MIP

Summary

MIP (major intrinsic protein of lens fiber, HGNC:7103) is a protein-coding gene on chromosome 12q13.3, encoding Lens fiber major intrinsic protein (P30301). Aquaporins form homotetrameric transmembrane channels, with each monomer independently mediating water transport across the plasma membrane along its osmotic gradient.

Major intrinsic protein is a member of the water-transporting aquaporins as well as the original member of the MIP family of channel proteins. The function of the fiber cell membrane protein encoded by this gene is undetermined, yet this protein is speculated to play a role in intracellular communication. The MIP protein is expressed in the ocular lens and is required for correct lens function. This gene has been mapped among aquaporins AQP2, AQP5, and AQP6, in a potential gene cluster at 12q13.

Source: NCBI Gene 4284 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cataract 15 multiple types (Definitive, GenCC) — +6 more curated relationships
• Clinical variants (ClinVar): 119 total — 15 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 1
• MANE Select transcript: NM_012064

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:7103
Approved symbol	MIP
Name	major intrinsic protein of lens fiber
Location	12q13.3
Locus type	gene with protein product
Status	Approved
Aliases	MP26, LIM1, AQP0
Ensembl gene	ENSG00000135517
Ensembl biotype	protein_coding
OMIM	154050
Entrez	4284

Gene structure

Transcript identifiers

Ensembl transcripts: 4 — 2 protein_coding_CDS_not_defined, 1 retained_intron, 1 protein_coding

ENST00000555551, ENST00000648442, ENST00000650166, ENST00000652304

RefSeq mRNA: 1 — MANE Select: NM_012064 NM_012064

CCDS: CCDS8919

Canonical transcript exons

ENST00000652304 — 4 exons

Exon	Start	End
ENSE00001181722	56449502	56451465
ENSE00003435175	56453072	56453152
ENSE00003505886	56453591	56453755
ENSE00003850042	56454254	56454657

Expression profiles

Bgee: expression breadth broad, 91 present calls, max score 81.65.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.0620 / max 63.5586, expressed in 8 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
131526	0.0620	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.65	silver quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	79.13	silver quality
right lobe of liver	UBERON:0001114	66.11	gold quality
liver	UBERON:0002107	61.29	gold quality
apex of heart	UBERON:0002098	51.85	gold quality
right adrenal gland cortex	UBERON:0035827	50.55	gold quality
right testis	UBERON:0004534	49.80	gold quality
testis	UBERON:0000473	49.37	gold quality
left testis	UBERON:0004533	49.07	gold quality
bone marrow cell	CL:0002092	48.56	gold quality
right adrenal gland	UBERON:0001233	47.98	gold quality
left adrenal gland	UBERON:0001234	47.27	gold quality
body of pancreas	UBERON:0001150	46.82	gold quality
left adrenal gland cortex	UBERON:0035825	46.61	gold quality
ventricular zone	UBERON:0003053	46.20	gold quality
adrenal gland	UBERON:0002369	45.75	gold quality
tonsil	UBERON:0002372	45.68	gold quality
mucosa of transverse colon	UBERON:0004991	45.47	gold quality
right atrium auricular region	UBERON:0006631	45.28	gold quality
pancreas	UBERON:0001264	44.41	gold quality
calcaneal tendon	UBERON:0003701	43.58	gold quality
placenta	UBERON:0001987	42.93	gold quality
colonic epithelium	UBERON:0000397	42.47	gold quality
granulocyte	CL:0000094	40.94	gold quality
primary visual cortex	UBERON:0002436	40.83	gold quality
prefrontal cortex	UBERON:0000451	40.41	gold quality
skeletal muscle tissue	UBERON:0001134	40.09	gold quality
endometrium	UBERON:0001295	39.89	silver quality
sural nerve	UBERON:0015488	39.65	gold quality
rectum	UBERON:0001052	39.43	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.25

