CRYBB2

Summary

CRYBB2 (crystallin beta B2, HGNC:2398) is a protein-coding gene on chromosome 22q11.23, encoding Beta-crystallin B2 (P43320). Crystallins are the dominant structural components of the vertebrate eye lens.

Crystallins are separated into two classes: taxon-specific, or enzyme, and ubiquitous. The latter class constitutes the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. Since lens central fiber cells lose their nuclei during development, these crystallins are made and then retained throughout life, making them extremely stable proteins. Mammalian lens crystallins are divided into alpha, beta, and gamma families; beta and gamma crystallins are also considered as a superfamily. Alpha and beta families are further divided into acidic and basic groups. Seven protein regions exist in crystallins: four homologous motifs, a connecting peptide, and N- and C-terminal extensions. Beta-crystallins, the most heterogeneous, differ by the presence of the C-terminal extension (present in the basic group, none in the acidic group). Beta-crystallins form aggregates of different sizes and are able to self-associate to form dimers or to form heterodimers with other beta-crystallins. This gene, a beta basic group member, is part of a gene cluster with beta-A4, beta-B1, and beta-B3. A chain-terminating mutation was found to cause type 2 cerulean cataracts.

Source: NCBI Gene 1415 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cataract 3 multiple types (Definitive, GenCC) — +7 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 148 total — 6 pathogenic, 7 likely-pathogenic
• Phenotypes (HPO): 12
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency no evidence, triplosensitivity no evidence
• MANE Select transcript: NM_000496

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2398
Approved symbol	CRYBB2
Name	crystallin beta B2
Location	22q11.23
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000244752
Ensembl biotype	protein_coding
OMIM	123620
Entrez	1415

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 3 protein_coding

ENST00000398215, ENST00000651629, ENST00000855619

RefSeq mRNA: 1 — MANE Select: NM_000496 NM_000496

CCDS: CCDS13831

Canonical transcript exons

ENST00000398215 — 6 exons

Exon	Start	End
ENSE00000651772	25224918	25225036
ENSE00000651773	25227853	25227985
ENSE00000651774	25229436	25229578
ENSE00001532163	25221404	25221483
ENSE00001532164	25219639	25219666
ENSE00001725060	25231604	25231869

Expression profiles

Bgee: expression breadth ubiquitous, 144 present calls, max score 73.16.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 0.8060 / max 994.3102, expressed in 33 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
191466	0.7903	32
191465	0.0157	8

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
triceps brachii	UBERON:0001509	73.16	gold quality
gluteal muscle	UBERON:0002000	72.37	gold quality
trabecular bone tissue	UBERON:0002483	69.68	gold quality
dorsal motor nucleus of vagus nerve	UBERON:0002870	68.36	gold quality
stromal cell of endometrium	CL:0002255	67.81	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	67.56	gold quality
gingival epithelium	UBERON:0001949	67.38	gold quality
gingiva	UBERON:0001828	66.93	gold quality
inferior olivary complex	UBERON:0002127	66.49	gold quality
vastus lateralis	UBERON:0001379	66.03	gold quality
tongue squamous epithelium	UBERON:0006919	65.69	gold quality
quadriceps femoris	UBERON:0001377	64.95	gold quality
nucleus accumbens	UBERON:0001882	63.39	gold quality
mucosa of transverse colon	UBERON:0004991	63.11	gold quality
tendon of biceps brachii	UBERON:0008188	62.73	gold quality
decidua	UBERON:0002450	62.70	gold quality
vena cava	UBERON:0004087	62.61	gold quality
cartilage tissue	UBERON:0002418	62.45	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	62.09	gold quality
type B pancreatic cell	CL:0000169	61.24	gold quality
pancreatic ductal cell	CL:0002079	60.65	silver quality
anterior cingulate cortex	UBERON:0009835	60.44	gold quality
cingulate cortex	UBERON:0003027	60.39	gold quality
lower esophagus mucosa	UBERON:0035834	60.19	gold quality
periodontal ligament	UBERON:0008266	60.18	gold quality
putamen	UBERON:0001874	60.02	gold quality
orbitofrontal cortex	UBERON:0004167	59.93	gold quality
amygdala	UBERON:0001876	59.84	gold quality
caudate nucleus	UBERON:0001873	59.82	gold quality
oocyte	CL:0000023	59.73	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	2.41

