCT06683651	PHASE3	RECRUITING	A Study in Chinese Patients With Acquired Blepharoptosis
NCT02436759	PHASE3	COMPLETED	Study of the Safety and Efficacy of RVL-1201 in the Treatment of Acquired Blepharoptosis
NCT02878694	PHASE2/PHASE3	TERMINATED	Treatment of Ptosis to Muscular Dystrophy Oculopharyngeal by Myoblast Autologous Graft
NCT03536949	PHASE3	COMPLETED	Study of Safety of RVL-1201 in Treatment of Blepharoptosis
NCT03565887	PHASE3	COMPLETED	Study of Safety and Efficacy of RVL-1201 in the Treatment of Blepharoptosis
NCT05358977	PHASE2/PHASE3	UNKNOWN	Fibrin Sealant in Eyelid Surgery
NCT05945615	PHASE3	COMPLETED	Oxymetazoline Drops for Acquired Blepharoptosis From Synkinesis
NCT01848041	PHASE1/PHASE2	COMPLETED	Safety and Efficacy Study of RVL-1201 in Acquired Blepharoptosis
NCT03266081	PHASE2	WITHDRAWN	Bupivacaine Epiphora Trial
NCT05715346	PHASE1/PHASE2	COMPLETED	LEV102 Topical Gel in Acquired Blepharoptosis
NCT04807855	EARLY_PHASE1	COMPLETED	Custom Print Megnetic Levator Prosthesis Pilot Comparison
NCT06911216	EARLY_PHASE1	COMPLETED	A Pharmacokinetics (PK) Study in Healthy Adults
NCT03812016	Not specified	RECRUITING	A Feedback-enabled Magnetic Device for Temporary Management of Blepharoptosis
NCT05746078	Not specified	RECRUITING	Performance and Safety Assessment of SPRING THREAD® Elastic Tensor Thread in Patients with Mild to Moderate Facial Ptosis.
NCT07534436	Not specified	RECRUITING	A Prospective Cohort Study on Visual Function and Psychological Conditions Before and After Surgery for Congenital Ptosis
NCT00816270	Not specified	TERMINATED	Liquid Bandage (2-Octyl-Cyanoacrylate) in Upper Lid Blepharoplasty
NCT00864656	Not specified	COMPLETED	Eyelid Position Interdependence in Involutional Ptosis Patients Submitted to 10% Phenylephrine
NCT01350024	Not specified	COMPLETED	Comparison of Postoperative Pain With Two Different Types of Local Anesthesia in Surgery for a Drooping Eyelid
NCT01430247	Not specified	COMPLETED	Vision Screening for the Detection of Amblyopia
NCT01968174	Not specified	UNKNOWN	Astigmatic Changes Secondary to Eyelid Surgeries
NCT02201979	Not specified	COMPLETED	Laser Fluorescent Imaging of Nipple and Areola During Breast Lift
NCT02226016	Not specified	UNKNOWN	Levator Muscle Strength Evaluation
NCT02367677	Not specified	COMPLETED	Digital Photographs to Evaluate Blepharoptosis
NCT02376556	Not specified	COMPLETED	The Effect of Eyelid Surgery on Dry Eye - a Prospective Study
NCT02501187	Not specified	UNKNOWN	Risk of Dry Eye Post Different Surgeries for Blepharoptosis Repair
NCT02638610	Not specified	UNKNOWN	Assessment of Changes of Periocular Skin Sensation Following Eyelid and Ocular Surface Surgeries
NCT02959697	Not specified	UNKNOWN	Subconjunctival Injection of Local Anesthetic in Anterior Blepharoptosis Repair
NCT02988856	Not specified	COMPLETED	Magnetic Correction of Eye Lid Paralysis
NCT03149367	Not specified	UNKNOWN	Surgical Management of Blepharoptosis
NCT03239418	Not specified	TERMINATED	NMES to Improve Eyelid Functions in Cranial Nerve (CN) III and VII Palsy
NCT03375879	Not specified	UNKNOWN	Bandage Contact Lens in Post Operative Ptosis Patients
NCT03818204	Not specified	COMPLETED	Clinical Trial to Improve the Magnetic Levator Prosthesis
NCT04214379	Not specified	COMPLETED	Management of Severe Congenital Blepharoptosis
NCT04235803	Not specified	UNKNOWN	Telemedicine Follow-up for Routine, Low-Risk Oculoplastic Surgery
NCT04678115	Not specified	COMPLETED	Clinical Trial Comparing Two Non-Surgical Treatments for Severe Blepharoptosis

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
OXYMETAZOLINE	4	6
BRIMONIDINE	4	4
EPINEPHRINE	4	1
LIDOCAINE	4	1