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

104 targeting MIP, 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-4510	100.00	66.60	2050
HSA-MIR-6127	100.00	66.76	2188
HSA-MIR-6129	100.00	66.46	2080
HSA-MIR-6130	100.00	66.69	2012
HSA-MIR-6133	100.00	66.48	2064
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6825-5P	99.96	69.81	3431
HSA-MIR-4267	99.96	66.53	2368
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-627-3P	99.90	71.42	3316
HSA-MIR-548E-5P	99.89	72.73	4486
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-6124	99.87	69.78	3551
HSA-MIR-3151-5P	99.86	63.83	1069
HSA-MIR-6079	99.84	68.54	1170
HSA-MIR-1321	99.84	65.30	1811
HSA-MIR-4756-5P	99.84	64.98	1809

Literature-anchored findings (GeneRIF, showing 40)

• In human, multiple aquaporins are expressed in developing teeth and in selected orofacial tissues. (PMID:12522663)
• Analysis of C-terminal peptides of AQP0 from normal lenses of donors aged 34 to 38 reveals a remarkably similar pattern and distribution of truncation products, suggesting specific temporal mechanisms for post-translational modification of AQP0. (PMID:15274640)
• Expression of hMafF or MIP alone did not alter basal reporter transcription activity, whereas co-expression of hMafF and MIP activated transcription efficiently. (PMID:16549056)
• We identified a novel single base pair deletion in the MIP gene and conclude that it is a pathogenic sequence alteration. (PMID:16564824)
• First dominant cataract mutation in MIP that is located outside the phylogenetically conserved transmembrane domain. (PMID:17893667)
• The structure of aquaporin-0 (AQP0) has recently been determined by electron crystallography of two-dimensional crystals and by X-ray crystallography of three-dimensional crystals–REVIEW (PMID:17932686)
• Arginine in this domain plays a crucial role in the function of the carboxyl-end of this protein and provides a helpful clue to further studies on completely understanding the physiological significance of MIP and its role in the formation of cataract. (PMID:17960133)
• presence of measurable interactions between MIP26 and all crystallins, with the extent of interactions decreasing from alphaA- and alphaB-crystallin to betaB2- and gammaC-crystallin. (PMID:18004741)
• To map the disease locus for a congenital cataract family, and detect the disease-causing gene. (PMID:18247294)
• deletion mutation in AQP0 resulted in the localization of the mutant protein in the ER without trafficking to the plasma membrane, and cytotoxicity due to the accumulation of the mutant protein (PMID:18501347)
• This is the first report on an acceptor splice-site mutation in human genes associated with dominant congenital cataract. (PMID:19137077)
• Only in the presence of both MIP and hMafF could the nUS2-pLacZi reporter in yeast genome be activated. (PMID:19723544)
• this is the first report validating the possible structural role of intact AQP0 as a cell-to-cell adhesion protein, using an in vitro expression system. (PMID:19857466)
• This study has identified a novel MIP mutation, p.V107I in a Chinese family with congenital cataracts. (PMID:20361015)
• This is the first report of activation of a cryptic splice site in the 3’ UTR in the human MIP gene. (PMID:21139677)
• AQP-0 gene expression was 3.4-fold higher in rat retinas. AQP-0 was predominantly expressed in the bipolar cells of the non-diabetic rat retinas, whereas it was also expressed in the retinal nerve fibers of diabetic rat retinas (PMID:21232536)
• analysis of a novel disease-causing mutation p.R187C in MIP in a Chinese cataract family (PMID:21245956)
• A novel mutation in the MIP gene is associated with autosomal dominant congenital nuclear cataract in a Chinese family. (PMID:21647270)
• Cerulean cataract has been mapped to chromosome 12q13 and associated with a novel initiation codon mutation in MIP. (PMID:21850180)
• Major intrinsic protein (MIP) polymorphism is associated with age-related cataract in Chinese. (PMID:21921980)
• Direct tissue analysis led to the detection of aging-related AQP0 modifications including carbamylation, acetylation, and oleoylation. (PMID:22036630)
• Aquaporin 0 R233K mutation did not affect the expression, location and trafficking of the protein but did influence the interaction between AQP0 and CaM. (PMID:22662182)
• Mutation of this conserved glycine residue leads to improper trafficking of AQP0-G165D and loss of water channel function. (PMID:23116563)
• A novel donor splice-site mutation (c.606+1G>A) in the MIP gene causes congenital cataract in a Chinese family. (PMID:24319327)
• the first nonsense mutation of MIP identified in autosomal dominant congenital cataracts (PMID:24405844)
• Functional evidence linking the new MIP mutation of G215D to autosomal dominant congenital cataracts. (PMID:25033405)
• Authors identified a novel nonsense mutation in MIP (c.657 C>G; p.Y219*) (major intrinsic protein gene) that segregates with congenital posterior polar cataract in a Chinese family. (PMID:25803033)
• the p.D150H mutation is a novel disease-causing mutation in MIP, which leads to congenital progressive cortical punctate cataract by impairing the trafficking mechanism of AQP0. (PMID:25946197)
• defects in AQP-0 permeability may be a cause for presbyopia. (PMID:26615967)
• The data evidence a broad lipidation profile of AQP0 that is both species and site independent, suggesting a chemical-based ester aminolysis mechanism to explain such modifications. (PMID:27378310)
• A novel MIP frame-shift mutation in familial congenital nuclear cataract patient (PMID:27456987)
• Study presented genetic and functional evidence for a novel major intrinsic protein mutation of G212R, which leads to congenital progressive cortical punctate with or without Y suture. (PMID:28059152)
• In summary, whole-exome sequencing identifies a novel heterozygous missense variant (c.402G > T) in rarely reported cataract gene of MIP in an unconsanguineous marriage of three-generation Chinese family with congenital cataracts. (PMID:28836894)
• Our study generated genetic and primary functional evidence for a novel c.682_683delAA mutation in MIP that expands the variant spectrum of MIP and help us better understand the molecular basis of cataract. (PMID:29695758)
• The novel missense mutation c.572C>Gp.P191Rat exon 3 of the MIP gene was identified in a Chinese family of congenital cataract. The mutation affects the traffic of MIP protein in the cells and reduces the expression level of MIP protein in the cell membrane. (PMID:29947569)
• AQP0 is a novel surface marker for deciphering abnormal erythropoiesis. (PMID:33957977)
• Anterior Umbilication of Lens in a Family with Congenital Cataracts Associated with a Missense Mutation of MIP Gene. (PMID:36360224)
• First implication of MIP in bilateral microphthalmia with persistent fetal vasculature. (PMID:36734406)
• The role of phosphorylation in calmodulin-mediated gating of human AQP0. (PMID:38032258)
• A novel single-base deletional mutation of MIP impairs protein distribution and cell-to-cell adhesion in autosomal dominant cataracts in a Chinese family. (PMID:38153133)

