P3H2

Summary

P3H2 (prolyl 3-hydroxylase 2, HGNC:19317) is a protein-coding gene on chromosome 3q28, encoding Prolyl 3-hydroxylase 2 (Q8IVL5). Prolyl 3-hydroxylase that catalyzes the post-translational formation of 3-hydroxyproline on collagens.

This gene encodes a member of the prolyl 3-hydroxylase subfamily of 2-oxo-glutarate-dependent dioxygenases. These enzymes play a critical role in collagen chain assembly, stability and cross-linking by catalyzing post-translational 3-hydroxylation of proline residues. Mutations in this gene are associated with nonsyndromic severe myopia with cataract and vitreoretinal degeneration, and downregulation of this gene may play a role in breast cancer. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 55214 — RefSeq curated summary.

At a glance

• Gene–disease (curated): myopia, high, with cataract and vitreoretinal degeneration (Strong, GenCC)
• GWAS associations: 6
• Clinical variants (ClinVar): 737 total — 35 pathogenic, 14 likely-pathogenic
• Phenotypes (HPO): 10
• MANE Select transcript: NM_018192

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:19317
Approved symbol	P3H2
Name	prolyl 3-hydroxylase 2
Location	3q28
Locus type	gene with protein product
Status	Approved
Aliases	FLJ10718, MLAT4
Ensembl gene	ENSG00000090530
Ensembl biotype	protein_coding
OMIM	610341
Entrez	55214

Gene structure

Transcript identifiers

Ensembl transcripts: 14 — 8 protein_coding, 6 retained_intron

ENST00000319332, ENST00000426003, ENST00000427335, ENST00000444866, ENST00000463171, ENST00000467131, ENST00000470925, ENST00000475095, ENST00000482780, ENST00000490940, ENST00000895814, ENST00000895815, ENST00000895816, ENST00000943436

RefSeq mRNA: 2 — MANE Select: NM_018192 NM_001134418, NM_018192

CCDS: CCDS3294, CCDS46981

Canonical transcript exons

ENST00000319332 — 15 exons

Exon	Start	End
ENSE00000781609	189963958	189964098
ENSE00000781615	189973909	189974004
ENSE00000781617	189974558	189974685
ENSE00000781620	189987527	189987669
ENSE00001073569	189994094	189994283
ENSE00001220387	190120252	190120897
ENSE00001220398	189956728	189958004
ENSE00003509167	189971890	189972007
ENSE00003509946	189986788	189986877
ENSE00003557361	189983046	189983140
ENSE00003558970	189984550	189984590
ENSE00003648985	189995290	189995442
ENSE00003657022	189972874	189973024
ENSE00003662140	189970816	189970891
ENSE00003787180	189988907	189989038

Expression profiles

Bgee: expression breadth ubiquitous, 215 present calls, max score 98.52.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 11.9924 / max 259.3485, expressed in 1188 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
46070	10.4561	1165
46068	0.5887	275
46069	0.3917	233
46071	0.3627	205
46067	0.1041	42
46075	0.0327	10
46077	0.0169	5
46076	0.0135	6
46073	0.0105	3
46074	0.0077	5

Top tissues by expression

278 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
adrenal tissue	UBERON:0018303	98.52	gold quality
cartilage tissue	UBERON:0002418	97.21	gold quality
metanephros cortex	UBERON:0010533	96.30	gold quality
metanephric glomerulus	UBERON:0004736	95.66	gold quality
renal glomerulus	UBERON:0000074	95.56	gold quality
tibia	UBERON:0000979	95.47	gold quality
metanephros	UBERON:0000081	94.48	gold quality
left adrenal gland	UBERON:0001234	94.30	gold quality
spleen	UBERON:0002106	94.26	gold quality
left adrenal gland cortex	UBERON:0035825	94.26	gold quality
ventricular zone	UBERON:0003053	94.16	gold quality
right adrenal gland cortex	UBERON:0035827	93.81	gold quality
adrenal gland	UBERON:0002369	93.26	gold quality
right adrenal gland	UBERON:0001233	93.20	gold quality
adrenal cortex	UBERON:0001235	92.78	gold quality
adult mammalian kidney	UBERON:0000082	92.62	gold quality
cortex of kidney	UBERON:0001225	92.62	gold quality
kidney	UBERON:0002113	91.52	gold quality
kidney epithelium	UBERON:0004819	91.52	gold quality
decidua	UBERON:0002450	91.01	gold quality
muscle layer of sigmoid colon	UBERON:0035805	90.39	gold quality
prostate gland	UBERON:0002367	89.72	gold quality
ectocervix	UBERON:0012249	89.61	gold quality
smooth muscle tissue	UBERON:0001135	88.87	gold quality
right lung	UBERON:0002167	88.87	gold quality
nephron tubule	UBERON:0001231	88.74	gold quality
upper lobe of left lung	UBERON:0008952	88.62	gold quality
skin of abdomen	UBERON:0001416	88.51	gold quality
upper lobe of lung	UBERON:0008948	88.34	gold quality
body of uterus	UBERON:0009853	88.09	gold quality

