Pathologic nystagmus

disease

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Summary

Pathologic nystagmus (MONDO:0004843) is a disease with 39 cohort genes. The dominant Reactome pathway is Regulation of MITF-M-dependent genes involved in pigmentation (4 cohort genes).

At a glance

Cohort genes: 39
ClinVar variants: 56

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	pathologic nystagmus
Mondo ID	MONDO:0004843
MeSH	D009759
DOID	DOID:9650
UMLS	C0028738
MedGen	45166
Is cancer (heuristic)	no

Data availability: 56 ClinVar variants.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › cranial nerve neuropathy › ocular motility disease › pathologic nystagmus

Subtypes (3): spontaneous ocular nystagmus, dissociated nystagmus, congenital nystagmus

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

56 retrieved; paginated sample, class counts are floors:

19 pathogenic, 14 pathogenic/likely pathogenic, 9 likely pathogenic, 7 uncertain significance, 5 conflicting classifications of pathogenicity, 1 benign, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1804039	NM_003571.4(BFSP2):c.449G>A (p.Trp150Ter)	BFSP2	Pathogenic	criteria provided, single submitter
637058	NM_007374.3(SIX6):c.547G>C (p.Asp183His)	C14orf39	Pathogenic	criteria provided, single submitter
265316	NM_001367721.1(CASK):c.2521-2A>G	CASK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1339	NM_025114.4(CEP290):c.4723A>T (p.Lys1575Ter)	CEP290	Pathogenic	criteria provided, multiple submitters, no conflicts
373994	NM_025114.4(CEP290):c.2941C>T (p.Gln981Ter)	CEP290	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523261	GRCh37/hg19 17p13.3(chr17:2339561-2826073)	CLUH	Pathogenic	criteria provided, single submitter
374027	NM_019098.5(CNGB3):c.819_826del (p.Arg274fs)	CNGB3	Pathogenic	criteria provided, multiple submitters, no conflicts
373962	NM_001379500.1(COL18A1):c.929-2A>G	COL18A1	Pathogenic	criteria provided, single submitter
183336	NM_020247.5(COQ8A):c.1744dup (p.Ser582fs)	COQ8A	Pathogenic	criteria provided, single submitter
3474	NM_001368894.2(PAX6):c.1310A>T (p.Ter437Leu)	ELP4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
374024	NM_000153.4(GALC):c.850G>A (p.Gly284Ser)	GALC	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208722	NM_002074.5(GNB1):c.239T>C (p.Ile80Thr)	GNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224716	NM_002074.5(GNB1):c.284T>C (p.Leu95Pro)	GNB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
373941	NM_000273.3(GPR143):c.12_36del (p.Leu6fs)	GPR143	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
804285	NM_002109.6(HARS1):c.616G>T (p.Asp206Tyr)	HARS1	Pathogenic	criteria provided, single submitter
804286	NM_002109.6(HARS1):c.730delG	HARS1	Pathogenic	criteria provided, single submitter
37247	NM_133497.4(KCNV2):c.1381G>A (p.Gly461Arg)	KCNV2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1684631	Single allele	LOC126862799	Pathogenic	criteria provided, single submitter
523519	NM_017777.4(MKS1):c.1166-2A>C	MKS1	Pathogenic	criteria provided, single submitter
242881	NM_001382347.1(MYO5A):c.4200C>G (p.Ser1400Arg)	MYO5A	Pathogenic	no assertion criteria provided
37134	NM_022787.4(NMNAT1):c.769G>A (p.Glu257Lys)	NMNAT1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
523376	NM_000539.3(RHO):c.891C>G (p.Ser297Arg)	RHO	Pathogenic	criteria provided, multiple submitters, no conflicts
812758	NM_000329.3(RPE65):c.1084C>T (p.Gln362Ter)	RPE65	Pathogenic	reviewed by expert panel
1804042	NM_144643.4(SCLT1):c.1043del (p.Ser348fs)	SCLT1	Pathogenic	criteria provided, single submitter
183294	NM_015046.7(SETX):c.5222dup (p.Asp1742fs)	SETX	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
287037	NM_000199.5(SGSH):c.1272_1282del (p.Tyr424_Arg428delinsTer)	SGSH	Pathogenic	criteria provided, multiple submitters, no conflicts
30459	NM_000199.5(SGSH):c.892T>C (p.Ser298Pro)	SGSH	Pathogenic	criteria provided, multiple submitters, no conflicts
373961	NM_001379500.1(COL18A1):c.3448C>T (p.Arg1150Ter)	SLC19A1	Pathogenic	criteria provided, single submitter
523459	NM_001372066.1(TFAP2A):c.1043_1044del (p.Lys348fs)	TFAP2A	Pathogenic	criteria provided, multiple submitters, no conflicts
1383	NM_153704.6(TMEM67):c.1843T>C (p.Cys615Arg)	TMEM67	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 100 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RHO	Orphanet:215	Congenital stationary night blindness
RHO	Orphanet:52427	Retinitis punctata albescens
RHO	Orphanet:791	Retinitis pigmentosa
RPE65	Orphanet:364055	Severe early-childhood-onset retinal dystrophy
RPE65	Orphanet:65	Leber congenital amaurosis
RPE65	Orphanet:791	Retinitis pigmentosa
BFSP2	Orphanet:441452	Early-onset lamellar cataract
BFSP2	Orphanet:98984	Pulverulent cataract
BFSP2	Orphanet:98985	Early-onset sutural cataract
SGSH	Orphanet:79269	Sanfilippo syndrome type A
TFAP2A	Orphanet:1297	Branchio-oculo-facial syndrome
TYR	Orphanet:352734	Minimal pigment oculocutaneous albinism type 1
TYR	Orphanet:352737	Temperature-sensitive oculocutaneous albinism type 1
TYR	Orphanet:79431	Oculocutaneous albinism type 1A
TYR	Orphanet:79434	Oculocutaneous albinism type 1B
TYR	Orphanet:895	Waardenburg syndrome type 2
CASK	Orphanet:163937	X-linked intellectual disability, Najm type
CASK	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
CASK	Orphanet:777	X-linked non-syndromic intellectual disability
COQ8A	Orphanet:139485	Autosomal recessive ataxia due to ubiquinone deficiency
NMNAT1	Orphanet:1872	Cone rod dystrophy
NMNAT1	Orphanet:65	Leber congenital amaurosis
KCNV2	Orphanet:209932	Cone dystrophy with supernormal rod response
C14orf39	Orphanet:399805	Male infertility with azoospermia or oligozoospermia due to single gene mutation
GPR143	Orphanet:54	X-linked recessive ocular albinism
CNGB3	Orphanet:1871	Progressive cone dystrophy
CNGB3	Orphanet:49382	Achromatopsia
CNGB3	Orphanet:827	Stargardt disease
COL18A1	Orphanet:1571	Knobloch syndrome
SCLT1	Orphanet:110	Bardet-Biedl syndrome
TMEM67	Orphanet:140976	RHYNS syndrome
TMEM67	Orphanet:1454	Joubert syndrome with hepatic defect
TMEM67	Orphanet:475	Isolated Joubert syndrome
TMEM67	Orphanet:564	Meckel syndrome
TMEM67	Orphanet:84081	Senior-Boichis syndrome
RUBCN	Orphanet:404499	Autosomal recessive cerebellar ataxia-epilepsy-intellectual disability syndrome due to RUBCN deficiency
CEP290	Orphanet:110	Bardet-Biedl syndrome
CEP290	Orphanet:2318	Joubert syndrome with oculorenal defect
CEP290	Orphanet:3156	Senior-Loken syndrome
CEP290	Orphanet:564	Meckel syndrome
CEP290	Orphanet:65	Leber congenital amaurosis
TBC1D24	Orphanet:163727	Rolandic epilepsy-paroxysmal exercise-induced dystonia-writer’s cramp syndrome
TBC1D24	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
TBC1D24	Orphanet:352582	Familial infantile myoclonic epilepsy
TBC1D24	Orphanet:352587	Focal epilepsy-intellectual disability-cerebro-cerebellar malformation
TBC1D24	Orphanet:352596	Progressive myoclonic epilepsy with dystonia
TBC1D24	Orphanet:79500	DOORS syndrome
TBC1D24	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
TBC1D24	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
KIF7	Orphanet:166024	Multiple epiphyseal dysplasia-macrocephaly-facial dysmorphism syndrome