Cross-species orthologs

8 orthologs

Organism	Symbol	Gene ID
danio_rerio	mipb	ENSDARG00000013963
danio_rerio	mipa	ENSDARG00000037285
mus_musculus	Mip	ENSMUSG00000025389
rattus_norvegicus	Mip	ENSRNOG00000003132
drosophila_melanogaster	Eglp1	FBGN0034882
drosophila_melanogaster	Eglp2	FBGN0034883
drosophila_melanogaster	Eglp3	FBGN0034884
drosophila_melanogaster	Eglp4	FBGN0034885

Paralogs (11): AQP6 (ENSG00000086159), AQP8 (ENSG00000103375), AQP9 (ENSG00000103569), AQP10 (ENSG00000143595), AQP5 (ENSG00000161798), AQP7 (ENSG00000165269), AQP3 (ENSG00000165272), AQP2 (ENSG00000167580), AQP4 (ENSG00000171885), AQP1 (ENSG00000240583), AQP7B (ENSG00000259916)

Protein

Protein identifiers

Lens fiber major intrinsic protein — P30301 (reviewed: P30301)

Alternative names: Aquaporin-0, MIP26

All UniProt accessions (1): P30301

UniProt curated annotations — full annotation on UniProt →

Function. Aquaporins form homotetrameric transmembrane channels, with each monomer independently mediating water transport across the plasma membrane along its osmotic gradient. Specifically expressed in lens fiber cells, this aquaporin is crucial for maintaining lens water homeostasis and transparency. Beyond water permeability, it also acts as a cell-to-cell adhesion molecule, forming thin junctions between lens fiber cells that are essential for maintaining the ordered structure and transparency of the lens.