Single-cell (SCXA)

Detected in 3 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	22.96
E-CURD-112	yes	15.23
E-CURD-119	no	1803.27

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

46 targeting P3H2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6867-5P	100.00	82.21	3464
HSA-MIR-6740-5P	100.00	65.64	932
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-6873-3P	100.00	71.42	2626
HSA-MIR-6870-5P	99.99	68.55	2115
HSA-MIR-6077	99.99	68.04	2299
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-4723-5P	99.97	68.70	2034
HSA-MIR-5698	99.97	68.49	2029
HSA-MIR-7111-5P	99.97	68.48	2062
HSA-MIR-6778-3P	99.96	67.29	2693
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-5682	99.89	72.56	1005
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-6875-3P	99.82	70.26	2983
HSA-MIR-1825	99.72	68.11	1089
HSA-MIR-891B	99.59	69.81	1083
HSA-MIR-4524A-5P	99.57	71.73	1193
HSA-MIR-4524B-5P	99.57	71.68	1195
HSA-MIR-199A-5P	99.51	69.71	1107
HSA-MIR-199B-5P	99.51	69.74	1098
HSA-MIR-203A-3P	99.49	70.56	2806
HSA-MIR-1275	99.47	67.90	2749
HSA-MIR-4318	99.38	66.94	1505

Literature-anchored findings (GeneRIF, showing 10)

• P3H2 is responsible for the hydroxylation of collagen IV, which has the highest 3-hydroxyproline content of all collagens. It is thus possible that P3H2 mutations may lead to a disease with changes in basement membranes. (PMID:18487197)
• The restriction of silencing in P3H2 to breast carcinomas, and its association with oestrogen-receptor-positive cases, suggests that P3H2 may be a breast-cancer-specific tumour suppressor. (PMID:19436308)
• P3H2 has preferred substrate sequences among the classes of 3Hyp sites in clade A collagen chains (PMID:21757687)
• High myopia is caused by a mutation in LEPREL1, encoding prolyl 3-hydroxylase 2. (PMID:21885030)
• LEPREL1 plays an important role in eye development and homozygous loss-of-function mutation of this gene can cause severely high myopia and early-onset cataract. (PMID:24172257)
• Recessive LEPREL1 mutations should be recognized as part of the differential diagnosis of lens subluxation. (PMID:25469533)
• mutation in LRPAP1 is associated with high myopia. Further studies are expected to evaluate the pathogenicity of the variants in CTSH, LEPREL1, ZNF644, SLC39A5, and SCO2. (PMID:25525168)
• Data identified an enhancer region within the TP63/LEPREL1 locus containing genetic variants associated with bladder cancer risk. (PMID:29956121)
• Mutation in the LEPREL1 gene is associated with ectopia lentis. (PMID:30608193)
• Prolyl 3-Hydroxylase 2 Is a Molecular Player of Angiogenesis. (PMID:33918807)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	p3h2	ENSDARG00000103026
mus_musculus	P3h2	ENSMUSG00000038168
rattus_norvegicus	P3h2	ENSRNOG00000055751

Paralogs (2): P3H3 (ENSG00000110811), P3H1 (ENSG00000117385)

Protein

Protein identifiers

Prolyl 3-hydroxylase 2 — Q8IVL5 (reviewed: Q8IVL5)

Alternative names: Leprecan-like protein 1, Myxoid liposarcoma-associated protein 4

All UniProt accessions (3): Q8IVL5, C9J313, C9JSL4

UniProt curated annotations — full annotation on UniProt →

Function. Prolyl 3-hydroxylase that catalyzes the post-translational formation of 3-hydroxyproline on collagens. Contributes to proline 3-hydroxylation of collagen COL4A1 and COL1A1 in tendons, the eye sclera and in the eye lens capsule. Has high activity with the type IV collagen COL4A1, and lower activity with COL1A1. Catalyzes hydroxylation of the first Pro in Gly-Pro-Hyp sequences where Hyp is 4-hydroxyproline. Has no activity on substrates that lack 4-hydroxyproline in the third position.