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MAF

Functional genomics

ClinGen dosage: haploinsufficiency 0 (no evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• calculation of the standard free-energy by equilibrium unfolding transition in guanidine hydrochloride (PMID:12457849)
• Results show that betaB2-crystallin undergoes age-related truncation producing fragments with M(r) between 4 and 19kDa that are present in the beta(H)-crystallin oligomer. (PMID:12535638)
• Exon 6 of CRYBB2 appears to be a critical region susceptible for mutations leading to lens opacity. (PMID:15452067)
• Our finding expands the spectrum of cataract phenotypes caused by the Q155X mutation of CRYBB2, confirms the phenotypic heterogeneity of this mutation and suggests the mechanism that influences the congenital cataract formation. (PMID:16179907)
• The V60E and V144E mutants were found to be partially unfolded and incapable of forming a complete dimer. (PMID:16319073)
• These results suggest that deamidation at critical sites destabilizes betaB2 and may disrupt the function of betaB2 in the lens. (PMID:16519509)
• Cataracts in ADC53 Chilean family are caused by mutation in CRYBB2 gene; as 2 variations in CRYBB2 are identical to reference sequence of pseudogene CRYBB2P1, which has over 97% homology to CRYBB2, a gene conversion probably has occurred. (PMID:17234267)
• the CRYBB2 D128V mutation segregates only in family members affected with congenital cataracts and is not seen in representative controls; it represents the first mutation outside exon 6 of the human CRYBB2 gene (PMID:17653036)
• combined with previously reported observations of alpha-crystallin quaternary structure have led us to propose a structural model of how activated alpha-crystallin chaperones unfolded betaB2-crystallin (PMID:17937660)
• These results provide evidence that CRYBB2 is a pathogenic gene for congenital cataracts; at the same time, congenital cataracts are a clinically and genetically heterogeneous lens condition. (PMID:18449377)
• a novel cataract-causing mutation, c.92C>G in exon 2 of the CRYBB2 gene, which causes the 31st residue serine substituted by tryptophan (S31W), was identified in an autosomal dominant coronary cataract family. (PMID:18617901)
• deamidation decreased formation of hetero-oligomers between beta-crystallin subunits; excess accumulation of deamidated beta-crystallins in vivo may disrupt normal protein-protein interactions and diminish the stabilizing effects between them (PMID:19190732)
• This is the first report of congenital cerulean cataract associated with a mutation in CRYBB2 in a Chinese family. (PMID:19321936)
• This study identified a missense mutation in CRYBB2 in a family of Basotho with autosomal dominant congenital cataract (ADCC). (PMID:19649175)
• Variant alleles of the CRYBB1 and CRYBB2 genes were found, none are considered pathogenic. (PMID:20565250)
• Two new mutations, one in GJA3 and the other in CRYBB2, were identified co-segregating along with the respective cataract phenotype within the families that were not seen in healthy controls from India or Germany. (PMID:21031021)
• analysis of a novel CRYBB2 gene mutation, resulting in the amino substitution p. A2V in a Chinese family with posterior subcapsular congenital cataracts (PMID:21245961)
• Analyses of 20 Chinese families with hereditary nuclear congenital cataract revealed 3 novel mutations. Two of these mutations (V146M and I21N) affected betaB2-crystallin (CRYBB2). One mutation (R233H) was detected in betaB1-crystallin (CRYBB1). (PMID:21402992)
• The Asp residue at position 4 of betaB2-crystallin in the lenses of the aged human eye lenses undergoes a significant degree of inversion and isomerization to the biologically D-beta-Asp. (PMID:21877723)
• A novel missense mutation, p.Arg188His, in CRYBB2 is associated with congenital cataract in a family of Croatian origin. (PMID:22312185)
• Identification of the first CRYBB2 mutation in an Italian family causing a clinical picture of autosomal dominant congenital cataract. (PMID:22846113)
• The congenital cataract-linked A2V mutation impairs tetramer formation and promotes aggregation of betaB2-crystallin. (PMID:23236454)
• The last strand at the C-terminus of CRYBB2 is important for the protein stability and assembly. (PMID:24120835)
• missense mutation in CRYBB2 gene leads to progressive congenital membranous cataract by impacting the solubility and function of betaB2-crystallin (PMID:24312286)
• The distinct behaviors of the mutants suggested that the residue at position 188 might play a regulatory role in betaB2-crystallin aggregation/fibrillization but not reside in the core of the aggregates/fibrils. (PMID:24704203)
• Congenital cataracts were caused by the de novo gene conversion event in CRYBB2 in a consanguineous Jewish Ashkenazi family. (PMID:25489230)
• This is the first study to analyze the association between genetic variations in the CRYBB2 gene with PCa. rs9608380, associated with Prostate cancer, is a potentially functional variant (PMID:25964531)
• The first pregnancy was terminated in week 22. Copy number variation analysis revealed, in both the aborted fetus and the mother, a 495 kb duplication at 22q11.23 encompassing CRYBB3 and CRYBB2 (PMID:27256633)
• Study demonstrates that, in solution, human betaB2-crystallin is not domain swapped and exhibits a face-en-face dimer structure similar to the crystal structure of truncated betaB1-crystallin. (PMID:28238532)
• conserved Trp residues might play a more crucial role in the correct folding and structural integrity of beta-crystallin domains than in gamma-crystallins (PMID:28528950)
• We examined a cohort of Chinese patients with congenital cataracts and studied the phenotypes and genotypes. Extralenticular abnormalities, such as microcornea and ocular coloboma, can also be found in patients with congenital cataracts. The phenotype of congenital cataracts associated with macular and optic disc coloboma was reported for the first time in this study. (PMID:29386872)
• Here we identify the first Taiwanese cerulean cataract family carrying a CRYBB2_Q155X mutation. (PMID:29395391)
• CRYB2 cataract-associating mutations S31W and R145W destabilize CRYB2 and promote thermal aggregation.The number of Trp fluorophores in CRYB2 is evolutionarily optimized to exquisitely perform their structural roles in the lens. (PMID:30219234)
• Crystallin beta B2 (CRYbetaB2) overexpression in triple-negative breast cancers increases invasive cellular behaviors, tumor growth, IL6 production, immune cell chemoattraction, and the expression of metastasis-associated genes. Combined overexpression of both CRYbetaB2 and the pseudogene, CRYbetaB2P1, is found to suppress cell growth. (PMID:31511085)
• Polymorphisms in CRYBB2 encoding betaB2-crystallin are associated with antisaccade performance and memory function. (PMID:32317624)
• A novel CRYBB2 mutation causes autosomal dominant cataract: A report from a Chinese family. (PMID:32498547)
• Cataract-Associated New Mutants S175G/H181Q of betaBeta2-Crystallin and P24S/S31G of gammaD-Crystallin Are Involved in Protein Aggregation by Structural Changes. (PMID:32899552)
• betaB2 W151R mutant is prone to degradation, aggregation and exposes the hydrophobic side chains in the fourth Greek Key motif. (PMID:33246011)
• CRYbetaB2 enhances tumorigenesis through upregulation of nucleolin in triple negative breast cancer. (PMID:34341513)
• Conformational stability of the deamidated and mutated human betaB2-crystallin. (PMID:36905841)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	crybb2	ENSDARG00000053512
mus_musculus	Crybb2	ENSMUSG00000042240
rattus_norvegicus	Crybb2	ENSRNOG00000050023