Subunit / interactions. Homotetramer; each monomer provides an independent water pore. Two homotetramers on opposing membranes can dimerize, forming a cell-cell junction. Interacts with CALM; the calcium-calmodulin/CALM complex interacts with the cytoplasmic domains of two aquaporins, leading to channel closure. Interacts with BFSP1 (via C-terminus); prevents calcium-dependent inhibition of the water channel activity.

Subcellular location. Cell membrane. Cell junction.

Tissue specificity. Expressed in the cortex and nucleus of the retina lens (at protein level). Major component of lens fiber gap junctions.

Post-translational modifications. Subject to partial proteolytic cleavage in the eye lens core. Partial proteolysis promotes interactions between tetramers from adjoining membranes. Fatty acylated at Met-1 and Lys-238. The acyl modifications, in decreasing order of ion abundance, are: oleoyl (C18:1) > palmitoyl (C16:0) > stearoyl (C18:0) > eicosenoyl (C20:1) > dihomo-gamma-linolenoyl (C20:3) > palmitoleoyl (C16:1) > eicosadienoyl (C20:2).

Disease relevance. Cataract 15, multiple types (CTRCT15) [MIM:615274] An opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. CTRCT15 includes polymorphic, progressive punctate lamellar, cortical, anterior and posterior polar, nonprogressive lamellar with sutural opacities, embryonic nuclear, and pulverulent cortical, among others. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. The water channel activity is inhibited by calcium through calmodulin/CALM.

Domain organisation. Aquaporins contain two tandem repeats each containing three membrane-spanning domains and a pore-forming loop with the signature motif Asn-Pro-Ala (NPA).

Similarity. Belongs to the MIP/aquaporin (TC 1.A.8) family.

RefSeq proteins (1): NP_036196* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000425	MIP	Family
IPR022357	MIP_CS	Conserved_site
IPR023271	Aquaporin-like	Homologous_superfamily
IPR034294	Aquaporin_transptr	Family

Pfam: PF00230

Catalyzed reactions (Rhea), 1 shown:

• H2O(in) = H2O(out) (RHEA:29667)

UniProt features (39 total): sequence variant 11, topological domain 9, transmembrane region 6, modified residue 4, site 3, intramembrane region 2, short sequence motif 2, chain 1, region of interest 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P30301-F1	91.08	0.81

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 (3): 149 (important for water channel gating); 246 (interaction with bfsp1); 250 (interaction with bfsp1)

Post-translational modifications (4): 235, 245, 246, 259

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-432047	Passive transport by Aquaporins
R-HSA-382551	Transport of small molecules
R-HSA-445717	Aquaporin-mediated transport

MSigDB gene sets: 126 (showing top): SP3_Q3, GOBP_CELL_CELL_ADHESION, GOBP_WATER_TRANSPORT, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, ARGGGTTAA_UNKNOWN, GOCC_APICAL_PLASMA_MEMBRANE, GOBP_MULTICELLULAR_ORGANISMAL_LEVEL_HOMEOSTASIS, GOBP_SENSORY_PERCEPTION, GOBP_HOMOTYPIC_CELL_CELL_ADHESION, GOBP_SENSORY_ORGAN_DEVELOPMENT, GOBP_TRANSMEMBRANE_TRANSPORT, PITX2_Q2, GOBP_LENS_DEVELOPMENT_IN_CAMERA_TYPE_EYE, GOBP_FLUID_TRANSPORT, GOCC_APICAL_PART_OF_CELL

GO Biological Process (7): lens development in camera-type eye (GO:0002088), water transport (GO:0006833), visual perception (GO:0007601), homotypic cell-cell adhesion (GO:0034109), maintenance of lens transparency (GO:0036438), gap junction-mediated intercellular transport (GO:1990349), transmembrane transport (GO:0055085)

GO Molecular Function (6): structural constituent of eye lens (GO:0005212), calmodulin binding (GO:0005516), water channel activity (GO:0015250), cell adhesion mediator activity (GO:0098631), protein binding (GO:0005515), channel activity (GO:0015267)