Subcellular location. Endoplasmic reticulum. Sarcoplasmic reticulum. Golgi apparatus.

Tissue specificity. Expression localized to the epithelia of bile ducts and to the sacroplasm of heart muscle and skeletal muscle. In the pancreas, localized to a subpopulation of Langerhans islet cells and in the salivary gland, expressed in acinar cells (at protein level). Expressed in adult heart, placenta, lung, liver, skeletal muscle and kidney. Detected in fetal heart, spleen, lung, liver skeletal muscle and kidney.

Disease relevance. Myopia, high, with cataract and vitreoretinal degeneration (MCVD) [MIM:614292] A disorder characterized by severe myopia with variable expressivity of cataract and vitreoretinal degeneration. Some patients manifest lens subluxation, lens instability and retinal detachment. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by pyridine 2,4-dicarboxylate, an analog of 2-oxoglutarate.

Similarity. Belongs to the leprecan family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q8IVL5-1	1	yes
Q8IVL5-2	2

RefSeq proteins (2): NP_001127890, NP_060662* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR005123	Oxoglu/Fe-dep_dioxygenase_dom	Domain
IPR006620	Pro_4_hyd_alph	Domain
IPR011990	TPR-like_helical_dom_sf	Homologous_superfamily
IPR039575	P3H	Family
IPR044862	Pro_4_hyd_alph_FE2OG_OXY	Domain
IPR056585	Leprecan_dom	Domain

Pfam: PF13640, PF23557

Enzyme classification (BRENDA):

• EC 1.14.11.7 — procollagen-proline 3-dioxygenase (BRENDA: 5 organisms, 27 substrates, 31 inhibitors, 8 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

7 substrates with measured Km, best-characterized 7. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
2-OXOGLUTARATE	0.003–0.08	2
(GLY-L-PRO-L-4-HYDROXYPROLINE)5	0.07	1
L-LEU-L-ASN-GLY-L-LEU-L-4HYP-GLY-L-PRO-L-ILE-GLY	0.26	1
L-PRO-L-THR-GLY-L-PRO-L-ARG-GLY-L-PHE-L-PRO-GLY-	0.07	1
L-SER-L-LYS-GLY-L-GLU-L-GLN-GLY-L-PHE-L-MET-GLY-	0.26	1
O2	0.03	1
PROCOLLAGEN	—	1

Catalyzed reactions (Rhea), 1 shown:

• L-prolyl-[collagen] + 2-oxoglutarate + O2 = trans-3-hydroxy-L-prolyl-[collagen] + succinate + CO2 (RHEA:22872)

UniProt features (18 total): repeat 4, binding site 3, glycosylation site 2, sequence variant 2, signal peptide 1, chain 1, splice variant 1, sequence conflict 1, domain 1, short sequence motif 1, active site 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IVL5-F1	83.62	0.60

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 662

Ligand- & substrate-binding residues (3): 582; 652; 580

Glycosylation sites (2): 449, 549

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-1650814	Collagen biosynthesis and modifying enzymes

MSigDB gene sets: 187 (showing top): GOMF_OXIDOREDUCTASE_ACTIVITY_ACTING_ON_PAIRED_DONORS_WITH_INCORPORATION_OR_REDUCTION_OF_MOLECULAR_OXYGEN, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, HUPER_BREAST_BASAL_VS_LUMINAL_UP, GATA1_04, CHARAFE_BREAST_CANCER_LUMINAL_VS_BASAL_DN, NAKAYAMA_SOFT_TISSUE_TUMORS_PCA2_DN, GOBP_PEPTIDYL_PROLINE_MODIFICATION, GOCC_BASEMENT_MEMBRANE, CUI_TCF21_TARGETS_2_DN, MARTORIATI_MDM4_TARGETS_FETAL_LIVER_UP, NAKAMURA_METASTASIS_MODEL_DN, LIEN_BREAST_CARCINOMA_METAPLASTIC_VS_DUCTAL_UP, GOBP_PROTEIN_HYDROXYLATION, WANG_HCP_PROSTATE_CANCER, GOCC_ENDOPLASMIC_RETICULUM_LUMEN

GO Biological Process (3): negative regulation of cell population proliferation (GO:0008285), peptidyl-proline hydroxylation (GO:0019511), collagen metabolic process (GO:0032963)