Cohort genes → proteins

39 cohort genes, 39 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	39

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RHO	HGNC:10012	ENSG00000163914	P08100	Rhodopsin	clinvar
RPE65	HGNC:10294	ENSG00000116745	Q16518	Retinoid isomerohydrolase	clinvar
BFSP2	HGNC:1041	ENSG00000170819	Q13515	Phakinin	clinvar
SGSH	HGNC:10818	ENSG00000181523	P51688	N-sulphoglucosamine sulphohydrolase	clinvar
SLC19A1	HGNC:10937	ENSG00000173638	P41440	Reduced folate transporter	clinvar
ELP4	HGNC:1171	ENSG00000109911	Q96EB1	Elongator complex protein 4	clinvar
TFAP2A	HGNC:11742	ENSG00000137203	P05549	Transcription factor AP-2-alpha	clinvar
TYR	HGNC:12442	ENSG00000077498	P14679	Tyrosinase	clinvar
CASK	HGNC:1497	ENSG00000147044	O14936	Peripheral plasma membrane protein CASK	clinvar
COQ8A	HGNC:16812	ENSG00000163050	Q8NI60	Atypical kinase COQ8A, mitochondrial	clinvar
NMNAT1	HGNC:17877	ENSG00000173614	Q9HAN9	Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1	clinvar
KCNV2	HGNC:19698	ENSG00000168263	Q8TDN2	Potassium voltage-gated channel subfamily V member 2	clinvar
C14orf39	HGNC:19849	ENSG00000179008	Q8N1H7	Protein SIX6OS1	clinvar
GPR143	HGNC:20145	ENSG00000101850	P51810	G-protein coupled receptor 143	clinvar
CNGB3	HGNC:2153	ENSG00000170289	Q9NQW8	Cyclic nucleotide-gated channel beta-3	clinvar
COL18A1	HGNC:2195	ENSG00000182871	P39060	Collagen alpha-1(XVIII) chain	clinvar
SCLT1	HGNC:26406	ENSG00000151466	Q96NL6	Sodium channel and clathrin linker 1	clinvar
TMEM67	HGNC:28396	ENSG00000164953	Q5HYA8	Meckelin	clinvar
RUBCN	HGNC:28991	ENSG00000145016	Q92622	Run domain Beclin-1-interacting and cysteine-rich domain-containing protein	clinvar
CEP290	HGNC:29021	ENSG00000198707	O15078	Centrosomal protein of 290 kDa	clinvar
CLUH	HGNC:29094	ENSG00000132361	O75153	Clustered mitochondria protein homolog	clinvar
TBC1D24	HGNC:29203	ENSG00000162065	Q9ULP9	TBC1 domain family member 24	clinvar
KIF7	HGNC:30497	ENSG00000166813	Q2M1P5	Kinesin-like protein KIF7	clinvar
AIPL1	HGNC:359	ENSG00000129221	Q9NZN9	Aryl-hydrocarbon-interacting protein-like 1	clinvar
GALC	HGNC:4115	ENSG00000054983	P54803	Galactocerebrosidase	clinvar
GNB1	HGNC:4396	ENSG00000078369	P62873	Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1	clinvar
SETX	HGNC:445	ENSG00000107290	Q7Z333	Helicase senataxin	clinvar
GUCY2D	HGNC:4689	ENSG00000132518	Q02846	Retinal guanylyl cyclase 1	clinvar
HARS1	HGNC:4816	ENSG00000170445	P12081	Histidine–tRNA ligase, cytoplasmic	clinvar
INPP4A	HGNC:6074	ENSG00000040933	Q96PE3	Inositol polyphosphate-4-phosphatase type I A	clinvar
KARS1	HGNC:6215	ENSG00000065427	Q15046	Lysine–tRNA ligase	clinvar
TNPO1	HGNC:6401	ENSG00000083312	Q92973	Transportin-1	clinvar
MIP	HGNC:7103	ENSG00000135517	P30301	Lens fiber major intrinsic protein	clinvar
MKS1	HGNC:7121	ENSG00000011143	Q9NXB0	Tectonic-like complex member MKS1	clinvar
MYO5A	HGNC:7602	ENSG00000197535	Q9Y4I1	Unconventional myosin-Va	clinvar
NDP	HGNC:7678	ENSG00000124479	Q00604	Norrin	clinvar
ATP1A3	HGNC:801	ENSG00000105409	P13637	Sodium/potassium-transporting ATPase subunit alpha-3	clinvar
OPHN1	HGNC:8148	ENSG00000079482	O60890	Oligophrenin-1	clinvar
OTX2	HGNC:8522	ENSG00000165588	P32243	Homeobox protein OTX2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RHO	Rhodopsin	Photoreceptor required for image-forming vision at low light intensity.
RPE65	Retinoid isomerohydrolase	Critical isomerohydrolase in the retinoid cycle involved in regeneration of 11-cis-retinal, the chromophore of rod and cone opsins.
BFSP2	Phakinin	Required for the correct formation of lens intermediate filaments as part of a complex composed of BFSP1, BFSP2 and CRYAA.
SGSH	N-sulphoglucosamine sulphohydrolase	Catalyzes a step in lysosomal heparan sulfate degradation.
SLC19A1	Reduced folate transporter	Antiporter that mediates the import of reduced folates or a subset of cyclic dinucleotides, driven by the export of organic anions.
ELP4	Elongator complex protein 4	Component of the elongator complex which is required for multiple tRNA modifications, including mcm5U (5-methoxycarbonylmethyl uridine), mcm5s2U (5-methoxycarbonylmethyl-2-thiouridine), and ncm5U (5-carbamoylmethyl uridine).
TFAP2A	Transcription factor AP-2-alpha	Sequence-specific DNA-binding protein that interacts with inducible viral and cellular enhancer elements to regulate transcription of selected genes.
TYR	Tyrosinase	This is a copper-containing oxidase that functions in the formation of pigments such as melanins and other polyphenolic compounds.