GO Cellular Component (4): plasma membrane (GO:0005886), apical plasma membrane (GO:0016324), anchoring junction (GO:0070161), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Aquaporin-mediated transport	1
Transport of small molecules	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
camera-type eye development	1
anatomical structure development	1
fluid transport	1
sensory perception of light stimulus	1
cell-cell adhesion	1
tissue homeostasis	1
intercellular transport	1
transport	1
cellular process	1
structural molecule activity	1
protein binding	1
water transmembrane transporter activity	1
channel activity	1
cell adhesion	1
cell adhesion molecule binding	1
binding	1
passive transmembrane transporter activity	1
membrane	1
cell periphery	1
apical part of cell	1
plasma membrane region	1
cell junction	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2315 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MIP	CALML6	Q8TD86	982
MIP	CALML3	P27482	982
MIP	CALML5	Q9NZT1	982
MIP	CALML4	Q96GE6	982
MIP	GJA8	P48165	957
MIP	BFSP1	Q12934	936
MIP	CALM1	P02593	923
MIP	AQP12A	Q8IXF9	899
MIP	AQP10	Q96PS8	889
MIP	AQP11	Q8NBQ7	886
MIP	LIM2	P55344	868
MIP	GJA3	Q9Y6H8	821
MIP	BFSP2	Q13515	775
MIP	CRYGS	P22914	723
MIP	GJC1	P36383	687

IntAct

129 interactions, top by confidence:

A	B	Type	Score
MIP	LRP10	psi-mi:“MI:0915”(physical association)	0.560
MIP	TM4SF18	psi-mi:“MI:0915”(physical association)	0.560
MIP	AMIGO1	psi-mi:“MI:0915”(physical association)	0.560
MIP	SLC14A1	psi-mi:“MI:0915”(physical association)	0.560
MIP	FCGR2A	psi-mi:“MI:0915”(physical association)	0.560
MIP	LRRC4C	psi-mi:“MI:0915”(physical association)	0.560
MIP	SAR1A	psi-mi:“MI:0915”(physical association)	0.560
MIP	ERVFRD-1	psi-mi:“MI:0915”(physical association)	0.560
MIP	ERGIC3	psi-mi:“MI:0915”(physical association)	0.560
MIP	STX2	psi-mi:“MI:0915”(physical association)	0.560
MIP	STX1A	psi-mi:“MI:0915”(physical association)	0.560
MIP	MFF	psi-mi:“MI:0915”(physical association)	0.560
MIP	CISD2	psi-mi:“MI:0915”(physical association)	0.560
SGPL1	MIP	psi-mi:“MI:0915”(physical association)	0.560
GJB5	MIP	psi-mi:“MI:0915”(physical association)	0.560
MIP	FAM209A	psi-mi:“MI:0915”(physical association)	0.560
MIP	LHFPL5	psi-mi:“MI:0915”(physical association)	0.560
MIP	MRM3	psi-mi:“MI:0915”(physical association)	0.560
CD40	MIP	psi-mi:“MI:0915”(physical association)	0.560
MIP	GOLM1	psi-mi:“MI:0915”(physical association)	0.560
MIP	GPX8	psi-mi:“MI:0915”(physical association)	0.560
MIP	SYT2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (52): MIP (Two-hybrid), MIP (Two-hybrid), MIP (Two-hybrid), MIP (Two-hybrid), MIP (Two-hybrid), MIP (Two-hybrid), MIP (Two-hybrid), MIP (Two-hybrid), MIP (Two-hybrid), MIP (Two-hybrid), MIP (Two-hybrid), MIP (Two-hybrid), SLC14A1 (Two-hybrid), MGST3 (Two-hybrid), FCGR2A (Two-hybrid)

ESM2 similar proteins: A2IBY8, A4L9J0, A8W649, A9Y006, G5CTG2, G5CTG4, O43315, O62735, O77750, P06624, P09011, P29972, P29975, P30301, P34080, P41181, P47862, P47863, P47864, P47865, P50501, P51180, P55064, P55087, P55088, P56401, P56402, P56627, P79099, Q02013, Q06019, Q08DE6, Q13520, Q23808, Q5I4F9, Q5R819, Q6J8I9, Q6PQZ1, Q6RZ07, Q866S3