GO Molecular Function (8): iron ion binding (GO:0005506), procollagen-proline 3-dioxygenase activity (GO:0019797), L-ascorbic acid binding (GO:0031418), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen (GO:0016705), metal ion binding (GO:0046872), dioxygenase activity (GO:0051213)

GO Cellular Component (7): basement membrane (GO:0005604), nucleoplasm (GO:0005654), endoplasmic reticulum (GO:0005783), endoplasmic reticulum lumen (GO:0005788), Golgi apparatus (GO:0005794), cytosol (GO:0005829), sarcoplasmic reticulum (GO:0016529)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Collagen formation	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cytoplasm	3
oxidoreductase activity	2
cellular anatomical structure	2
endomembrane system	2
intracellular membrane-bounded organelle	2
endoplasmic reticulum	2
cell population proliferation	1
regulation of cell population proliferation	1
negative regulation of cellular process	1
protein hydroxylation	1
peptidyl-proline modification	1
metabolic process	1
transition metal ion binding	1
procollagen-proline dioxygenase activity	1
peptidyl-proline 3-dioxygenase activity	1
vitamin binding	1
carboxylic acid binding	1
monosaccharide binding	1
heterocyclic compound binding	1
binding	1
catalytic activity	1
cation binding	1
extracellular matrix	1
nuclear lumen	1
intracellular organelle lumen	1
sarcoplasm	1

Protein interactions and networks

STRING

800 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
P3H2	P4HA2	O15460	886
P3H2	P4HA1	P13674	779
P3H2	ZNF644	Q9H582	670
P3H2	P4HB	P07237	664
P3H2	SLC39A5	Q6ZMH5	628
P3H2	SCO2	O43819	610
P3H2	LRPAP1	P30533	566
P3H2	CTSH	P09668	526
P3H2	P4HA3	Q7Z4N8	484
P3H2	ADAMTSL4	Q6UY14	478
P3H2	COL6A2	P12110	463
P3H2	PLOD1	Q02809	451
P3H2	PCOLCE	Q15113	448
P3H2	CHADL	Q6NUI6	410
P3H2	CPAMD8	Q8IZJ3	401

IntAct

52 interactions, top by confidence:

A	B	Type	Score
CPSF6	NUDT21	psi-mi:“MI:0914”(association)	0.890
PRELID1	TRIAP1	psi-mi:“MI:0914”(association)	0.730
ZNF219	CDK2AP1	psi-mi:“MI:0914”(association)	0.640
BCL7A	ARID1A	psi-mi:“MI:0914”(association)	0.640
CCDC120	AIP	psi-mi:“MI:0914”(association)	0.640
HOXC9	AHCYL1	psi-mi:“MI:0914”(association)	0.640
TSC22D4	TSC22D2	psi-mi:“MI:0914”(association)	0.640
ZNF397	ZNF213	psi-mi:“MI:0914”(association)	0.640
ZNF414	AHCYL1	psi-mi:“MI:0914”(association)	0.640
RBMX	PTCD1	psi-mi:“MI:0914”(association)	0.530
ALX3	CRTAP	psi-mi:“MI:0914”(association)	0.530
EDA	AP3B1	psi-mi:“MI:0914”(association)	0.530
THAP3	CASC3	psi-mi:“MI:0914”(association)	0.530
KRBA1	TRIM27	psi-mi:“MI:0914”(association)	0.530
LAIR2	LAMA5	psi-mi:“MI:0914”(association)	0.530
ATM	RBM47	psi-mi:“MI:0914”(association)	0.350
CCNA2	ZC3H18	psi-mi:“MI:0914”(association)	0.350
MYH13	C1orf226	psi-mi:“MI:0914”(association)	0.350
NUDT21	ZBTB48	psi-mi:“MI:0914”(association)	0.350
Srsf1	SRRM1	psi-mi:“MI:0914”(association)	0.350
RNPS1	CSNK2A1	psi-mi:“MI:0914”(association)	0.350
EDA	AP3B1	psi-mi:“MI:0914”(association)	0.350
COLQ	PLOD2	psi-mi:“MI:0914”(association)	0.350
ZNF232	ZNF197	psi-mi:“MI:0914”(association)	0.350
KRBA1	TOMM40	psi-mi:“MI:0914”(association)	0.350