CASK	Peripheral plasma membrane protein CASK	Multidomain scaffolding Mg(2+)-independent protein kinase that catalyzes the phosphotransfer from ATP to proteins such as NRXN1, and plays a role in synaptic transmembrane protein anchoring and ion channel trafficking.
COQ8A	Atypical kinase COQ8A, mitochondrial	Atypical kinase involved in the biosynthesis of coenzyme Q, also named ubiquinone, an essential lipid-soluble electron transporter for aerobic cellular respiration.
NMNAT1	Nicotinamide/nicotinic acid mononucleotide adenylyltransferase 1	Catalyzes the formation of NAD(+) from nicotinamide mononucleotide (NMN) and ATP.
KCNV2	Potassium voltage-gated channel subfamily V member 2	Potassium channel subunit.
C14orf39	Protein SIX6OS1	Meiotic protein that localizes to the central element of the synaptonemal complex and is required for chromosome synapsis during meiotic recombination.
GPR143	G-protein coupled receptor 143	Receptor for tyrosine, L-DOPA and dopamine.
CNGB3	Cyclic nucleotide-gated channel beta-3	Pore-forming subunit of the cone cyclic nucleotide-gated channel.
COL18A1	Collagen alpha-1(XVIII) chain	Probably plays a major role in determining the retinal structure as well as in the closure of the neural tube.
SCLT1	Sodium channel and clathrin linker 1	Adapter protein that links SCN10A to clathrin.
TMEM67	Meckelin	Required for ciliary structure and function.
RUBCN	Run domain Beclin-1-interacting and cysteine-rich domain-containing protein	Inhibits PIK3C3 activity; under basal conditions negatively regulates PI3K complex II (PI3KC3-C2) function in autophagy.
CEP290	Centrosomal protein of 290 kDa	Involved in early and late steps in cilia formation.
CLUH	Clustered mitochondria protein homolog	mRNA-binding protein involved in proper cytoplasmic distribution of mitochondria.
TBC1D24	TBC1 domain family member 24	May act as a GTPase-activating protein for Rab family protein(s).
KIF7	Kinesin-like protein KIF7	Essential for hedgehog signaling regulation: acts both as a negative and positive regulator of sonic hedgehog (Shh) and Indian hedgehog (Ihh) pathways, acting downstream of SMO, through both SUFU-dependent and -independent mechanisms.
AIPL1	Aryl-hydrocarbon-interacting protein-like 1	May be important in protein trafficking and/or protein folding and stabilization.
GALC	Galactocerebrosidase	Hydrolyzes the galactose ester bonds of glycolipids such as galactosylceramide and galactosylsphingosine.
GNB1	Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1	Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems.
SETX	Helicase senataxin	ATP-dependent 5’->3’ DNA/RNA helicase that preferentially unwinds RNA substrates over DNA, playing a crucial role in resolving R-loops and promoting transcription termination.
GUCY2D	Retinal guanylyl cyclase 1	Catalyzes the synthesis of cyclic GMP (cGMP) in rods and cones of photoreceptors.
HARS1	Histidine–tRNA ligase, cytoplasmic	Catalyzes the ATP-dependent ligation of histidine to the 3’-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (His-AMP).
INPP4A	Inositol polyphosphate-4-phosphatase type I A	Catalyzes the hydrolysis of the 4-position phosphate of phosphatidylinositol 3,4-bisphosphate (PtdIns(3,4)P2).
KARS1	Lysine–tRNA ligase	Catalyzes the specific attachment of an amino acid to its cognate tRNA in a 2 step reaction: the amino acid (AA) is first activated by ATP to form AA-AMP and then transferred to the acceptor end of the tRNA.
TNPO1	Transportin-1	Functions in nuclear protein import as nuclear transport receptor.
MIP	Lens fiber major intrinsic protein	Aquaporins form homotetrameric transmembrane channels, with each monomer independently mediating water transport across the plasma membrane along its osmotic gradient.
MKS1	Tectonic-like complex member MKS1	Component of the tectonic-like complex, a complex localized at the transition zone of primary cilia and acting as a barrier that prevents diffusion of transmembrane proteins between the cilia and plasma membranes.
MYO5A	Unconventional myosin-Va	Processive actin-based motor that can move in large steps approximating the 36-nm pseudo-repeat of the actin filament.
NDP	Norrin	Activates the canonical Wnt signaling pathway through FZD4 and LRP5 coreceptor.
ATP1A3	Sodium/potassium-transporting ATPase subunit alpha-3	This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane.
OPHN1	Oligophrenin-1	Stimulates GTP hydrolysis of members of the Rho family.
OTX2	Homeobox protein OTX2	Transcription factor probably involved in the development of the brain and the sense organs.