Diamond homologs: A0A125YZH9, A0A6M3QG69, A2IBY8, A4L9J0, F9UUD2, O64964, O68874, O82316, O94778, P06624, P09011, P25818, P28238, P30301, P50156, P51180, P55064, P56404, P56405, P60844, P60845, Q06019, Q0JPT5, Q13520, Q41963, Q5I4F8, Q651D5, Q6J8I9, Q6RZ07, Q6Z2T3, Q75GA5, Q7N5C1, Q7NNP3, Q7XLR1, Q84RL7, Q8GRI8, Q8X6K6, Q92R43, Q94CS9, Q9AR14

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
PRKACA	“down-regulates activity”	MIP	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 44 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
Neuronal System	5	9.6×	5e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	7
Uncertain significance	59
Likely benign	10
Benign	21

Top pathogenic / likely-pathogenic (22)

Variant ID	HGVS	Classification
1069403	NM_012064.4(MIP):c.606+1G>C	Pathogenic
14354	NM_012064.4(MIP):c.413C>G (p.Thr138Arg)	Pathogenic
14355	NM_012064.4(MIP):c.401A>G (p.Glu134Gly)	Pathogenic
1806189	NM_012064.4(MIP):c.616_632del (p.Val206fs)	Pathogenic
217342	NM_012064.4(MIP):c.97C>T (p.Arg33Cys)	Pathogenic
217345	NM_012064.4(MIP):c.597_598insGGGAACATTCCACT (p.Asn200fs)	Pathogenic
252956	NM_012064.4(MIP):c.631G>T (p.Gly211Ter)	Pathogenic
2629509	NM_012064.4(MIP):c.605G>A (p.Trp202Ter)	Pathogenic
2722298	NM_012064.4(MIP):c.606+1G>T	Pathogenic
377392	NM_012064.4(MIP):c.508dup (p.Leu170fs)	Pathogenic
432015	NM_012064.4(MIP):c.698G>A (p.Arg233Lys)	Pathogenic
4727827	NM_012064.4(MIP):c.162dup (p.Leu55fs)	Pathogenic
4734471	NM_012064.4(MIP):c.530_531del (p.Tyr177fs)	Pathogenic
474241	NM_012064.4(MIP):c.623del (p.Pro208fs)	Pathogenic
992878	NM_012064.4(MIP):c.615G>A (p.Trp205Ter)	Pathogenic
1176948	NM_012064.4(MIP):c.698_699del (p.Arg233fs)	Likely pathogenic
1703071	NM_012064.4(MIP):c.559del (p.Arg187fs)	Likely pathogenic
3061915	NM_012064.4(MIP):c.493_494insT (p.Gly165fs)	Likely pathogenic
3345576	NM_012064.4(MIP):c.494G>A (p.Gly165Asp)	Likely pathogenic
391974	NM_012064.4(MIP):c.401A>C (p.Glu134Ala)	Likely pathogenic
392878	NM_012064.4(MIP):c.526-2A>C	Likely pathogenic
944316	NM_012064.4(MIP):c.525+1G>A	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

1674 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:56453126:A:C	N184K	0.998
12:56453126:A:T	N184K	0.998
12:56454410:A:C	N68K	0.997
12:56454410:A:T	N68K	0.997
12:56451459:A:G	W205R	0.993
12:56451459:A:T	W205R	0.993
12:56454470:A:C	F48L	0.993
12:56454470:A:T	F48L	0.993
12:56454472:A:G	F48L	0.993
12:56453605:C:G	G171R	0.991
12:56453605:C:T	G171R	0.991
12:56453622:C:T	G165D	0.991
12:56454315:C:T	G100E	0.991
12:56454316:C:A	G100W	0.991
12:56451440:C:T	G211E	0.990
12:56451453:C:G	G207R	0.990
12:56453074:A:G	W202R	0.990
12:56453074:A:T	W202R	0.990
12:56453592:C:T	G175E	0.990
12:56453715:T:A	E134V	0.990
12:56454327:C:T	G96E	0.990
12:56454393:G:T	A74D	0.990
12:56454399:G:A	T72I	0.990
12:56454402:A:T	V71D	0.990
12:56454412:T:C	N68D	0.989
12:56454425:A:C	S63R	0.989
12:56454425:A:T	S63R	0.989
12:56454427:T:G	S63R	0.989
12:56453142:G:A	T179I	0.988
12:56453605:C:A	G171W	0.988