BioGRID (43): P3H2 (Affinity Capture-MS), P3H2 (Affinity Capture-MS), P3H2 (Affinity Capture-MS), P3H2 (Affinity Capture-MS), P3H2 (Affinity Capture-MS), P3H2 (Affinity Capture-MS), P3H2 (Affinity Capture-MS), P3H2 (Affinity Capture-MS), P3H2 (Affinity Capture-MS), P3H2 (Affinity Capture-MS), P3H2 (Affinity Capture-MS), P3H2 (Affinity Capture-MS), P3H2 (Affinity Capture-MS), P3H2 (Affinity Capture-MS), P3H2 (Affinity Capture-MS)

ESM2 similar proteins: A2ARP1, A2VDZ5, A7SAZ1, B4K4M0, B4LZT9, D3Z7H8, O00562, O08721, O08722, O14976, O35954, O75460, P0C644, P52802, Q2TA35, Q3SZL5, Q3V1T4, Q4KLM6, Q5RCC0, Q5U2N3, Q5XI31, Q5XIL0, Q5ZLK8, Q68J42, Q6AY64, Q6DIW0, Q6JHU7, Q6NZZ3, Q6PD26, Q6ZN44, Q7T2Z5, Q7Z4R8, Q8BH02, Q8CG71, Q8IUL8, Q8IVL5, Q8IZJ1, Q8K1S3, Q8K1S4, Q8N159

Diamond homologs: O75718, Q32P28, Q3V1T4, Q4KLM6, Q64375, Q6JHU7, Q6JHU8, Q8CG71, Q8IVL5, Q8K2B0, Q90830, Q92791, Q9CYD3, Q9R1J8, Q6PK18, Q8CG70, Q8IVL6, Q5M843, Q5XGE0, Q9D136

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 72 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
mRNA 3’-end processing	6	24.6×	5e-05
RNA Polymerase II Transcription Termination	5	22.9×	4e-04
Dengue Virus-Host Interactions	7	6.7×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

737 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	35
Likely pathogenic	14
Uncertain significance	328
Likely benign	245
Benign	83

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1070342	NM_018192.4(P3H2):c.233_258dup (p.His87fs)	Pathogenic
1070875	NM_018192.4(P3H2):c.976del (p.Leu326fs)	Pathogenic
1073024	NM_018192.4(P3H2):c.389del (p.Gly130fs)	Pathogenic
1073361	NM_018192.4(P3H2):c.1615C>T (p.Arg539Ter)	Pathogenic
1332864	NM_018192.4(P3H2):c.1782G>A (p.Trp594Ter)	Pathogenic
1363412	NM_018192.4(P3H2):c.1638del (p.Phe546fs)	Pathogenic
1384187	NM_018192.4(P3H2):c.1126A>T (p.Lys376Ter)	Pathogenic
1386761	NM_018192.4(P3H2):c.1208del (p.Gly403fs)	Pathogenic
1449634	NM_018192.4(P3H2):c.952C>T (p.Arg318Ter)	Pathogenic
1451124	NM_018192.4(P3H2):c.184C>T (p.Arg62Ter)	Pathogenic
1452794	NM_018192.4(P3H2):c.1336_1340del (p.Leu445_Leu446insTer)	Pathogenic
1454106	NM_018192.4(P3H2):c.1289dup (p.Leu431fs)	Pathogenic
1454421	NM_018192.4(P3H2):c.722del (p.Phe241fs)	Pathogenic
1455362	NM_018192.4(P3H2):c.1309C>T (p.Arg437Ter)	Pathogenic
1456796	NM_018192.4(P3H2):c.1510G>T (p.Glu504Ter)	Pathogenic
1458271	NM_018192.4(P3H2):c.1697_1698del (p.Ser566fs)	Pathogenic
1460022	NC_000003.11:g.(?189692327)(189692494_?)del	Pathogenic
1460245	NC_000003.11:g.(?189838021)(189838520_?)del	Pathogenic
162462	NM_018192.4(P3H2):c.556C>T (p.Gln186Ter)	Pathogenic
1912344	NM_018192.4(P3H2):c.835C>T (p.Gln279Ter)	Pathogenic
1928251	NM_018192.4(P3H2):c.415G>T (p.Glu139Ter)	Pathogenic
2022445	NM_018192.4(P3H2):c.1594del (p.Tyr532fs)	Pathogenic
2035113	NM_018192.4(P3H2):c.1415C>A (p.Ser472Ter)	Pathogenic
225632	NM_018192.4(P3H2):c.297del (p.Gly100fs)	Pathogenic
2426456	NC_000003.11:g.(?189689659)(189690833_?)del	Pathogenic
2836166	NM_018192.4(P3H2):c.96_97del (p.Glu33fs)	Pathogenic
3612440	NM_018192.4(P3H2):c.453C>G (p.Tyr151Ter)	Pathogenic
3633288	NM_018192.4(P3H2):c.1197G>A (p.Trp399Ter)	Pathogenic
3776034	NM_018192.4(P3H2):c.797_809del (p.Lys266fs)	Pathogenic
424203	NM_018192.4(P3H2):c.1726del (p.Ser576fs)	Pathogenic