Protein-family classification

Druggable: 15 · Difficult: 6 · Unknown: 18 · Druggable fraction: 0.38

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	2	5.7×	0.215
Enzyme (other)	7	2.1×	0.215
Kinase	3	2.1×	0.496
Phosphatase	1	2.1×	0.595
Transporter	1	2.0×	0.595
Scaffold/PPI	3	1.3×	0.595
Other/Unknown	18	0.8×	0.915
Transcription factor	3	0.6×	0.915
GPCR	1	0.6×	0.915

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RHO	GPCR	yes		GPCR_Rhodpsn, Rhodopsin, Opsin
RPE65	Enzyme (other)	yes	3.1.1.64	Carotenoid_Oase
BFSP2	Other/Unknown	no		Keratin_I, IF_rod_dom
SGSH	Phosphatase	yes	3.10.1.1	Sulfatase_N, Alkaline_phosphatase_core_sf, Sulfatase_CS
SLC19A1	Transporter	yes		Folate_carrier, SLC19A1, MFS_trans_sf
ELP4	Other/Unknown	no		Elongator_complex_protein_4, P-loop_NTPase
TFAP2A	Transcription factor	no		TF_AP2, TF_AP2_alpha_N, TF_AP2_C
TYR	Enzyme (other)	yes	1.14.18.1	Tyrosinase_Cu-bd, Di-copper_centre_dom_sf, Tyrosinase/Hemocyanin
CASK	Kinase	yes	2.7.11.1	Prot_kinase_dom, SH3_domain, PDZ
COQ8A	Kinase	yes		ABC1_dom, Kinase-like_dom_sf, ADCK3_dom
NMNAT1	Enzyme (other)	yes	2.7.7.1	Cyt_trans-like, NadD/NMNAT, Rossmann-like_a/b/a_fold
KCNV2	Ion channel	yes		T1-type_BTB, K_chnl_volt-dep_Kv, K_chnl_volt-dep_Kv5/Kv9
C14orf39	Other/Unknown	no		SIX6OS1
GPR143	Other/Unknown	no		GPR143
CNGB3	Ion channel	yes		cNMP-bd_dom, Ion_trans_dom, RmlC-like_jellyroll
COL18A1	Other/Unknown	no		Collagen, DUF959_COL18_N, Collagenase_NC10/endostatin
SCLT1	Other/Unknown	no		SCLT1
TMEM67	Other/Unknown	no		Growth_fac_rcpt_cys_sf, Meckelin
RUBCN	Other/Unknown	no		Run_dom, RH_dom, Run_dom_sf
CEP290	Other/Unknown	no		Cep290, Cep209_CC5
CLUH	Other/Unknown	no		TPR-like_helical_dom_sf, GSKIP_dom_sf, CLU_dom
TBC1D24	Other/Unknown	no		Rab-GAP-TBC_dom, TLDc_dom, Rab-GAP_TBC_sf
KIF7	Other/Unknown	no		Kinesin_motor_dom, Kinesin_motor_CS, P-loop_NTPase
AIPL1	Other/Unknown	no		TPR-like_helical_dom_sf, TPR_rpt, AIP/AIPL1/TTC9
GALC	Enzyme (other)	yes	3.2.1.46	Glyco_hydro_59, Aldolase_TIM, GH_hydrolase_sf
GNB1	Scaffold/PPI	no		WD40_G-protein_beta-like, WD40_rpt, WD40/YVTN_repeat-like_dom_sf
SETX	Other/Unknown	no		P-loop_NTPase, DNA2/NAM7_AAA_11, DNA2/NAM7-like_C
GUCY2D	Kinase	yes	4.6.1.2	Prot_kinase_dom, A/G_cyclase, Ser-Thr/Tyr_kinase_cat_dom
HARS1	Enzyme (other)	yes	6.1.1.21	WHEP-TRS_dom, Anticodon-bd, HisRS/HisZ
INPP4A	Enzyme (other)	yes	3.1.3.66	C2_dom, C2_domain_sf, INPP4
KARS1	Enzyme (other)	yes	6.1.1.6	Lys-tRNA-ligase_II, Aa-tRNA-synt_II, NA-bd_OB_tRNA
TNPO1	Other/Unknown	no		Importin-beta_N, ARM-like, ARM-type_fold
MIP	Other/Unknown	no		MIP, MIP_CS, Aquaporin-like
MKS1	Other/Unknown	no		C2_B9-type_dom
MYO5A	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Dilute_dom
NDP	Other/Unknown	no		Norrie_dis, Cys_knot_C, Glyco_hormone_CN
ATP1A3	Transcription factor	no		P_typ_ATPase, ATPase_P-typ_cation-transptr_N, P-type_ATPase_IIC
OPHN1	Scaffold/PPI	no		RhoGAP_dom, PH_domain, BAR_dom
OTX2	Transcription factor	no		HD, Otx2_TF, Otx_TF

Expression context

Cohort genes with no expression data: 0.

34 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)	39
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	7
pigmented layer of retina	5