Paralogs (14): CRYBG3 (ENSG00000080200), CRYBB3 (ENSG00000100053), CRYBB1 (ENSG00000100122), CRYBA1 (ENSG00000108255), CRYBG1 (ENSG00000112297), CRYGD (ENSG00000118231), CRYGN (ENSG00000127377), CRYGC (ENSG00000163254), CRYBA2 (ENSG00000163499), CRYGA (ENSG00000168582), CRYBG2 (ENSG00000176092), CRYGB (ENSG00000182187), CRYBA4 (ENSG00000196431), CRYGS (ENSG00000213139)

Protein

Protein identifiers

Beta-crystallin B2 — P43320 (reviewed: P43320)

Alternative names: Beta-B2 crystallin, Beta-crystallin Bp

All UniProt accessions (2): P43320, R4UMM2

UniProt curated annotations — full annotation on UniProt →

Function. Crystallins are the dominant structural components of the vertebrate eye lens.

Subunit / interactions. Homo/heterodimer, or complexes of higher-order. The structure of beta-crystallin oligomers seems to be stabilized through interactions between the N-terminal arms.

Disease relevance. Cataract 3, multiple types (CTRCT3) [MIM:601547] 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. CTRCT3 includes congenital cerulean and sutural cataract with punctate and cerulean opacities, among others. Cerulean cataract is characterized by peripheral bluish and white opacifications organized in concentric layers with occasional central lesions arranged radially. The opacities are observed in the superficial layers of the fetal nucleus as well as the adult nucleus of the lens. Involvement is usually bilateral. Visual acuity is only mildly reduced in childhood. In adulthood, the opacifications may progress, making lens extraction necessary. Histologically the lesions are described as fusiform cavities between lens fibers which contain a deeply staining granular material. Although the lesions may take on various colors, a dull blue is the most common appearance and is responsible for the designation cerulean cataract. Sutural cataract with punctate and cerulean opacities is characterized by white opacification around the anterior and posterior Y sutures, and grayish and bluish, spindle shaped, oval punctate and cerulean opacities of various sizes arranged in lamellar form. The spots are more concentrated towards the peripheral layers and do not delineate the embryonal or fetal nucleus. Phenotypic variation with respect to the size and density of the sutural opacities as well as the number and position of punctate and cerulean spots is observed among affected subjects. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. Has a two-domain beta-structure, folded into four very similar Greek key motifs.

Similarity. Belongs to the beta/gamma-crystallin family.