SpliceAI

2899 predictions. Top by Δscore:

Variant	Effect	Δscore
3:189970808:TTAC:T	donor_loss	1.0000
3:189970809:TACT:T	donor_loss	1.0000
3:189970810:ACT:A	donor_loss	1.0000
3:189970812:TT:T	donor_loss	1.0000
3:189970813:TA:T	donor_loss	1.0000
3:189970814:A:AC	donor_gain	1.0000
3:189970814:ACAGT:A	donor_gain	1.0000
3:189970815:C:CG	donor_gain	1.0000
3:189970815:CA:C	donor_gain	1.0000
3:189970815:CAGT:C	donor_gain	1.0000
3:189970815:CAGTC:C	donor_gain	1.0000
3:189970890:CA:C	acceptor_gain	1.0000
3:189970892:C:CC	acceptor_gain	1.0000
3:189971924:T:TA	donor_gain	1.0000
3:189972952:T:TA	donor_gain	1.0000
3:189973020:CCAGA:C	acceptor_gain	1.0000
3:189973021:CAGA:C	acceptor_gain	1.0000
3:189973021:CAGAC:C	acceptor_gain	1.0000
3:189973025:C:CC	acceptor_gain	1.0000
3:189973907:A:AC	donor_gain	1.0000
3:189973908:C:CC	donor_gain	1.0000
3:189974510:T:TA	donor_gain	1.0000
3:189974536:C:A	donor_gain	1.0000
3:189974539:T:TA	donor_gain	1.0000
3:189974557:CA:C	donor_gain	1.0000
3:189983045:CCTT:C	donor_gain	1.0000
3:189984544:ACTT:A	donor_loss	1.0000
3:189984545:CTT:C	donor_loss	1.0000
3:189984546:TTA:T	donor_loss	1.0000
3:189984547:T:TG	donor_loss	1.0000

AlphaMissense

4595 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
3:189963990:A:G	W668R	1.000
3:189963990:A:T	W668R	1.000
3:189964060:G:C	F644L	1.000
3:189964060:G:T	F644L	1.000
3:189964062:A:G	F644L	1.000
3:189964073:C:G	R640P	1.000
3:189971955:A:C	C584W	1.000
3:189971956:C:A	C584F	1.000
3:189971956:C:G	C584S	1.000
3:189971956:C:T	C584Y	1.000
3:189971957:A:G	C584R	1.000
3:189971957:A:T	C584S	1.000
3:189971962:T:A	D582V	1.000
3:189971979:A:C	S576R	1.000
3:189971979:A:T	S576R	1.000
3:189971981:T:G	S576R	1.000
3:189957992:C:G	A683P	0.999
3:189958000:C:G	R680P	0.999
3:189963986:A:G	F669S	0.999
3:189963988:C:A	W668C	0.999
3:189963988:C:G	W668C	0.999
3:189963992:A:G	L667P	0.999
3:189964006:C:A	R662S	0.999
3:189964006:C:G	R662S	0.999
3:189964007:C:A	R662M	0.999
3:189964022:A:T	V657D	0.999
3:189964034:C:T	G653E	0.999
3:189964035:C:A	G653W	0.999
3:189964038:G:C	H652D	0.999
3:189964042:G:C	N650K	0.999

dbSNP variants (sampled 300 via entrez): RS1000052201 (3:190045462 T>C), RS1000064735 (3:190084297 T>C), RS1000073909 (3:190124035 G>A), RS1000082597 (3:190049148 T>C), RS1000100094 (3:189956593 G>A), RS1000125701 (3:190090074 C>T), RS1000154051 (3:190101588 G>A), RS1000154301 (3:190039195 A>T), RS1000213311 (3:190054797 T>C), RS1000240080 (3:190090095 A>G), RS1000246475 (3:190015461 A>C,G), RS1000251881 (3:190108003 C>T), RS1000265973 (3:189973538 T>A), RS1000280233 (3:189979823 C>G,T), RS1000288443 (3:190096091 G>A)