primordial germ cell in gonad	5
buccal mucosa cell	5
calcaneal tendon	4
endothelial cell	3
gingival epithelium	3
cortical plate	3
secondary oocyte	3
right uterine tube	3
diaphragm	2
jejunal mucosa	2
ventricular zone	2
upper leg skin	2
hindlimb stylopod muscle	2
adenohypophysis	2
oocyte	2
sural nerve	2
right lobe of liver	2
Brodmann (1909) area 23	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RHO	38	tissue_specific	marker	optic choroid, neuron projection bundle connecting eye with brain, diaphragm
RPE65	92	tissue_specific	marker	pigmented layer of retina, retina, male germ line stem cell (sensu Vertebrata) in testis
BFSP2	111	tissue_specific	yes	lens of camera-type eye, male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad
SGSH	272	ubiquitous	marker	left adrenal gland, left adrenal gland cortex, adrenal cortex
SLC19A1	238	ubiquitous	marker	jejunal mucosa, blood, endothelial cell
ELP4	250	ubiquitous	marker	ventricular zone, calcaneal tendon, primordial germ cell in gonad
TFAP2A	220	ubiquitous	marker	upper leg skin, gingival epithelium, gingiva
TYR	59	tissue_specific	marker	pigmented layer of retina, male germ line stem cell (sensu Vertebrata) in testis, upper leg skin
CASK	284	ubiquitous	marker	buccal mucosa cell, hair follicle, cortical plate
COQ8A	134	ubiquitous	marker	gastrocnemius, skeletal muscle tissue, hindlimb stylopod muscle
NMNAT1	225	ubiquitous	yes	hindlimb stylopod muscle, muscle of leg, mucosa of transverse colon
KCNV2	61	tissue_specific	marker	sperm, male germ cell, primordial germ cell in gonad
C14orf39	129	broad	marker	primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis, adenohypophysis
GPR143	170	broad	marker	oocyte, secondary oocyte, pigmented layer of retina
CNGB3	161	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, pigmented layer of retina, diaphragm
COL18A1	266	ubiquitous	marker	right coronary artery, popliteal artery, tibial artery
SCLT1	217	ubiquitous	marker	buccal mucosa cell, monocyte, leukocyte
TMEM67	203	ubiquitous	marker	buccal mucosa cell, right uterine tube, calcaneal tendon
RUBCN	285	ubiquitous	marker	sural nerve, postcentral gyrus, middle frontal gyrus
CEP290	278	ubiquitous	marker	right uterine tube, male germ line stem cell (sensu Vertebrata) in testis, ventricular zone
CLUH	283	ubiquitous	marker	gingival epithelium, apex of heart, right lobe of liver
TBC1D24	227	ubiquitous	marker	parotid gland, Brodmann (1909) area 23, middle temporal gyrus
KIF7	165	ubiquitous	yes	kidney epithelium, cardiac muscle of right atrium, left ventricle myocardium
AIPL1	62	tissue_specific	marker	buccal mucosa cell, pancreatic ductal cell, tendon of biceps brachii
GALC	295	ubiquitous	marker	adrenal tissue, bronchial epithelial cell, jejunal mucosa
GNB1	295	ubiquitous	marker	cortical plate, ganglionic eminence, secondary oocyte
SETX	281	ubiquitous	marker	right testis, calcaneal tendon, left testis
GUCY2D	121	tissue_specific	marker	buccal mucosa cell, esophagus mucosa, lower esophagus mucosa
HARS1	291	ubiquitous	marker	lateral nuclear group of thalamus, right frontal lobe, adenohypophysis
INPP4A	279	ubiquitous	marker	Brodmann (1909) area 23, endothelial cell, tibia