dbSNP variants (sampled 300 via entrez): RS1000243332 (12:56451400 G>A,T), RS1000662095 (12:56454982 A>G), RS1000765461 (12:56455286 C>T), RS1001596371 (12:56454889 G>T), RS1001940981 (12:56454600 C>A,G,T), RS1001975129 (12:56449425 G>GCGGGGCGAGC), RS1003214033 (12:56453193 C>T), RS1003234391 (12:56453849 AG>A), RS1004665562 (12:56455930 C>T), RS1005464543 (12:56452251 A>G), RS1006059421 (12:56453867 G>A), RS1006288130 (12:56454192 G>A), RS1006340453 (12:56454545 A>G), RS1006623653 (12:56458407 A>T), RS1006781900 (12:56452233 T>A)

Disease associations

OMIM: gene MIM:154050 | disease phenotypes: MIM:615274, MIM:221900

GenCC curated gene-disease

Disease	Classification	Inheritance
cataract 15 multiple types	Definitive	Autosomal dominant
early-onset lamellar cataract	Supportive	Autosomal dominant
early-onset sutural cataract	Supportive	Autosomal dominant
cerulean cataract	Supportive	Autosomal dominant
early-onset nuclear cataract	Supportive	Autosomal dominant
early-onset posterior polar cataract	Supportive	Autosomal dominant
total early-onset cataract	Supportive	Autosomal dominant

Mondo (10): cataract 15 multiple types (MONDO:0014110), persistent hyperplastic primary vitreous (MONDO:0019631), pathologic nystagmus (MONDO:0004843), microphthalmia (MONDO:0021129), early-onset lamellar cataract (MONDO:0018611), early-onset sutural cataract (MONDO:0020372), cerulean cataract (MONDO:0020374), early-onset nuclear cataract (MONDO:0020376), early-onset posterior polar cataract (MONDO:0020378), total early-onset cataract (MONDO:0021548)

Orphanet (2): Early onset non-syndromic cataract (Orphanet:91492), Persistent hyperplastic primary vitreous (Orphanet:91495)

HPO phenotypes

1 total (1 of 1 shown, HPO-id order):

HPO	Term
HP:0000568	Microphthalmia

GWAS associations

0 associations (top):

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
D008850	Microphthalmos	C11.250.566; C16.131.384.666
D009759	Nystagmus, Pathologic	C10.292.562.675; C11.590.400
D054514	Persistent Hyperplastic Primary Vitreous	C11.250.616; C16.131.384.725
C563333	Cataract, Age-Related Nuclear (supp.)
C537955	Cerulean cataract (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: other ic — Aquaporins

CTD chemical–gene interactions

14 total (human), top 14 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	decreases expression, decreases methylation, increases expression	4
bisphenol A	affects cotreatment, decreases methylation	1
ethyl-p-hydroxybenzoate	decreases expression	1
abrine	increases expression	1
bisphenol S	affects cotreatment, increases methylation	1
(+)-JQ1 compound	increases expression	1
Irinotecan	decreases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Fulvestrant	affects cotreatment, decreases methylation, increases methylation	1
Air Pollutants	decreases expression	1
Methotrexate	increases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Valproic Acid	increases methylation	1
Aflatoxin B1	increases methylation	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06068348	Not specified	ACTIVE_NOT_RECRUITING	Liquid Biopsy Collection Study
NCT01778543	Not specified	RECRUITING	Pathogenesis and Genetics of Microphthalmia, Anophthalmia and Uveal Coloboma (MAC)
NCT03748732	Not specified	UNKNOWN	Extensive Circumferential Partial Thickness Sclerectomy in Nanophthalmic Eyes
NCT04759560	Not specified	UNKNOWN	Biometric Characteristics of the Eye With Microcornea/Microphthalmia and Congenital Cataract Before And After Cataract Extraction
NCT05954403	Not specified	RECRUITING	National Cohort on Congenital Defects of the Eye
NCT06293560	Not specified	RECRUITING	Microphthalmia, Anophthalmia, and Coloboma Genetic Epidemiology in Children