Disease associations

OMIM: gene MIM:610341 | disease phenotypes: MIM:614292, MIM:160700, MIM:268000

GenCC curated gene-disease

Disease	Classification	Inheritance
myopia, high, with cataract and vitreoretinal degeneration	Strong	Autosomal recessive

Mondo (3): myopia, high, with cataract and vitreoretinal degeneration (MONDO:0013670), myopia (MONDO:0001384), retinitis pigmentosa (MONDO:0019200)

Orphanet (2): Rare isolated myopia (Orphanet:98619), Retinitis pigmentosa (Orphanet:791)

HPO phenotypes

10 total (11 of 10 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000518	Cataract
HP:0000541	Retinal detachment
HP:0001132	Lens subluxation
HP:0007992	Lattice retinal degeneration
HP:0011003	High myopia
HP:0011463	Childhood onset
HP:0032037	Mildly reduced visual acuity
HP:0100832	Vitreous floaters
HP:0200071	Peripheral vitreoretinal degeneration
HP:0000545	Myopia

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST004862_45	Itch intensity from mosquito bite adjusted by bite size	2.000000e-06
GCST006631_37	Nicotine dependence and major depression (severity of comorbidity)	3.000000e-06
GCST011985_4	Congenital heart disease (septal defects)	2.000000e-08
GCST90002400_420	Plateletcrit	3.000000e-17
GCST90002401_139	Platelet distribution width	2.000000e-09
GCST90002402_671	Platelet count	3.000000e-11

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0008377	mosquito bite reaction itch intensity measurement
EFO:0008378	mosquito bite reaction size measurement
EFO:0007006	depressive symptom measurement
EFO:0009262	nicotine dependence symptom count
EFO:0007985	platelet crit
EFO:0007984	platelet component distribution width
EFO:0004309	platelet count

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D009216	Myopia	C11.744.636
D012174	Retinitis Pigmentosa	C11.270.684; C11.768.585.658.500; C16.320.290.684

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

51 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects methylation, decreases expression, increases expression, increases methylation	3
Valproic Acid	increases expression	3
bisphenol A	decreases methylation, decreases expression	2
sodium arsenite	decreases expression	2
entinostat	increases expression, affects cotreatment	2
Cisplatin	affects response to substance, increases expression	2
Phenylmercuric Acetate	increases expression, affects cotreatment	2
Progesterone	affects cotreatment, increases expression	2
sotorasib	affects cotreatment, increases expression	1
2,5,2’,5’-tetrachlorobiphenyl	increases expression	1
3,4,5,3’,4’-pentachlorobiphenyl	decreases expression	1
cupric chloride	decreases expression	1
S-(1,2-dichlorovinyl)cysteine	decreases reaction, increases expression, decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	increases expression, affects cotreatment	1
abrine	increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
bisphenol S	affects expression	1
jinfukang	decreases expression	1
incobotulinumtoxinA	decreases expression	1
NSC 689534	increases expression	1
trametinib	affects cotreatment, increases expression	1
NVP-BKM120	affects cotreatment, increases expression	1
Temozolomide	increases expression	1
Sunitinib	increases expression	1
Zoledronic Acid	decreases expression	1
Acetaminophen	increases expression	1
Ethanol	affects cotreatment, increases expression	1
Arsenic	decreases expression	1

Clinical trials (associated diseases)