Protein interactions among cohort

Intra-cohort edges: 18.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KARS1	4,681
MYO5A	4,333
CASK	4,223
ATP1A3	3,876
TYR	3,663
RHO	3,578
TNPO1	3,147
SETX	3,127
CEP290	2,778
TFAP2A	2,734

Intra-cohort edges

A	B	Sources
AIPL1	CEP290	string_interaction
AIPL1	GUCY2D	string_interaction
AIPL1	NMNAT1	string_interaction
AIPL1	RPE65	string_interaction
BFSP2	MIP	string_interaction
CEP290	MKS1	string_interaction
CEP290	TMEM67	string_interaction
CNGB3	GUCY2D	string_interaction
CNGB3	KCNV2	string_interaction
CNGB3	RPE65	string_interaction
GPR143	TYR	intact, string_interaction
GUCY2D	KCNV2	string_interaction
GUCY2D	NMNAT1	string_interaction
GUCY2D	RPE65	string_interaction
HARS1	KARS1	string_interaction
MKS1	TMEM67	string_interaction
NDP	TMEM67	biogrid_interaction
RHO	RPE65	string_interaction

Structural data

PDB: 21 · AlphaFold-only: 18 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNB1	P62873	1,262
CASK	O14936	22
TNPO1	Q92973	21
SLC19A1	P41440	19
KARS1	Q15046	14
NDP	Q00604	12
HARS1	P12081	10
CNGB3	Q9NQW8	9
COL18A1	P39060	9
MYO5A	Q9Y4I1	7
NMNAT1	Q9HAN9	6
AIPL1	Q9NZN9	6
KIF7	Q2M1P5	5
ATP1A3	P13637	5
RHO	P08100	4
COQ8A	Q8NI60	4
TFAP2A	P05549	3
SGSH	P51688	2
RUBCN	Q92622	2
TYR	P14679	1
TMEM67	Q5HYA8	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
RPE65	Q16518	95.34
GALC	P54803	94.56
MIP	P30301	91.08
TBC1D24	Q9ULP9	84.46
CLUH	O75153	83.11
SCLT1	Q96NL6	82.44
GUCY2D	Q02846	82.37
INPP4A	Q96PE3	80.39
BFSP2	Q13515	78.15
KCNV2	Q8TDN2	75.55
OPHN1	O60890	74.86
ELP4	Q96EB1	74.49
GPR143	P51810	74.37
MKS1	Q9NXB0	74.05
OTX2	P32243	60.99
CEP290	O15078	60.90
C14orf39	Q8N1H7	58.97
SETX	Q7Z333	52.93

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 173. Enrichment computed across 39 evidence-associated genes (31 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 31 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Regulation of MITF-M-dependent genes involved in pigmentation	4	34.3×	9e-04	TFAP2A, TYR, GPR143, MYO5A
Inactivation, recovery and regulation of the phototransduction cascade	3	30.7×	0.008	RHO, GNB1, GUCY2D
Anchoring of the basal body to the plasma membrane	4	14.6×	0.008	SCLT1, TMEM67, CEP290, MKS1
Cilium Assembly	4	14.0×	0.008	SCLT1, TMEM67, CEP290, MKS1
Activation of the phototransduction cascade	2	61.4×	0.016	RHO, GNB1
Organelle biogenesis and maintenance	4	8.5×	0.034	SCLT1, TMEM67, CEP290, MKS1
The canonical retinoid cycle in rods (twilight vision)	2	33.5×	0.039	RHO, RPE65
MPS IIIA - Sanfilippo syndrome A	1	368.4×	0.047	SGSH
Cytosolic tRNA aminoacylation	2	28.3×	0.047	HARS1, KARS1
MITF-M-regulated melanocyte development	3	11.1×	0.047	TFAP2A, KARS1, MYO5A
TFAP2 (AP-2) family regulates transcription of other transcription factors	1	92.1×	0.137	TFAP2A
Melanin biosynthesis	1	73.7×	0.137	TYR
TFAP2 (AP-2) family regulates transcription of cell cycle factors	1	73.7×	0.137	TFAP2A
TFAP2A acts as a transcriptional repressor during retinoic acid induced cell differentiation	1	73.7×	0.137	TFAP2A
Signaling by Hedgehog	2	11.9×	0.137	KIF7, MKS1
MITF-M-dependent gene expression	2	11.7×	0.137	TFAP2A, MYO5A
Hedgehog ‘off’ state	2	11.5×	0.137	KIF7, MKS1
Mucopolysaccharidoses	1	61.4×	0.156	SGSH
Opsins	1	40.9×	0.209	RHO
Negative regulation of activity of TFAP2 (AP-2) family transcription factors	1	36.8×	0.209	TFAP2A
Formation of the posterior neural plate	1	36.8×	0.209	OTX2
Formation of the anterior neural plate	1	33.5×	0.209	OTX2
Activation of the TFAP2 (AP-2) family of transcription factors	1	30.7×	0.209	TFAP2A
Positive Regulation of CDH1 Gene Transcription	1	30.7×	0.209	TFAP2A
Ubiquinol biosynthesis	1	28.3×	0.209	COQ8A
Passive transport by Aquaporins	1	28.3×	0.209	MIP
Diseases of carbohydrate metabolism	1	26.3×	0.209	SGSH
Synthesis of IP2, IP, and Ins in the cytosol	1	24.6×	0.209	INPP4A
TFAP2 (AP-2) family regulates transcription of growth factors and their receptors	1	24.6×	0.209	TFAP2A
Developmental Lineage of Mammary Stem Cells	1	24.6×	0.209	TFAP2A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 39 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
visual perception	11	22.4×	4e-10	RHO, RPE65, BFSP2, TYR, GPR143, CNGB3, COL18A1, AIPL1 (+3 more)
eye pigment biosynthetic process	2	432.1×	8e-04	TYR, GPR143
regulation of opsin-mediated signaling pathway	2	86.4×	0.024	AIPL1, GUCY2D
phototransduction, visible light	2	66.5×	0.032	RHO, AIPL1
retina homeostasis	2	57.6×	0.034	RPE65, AIPL1
smoothened signaling pathway involved in regulation of secondary heart field cardioblast proliferation	1	432.1×	0.048	MKS1
optic cup structural organization	1	432.1×	0.048	TFAP2A
lysyl-tRNA aminoacylation	1	432.1×	0.048	KARS1
positive regulation of termination of DNA-templated transcription	1	432.1×	0.048	SETX
zeaxanthin biosynthetic process	1	432.1×	0.048	RPE65
regulation of melanosome transport	1	432.1×	0.048	GPR143
melanosome transport	2	39.3×	0.048	GPR143, MYO5A
retina layer formation	2	33.2×	0.048	TFAP2A, NDP
regulation of smoothened signaling pathway	2	32.0×	0.048	MKS1, OTX2
cilium assembly	4	7.5×	0.048	SCLT1, TMEM67, CEP290, MKS1
positive regulation of DNA-templated transcription	6	4.3×	0.048	TFAP2A, NMNAT1, CEP290, KARS1, NDP, OTX2
basophil activation involved in immune response	1	216.1×	0.050	KARS1
optic vesicle morphogenesis	1	216.1×	0.050	TFAP2A
histidyl-tRNA aminoacylation	1	216.1×	0.050	HARS1
galactosylceramide catabolic process	1	216.1×	0.050	GALC
oculomotor nerve formation	1	216.1×	0.050	TFAP2A
thermotaxis	1	216.1×	0.050	RHO
methotrexate transport	1	216.1×	0.050	SLC19A1
negative regulation of cellular response to growth factor stimulus	1	216.1×	0.050	CASK
retina blood vessel maintenance	1	216.1×	0.050	NDP
obsolete ciliary basal body-plasma membrane docking	1	216.1×	0.050	CEP290
regulation of melanosome organization	1	216.1×	0.050	GPR143
rod bipolar cell differentiation	1	216.1×	0.050	RHO
synaptic vesicle endocytosis	2	22.2×	0.050	TBC1D24, OPHN1
lens development in camera-type eye	2	19.2×	0.051	MIP, NDP

Therapeutics

Drug target analysis

Approved (phase 4): 6 · Phase ≥3: 6 · Phased (≥1): 7 · Undrugged: 32

Druggability breadth: 19 of 39 evidence-associated genes (49%) 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
SLC19A1	PRALATREXATE
TYR	ASCORBIC ACID
CASK	FEDRATINIB
COQ8A	FEDRATINIB
KARS1	IMATINIB
ATP1A3	OMEPRAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COQ8A	14	4
TYR	10	4
CASK	9	4
ATP1A3	5	4
SLC19A1	4	4
GNB1	1	2
KARS1	1	4
RHO	0	0
RPE65	0	0
BFSP2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PRALATREXATE	4	SLC19A1
RALTITREXED	4	SLC19A1
PEMETREXED	4	SLC19A1
METHOTREXATE	4	SLC19A1
ASCORBIC ACID	4	TYR
HEXYLRESORCINOL	4	TYR
HYDROQUINONE	4	TYR
FEDRATINIB	4	CASK, COQ8A
RUXOLITINIB	4	CASK
BOSUTINIB	4	CASK
CRIZOTINIB	4	CASK
VANDETANIB	4	COQ8A
DASATINIB	4	COQ8A
ERLOTINIB	4	COQ8A
IMATINIB	4	KARS1
OMEPRAZOLE	4	ATP1A3
DIGOXIN	4	ATP1A3
DIGITOXIN	4	ATP1A3
LANSOPRAZOLE	4	ATP1A3
CURCUMIN	3	TYR
RESVERATROL	3	TYR
QUERCETIN	3	TYR
LESTAURTINIB	3	CASK
SARACATINIB	3	COQ8A
CANERTINIB	3	COQ8A
BUTYLATED HYDROXYTOLUENE	2	TYR
LUTEOLIN	2	TYR
ARBUTIN	2	TYR
CYC-065	2	CASK
RG-547	2	CASK

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 10.