300 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00347204	PHASE4	COMPLETED	Comparison of Acular LS Versus Nevanac for Pain Control in Eyes Undergoing PRK
NCT00349843	PHASE4	COMPLETED	Investigation of Multi-Purpose Solution-Based Corneal Staining and Ocular Comfort
NCT00349882	PHASE4	COMPLETED	Effects of Contact Lens Care Regimens on the Corneal Epithelium
NCT00350246	PHASE4	COMPLETED	Long-term Effects of Laser Refractive Surgery
NCT00404105	PHASE4	COMPLETED	A Comparison of PRK and LASIK for Correction of Myopia
NCT00455455	PHASE4	COMPLETED	Corneal and Conjunctival Sensitivity and Staining Study
NCT00541177	PHASE4	UNKNOWN	Study of Myopia Prevention in Children With Low Concentration of Atropine
NCT00627302	PHASE4	COMPLETED	Efficacy of PEG-400 and Systane Artificial Tears (Alcon) on Quality of Vision
NCT00640341	PHASE4	COMPLETED	Comparative Performance of PureVision, Acuvue Oasys and O2Optix
NCT00770094	PHASE4	UNKNOWN	Multi Laser Platform Comparison Study for LASIK
NCT00821236	PHASE4	COMPLETED	Contralateral Comparison of Three Excimer Laser Systems in Performing LASIK
NCT00889941	PHASE4	COMPLETED	Effect of Preoperative Pupil Size on Quality of Vision After Wavefront-Guided LASIK
NCT00937105	PHASE4	COMPLETED	Daily Wear Corneal Infiltrative Event Study
NCT01173198	PHASE4	COMPLETED	An Evaluation of Outcomes Following Wavefront Optimized or Wavefront Guided Lasik Procedure in Low to Moderate Myopic Patients
NCT01250925	PHASE4	COMPLETED	Effect of Contact Lens Wear on Immune Cell Density and Morphology of the Ocular Surface
NCT01387360	PHASE4	COMPLETED	Presbyopic Supracor Treatment for Near Myopic/Hyperopic Pseudophakic Eyes
NCT01454843	PHASE4	COMPLETED	LASIK Using the Alcon Allegretto Wavefront-Guided Excimer Laser vs AMO Visx Wavefront-Guided Excimer Laser
NCT01693939	PHASE4	COMPLETED	Evaluation of the Post-LASIK Flap Thickness of the FS200 Femtosecond Laser Flap
NCT01706237	PHASE4	WITHDRAWN	Visual Outcomes And Contrast Sensitivity After Myopic Wavefront-Optimized Lasik With Nexisvision Shield Or Bandage Contact Lens
NCT01746589	PHASE4	COMPLETED	Visual Outcomes and Contrast Sensitivity After Myopic LASIK
NCT01977807	PHASE4	UNKNOWN	A Prospective Safety and Effectiveness Study of the 500 Hz Technolas Perfect Vision Excimer Laser in Asian Eyes Using LASIK
NCT02071576	PHASE4	UNKNOWN	A Prospective Safety and Effectiveness Study of the 500 Hz Technolas Perfect Vision Excimer Laser Using LASIK
NCT02112968	PHASE4	UNKNOWN	A Prospective Safety and Effectiveness Study of a New High Repetition Rate Excimer Laser Using LASIK for the Correction of Ammetropia and Presbyopia
NCT02186184	PHASE4	COMPLETED	Effect of Orthokeratology Versus Spectacles on Myopia Progression in Chinese Children: A Crossover Trial
NCT02544529	PHASE4	WITHDRAWN	Echothiophate Iodide for the Prevention of Progression of Myopia
NCT03001401	PHASE4	UNKNOWN	Comparison of Next Generation Laser Techniques of Myopia Correction: iDesign vs. SMILE
NCT03158142	PHASE4	COMPLETED	The Influence of Atropine on Choroidal Thickness
NCT03544827	PHASE4	COMPLETED	The Effects of Low Dose Atropine on Choroidal Thickness
NCT03881670	PHASE4	COMPLETED	On-Eye Optical Quality of Lotrafilcon B Lenses Over 12 Hours
NCT03949101	PHASE4	UNKNOWN	Atropine for Children and Adolescent Myopia Progression Study
NCT04208750	PHASE4	COMPLETED	Clinical Investigation of the Vision-R800 Device.
NCT04283331	PHASE4	UNKNOWN	Anesthetic Impregnated Bandage Soft Contact Lens (BSCL) in Pain Management After Photorefractive Keratectomy (PRK)
NCT05357326	PHASE4	UNKNOWN	Myopia Intervention in Children and Adolescents and Establishment of a Precise Intervention Model
NCT05448989	PHASE4	UNKNOWN	Efficacy and Safety of 1% Atropine 5+3 Regimen in Children and Adolescents Controlling Myopia
NCT05449015	PHASE4	UNKNOWN	Study on the Effect of Two Ways of Cycloplegia on Biological Parameters of Ciliary Muscle
NCT05733741	PHASE4	COMPLETED	Preservative-free Topical Anesthetics for Post-PRK Pain
NCT05803863	PHASE4	UNKNOWN	Efficacy Comparison of 2 Low-dose Atropine Eye Drops in Vietnamese Children Myopia Management
NCT06431841	PHASE4	ACTIVE_NOT_RECRUITING	Atropine and Spectacle Combination Treatment (ASPECT): 12-month Results of a Randomized Clinical Trial for Myopia Control
NCT06450132	PHASE4	ACTIVE_NOT_RECRUITING	Changes in Eye Shape With Myopia Management Interventions
NCT06553404	PHASE4	ACTIVE_NOT_RECRUITING	Myoslow Lens Study to Control Myopia in Children