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

Symbol	Assays	Type breakdown
TYR	211	Binding:209, ADMET:2
COQ8A	93	Binding:93
CASK	92	Binding:92
KARS1	46	Binding:45, ADMET:1
ATP1A3	45	Binding:45
KCNV2	21	Binding:20, Toxicity:1
SLC19A1	18	Binding:18
GNB1	12	Binding:12
TNPO1	7	Binding:7
KIF7	5	Binding:5
HARS1	5	Binding:5
NMNAT1	3	Binding:3
GPR143	3	Binding:3
GALC	3	Binding:2, Functional:1
RHO	1	Binding:1
CLUH	1	Binding:1
AIPL1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RPE65	3.1.1.64, 5.3.3.22	retinoid isomerohydrolase, lutein isomerase
SGSH	3.10.1.1	N-sulfoglucosamine sulfohydrolase
TYR	1.14.18.1	tyrosinase
CASK	2.7.11.1, 2.7.4.8	non-specific serine/threonine protein kinase, guanylate kinase
NMNAT1	2.7.7.1, 2.7.7.18	nicotinamide-nucleotide adenylyltransferase, nicotinate-nucleotide adenylyltransferase
GALC	3.2.1.46	galactosylceramidase
GUCY2D	4.6.1.2	guanylate cyclase
HARS1	6.1.1.21	histidine-tRNA ligase
INPP4A	3.1.3.66	phosphatidylinositol-3,4-bisphosphate 4-phosphatase
KARS1	6.1.1.6	lysine-tRNA ligase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
TYR	211

Pharmacogenomics

Cohort genes with a PharmGKB record: 39; with CPIC/DPWG dosing guidelines: 0.

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

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)
PRALATREXATE	4	SLC19A1
RALTITREXED	4	SLC19A1
PEMETREXED	4	SLC19A1
METHOTREXATE	4	SLC19A1
ASCORBIC ACID	4	TYR
HEXYLRESORCINOL	4	TYR
HYDROQUINONE	4	TYR
FEDRATINIB	4	CASK, COQ8A
RUXOLITINIB	4	CASK
BOSUTINIB	4	CASK
CRIZOTINIB	4	CASK
VANDETANIB	4	COQ8A
DASATINIB	4	COQ8A
ERLOTINIB	4	COQ8A
IMATINIB	4	KARS1
OMEPRAZOLE	4	ATP1A3
DIGOXIN	4	ATP1A3
DIGITOXIN	4	ATP1A3
LANSOPRAZOLE	4	ATP1A3
CURCUMIN	3	TYR
RESVERATROL	3	TYR
QUERCETIN	3	TYR
LESTAURTINIB	3	CASK
SARACATINIB	3	COQ8A
CANERTINIB	3	COQ8A
BUTYLATED HYDROXYTOLUENE	2	TYR
LUTEOLIN	2	TYR
ARBUTIN	2	TYR
CYC-065	2	CASK
RG-547	2	CASK

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	6	SLC19A1, TYR, CASK, COQ8A, KARS1, ATP1A3
B	Phased (≥1) drug, not yet approved	1	GNB1
C	Druggable family + PDB, no drug	5	RHO, SGSH, NMNAT1, CNGB3, HARS1
D	Druggable family + AlphaFold only, no drug	5	RPE65, KCNV2, GALC, GUCY2D, INPP4A
E	Difficult family or no structure, no drug	22	BFSP2, ELP4, TFAP2A, C14orf39, GPR143, COL18A1, SCLT1, TMEM67, RUBCN, CEP290 (+12 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GPR143	3	TYR
RHO	1	—
RPE65	0	—
BFSP2	0	—
SGSH	0	—
ELP4	0	—
TFAP2A	0	—
NMNAT1	3	—
KCNV2	21	—
C14orf39	0	—
CNGB3	0	—
COL18A1	0	—
SCLT1	0	—
TMEM67	0	—
RUBCN	0	—
CEP290	0	—
CLUH	1	—
TBC1D24	0	—
KIF7	5	—
AIPL1	1	—
GALC	3	—
SETX	0	—
GUCY2D	0	—
HARS1	5	—
INPP4A	0	—
TNPO1	7	—
MIP	0	—
MKS1	0	—
MYO5A	0	—
NDP	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.

Cohort genes: RHO, RPE65, BFSP2, SGSH, SLC19A1, ELP4, TFAP2A, TYR, CASK, COQ8A, NMNAT1, KCNV2, C14orf39, GPR143, CNGB3, COL18A1, SCLT1, TMEM67, RUBCN, CEP290, CLUH, TBC1D24, KIF7, AIPL1, GALC, GNB1, SETX, GUCY2D, HARS1, INPP4A, KARS1, TNPO1, MIP, MKS1, MYO5A, NDP, ATP1A3, OPHN1, OTX2