RefSeq proteins (1): NP_000487* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001064	Beta/gamma_crystallin	Domain
IPR011024	G_crystallin-like	Homologous_superfamily
IPR050252	Beta/Gamma-Crystallin	Family

Pfam: PF00030

UniProt features (39 total): strand 15, sequence variant 6, helix 5, domain 4, turn 3, region of interest 3, initiator methionine 1, chain 1, modified residue 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
1YTQ	X-RAY DIFFRACTION	1.7
9D1V	X-RAY DIFFRACTION	2
7K7U	X-RAY DIFFRACTION	3.03

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P43320-F1	89.05	0.82

Functional residue map

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

Post-translational modifications (1): 2

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 84 (showing top): WALLACE_PROSTATE_CANCER_RACE_UP, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, GOBP_SENSORY_PERCEPTION, KIM_GASTRIC_CANCER_CHEMOSENSITIVITY, GOBP_SENSORY_ORGAN_DEVELOPMENT, GOBP_LENS_DEVELOPMENT_IN_CAMERA_TYPE_EYE, GOMF_STRUCTURAL_CONSTITUENT_OF_EYE_LENS, MODULE_248, YOSHIMURA_MAPK8_TARGETS_UP, LY_AGING_MIDDLE_UP, GOMF_STRUCTURAL_MOLECULE_ACTIVITY, GREGORY_SYNTHETIC_LETHAL_WITH_IMATINIB, LU_EZH2_TARGETS_UP, CERIBELLI_GENES_INACTIVE_AND_BOUND_BY_NFY, AZARE_NEOPLASTIC_TRANSFORMATION_BY_STAT3_UP

GO Biological Process (3): lens development in camera-type eye (GO:0002088), visual perception (GO:0007601), camera-type eye development (GO:0043010)

GO Molecular Function (4): structural molecule activity (GO:0005198), structural constituent of eye lens (GO:0005212), identical protein binding (GO:0042802), protein binding (GO:0005515)

GO Cellular Component (0):

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
camera-type eye development	1
anatomical structure development	1
sensory perception of light stimulus	1
eye development	1
molecular_function	1
structural molecule activity	1
protein binding	1
binding	1

Protein interactions and networks

STRING

500 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CRYBB2	CRYAA	P02489	956
CRYBB2	GJA8	P48165	937
CRYBB2	GJA3	Q9Y6H8	930
CRYBB2	BFSP2	Q13515	920
CRYBB2	CRYAB	P02511	836
CRYBB2	PITX3	O75364	826
CRYBB2	TRNT1	Q96Q11	803
CRYBB2	TMEM114	B3SHH9	750
CRYBB2	BFSP1	Q12934	742
CRYBB2	HSPB2	Q16082	705
CRYBB2	HSF4	Q9ULV5	697
CRYBB2	GCNT2	Q8N0V5	684
CRYBB2	LIM2	P55344	670
CRYBB2	MAF	O75444	668
CRYBB2	HSPB1	P04792	663

IntAct

29 interactions, top by confidence:

A	B	Type	Score
CRYGC	CRYBB2	psi-mi:“MI:0915”(physical association)	0.650
CRYBB2	CRYAA	psi-mi:“MI:0915”(physical association)	0.650
CRYAB	CRYBB2	psi-mi:“MI:0915”(physical association)	0.650
CRYBB2	CRYAB	psi-mi:“MI:0915”(physical association)	0.650
CRYBB2	CRYGC	psi-mi:“MI:0915”(physical association)	0.650
CRYAA	CRYBB2	psi-mi:“MI:0915”(physical association)	0.650
CRYGC	CRYBB2	psi-mi:“MI:0914”(association)	0.650
CRYBB2	CRYAA	psi-mi:“MI:0914”(association)	0.650
CRYAB	CRYBB2	psi-mi:“MI:0914”(association)	0.650
CRYBB2	CRYBB2	psi-mi:“MI:0915”(physical association)	0.630
CRYBA1	CRYBB2	psi-mi:“MI:0915”(physical association)	0.560
CRYBB2	LMO4	psi-mi:“MI:0915”(physical association)	0.560
HSPB1	CRYBB2	psi-mi:“MI:0407”(direct interaction)	0.440
CRYBB2	CRYBA1	psi-mi:“MI:0915”(physical association)	0.370
CRYBA4	CRYBB2	psi-mi:“MI:0915”(physical association)	0.370
CRYBA1	CRYBB2	psi-mi:“MI:0915”(physical association)	0.370
CRYBA2	CRYBB2	psi-mi:“MI:0915”(physical association)	0.370
CRYBB2	CRYBA1	psi-mi:“MI:0915”(physical association)	0.000
LMO4	CRYBB2	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (19): CRYBB2 (Two-hybrid), CRYBB2 (Two-hybrid), CRYBB2 (Two-hybrid), CRYAA (Two-hybrid), CRYBB2 (Two-hybrid), CRYAB (Two-hybrid), CRYGC (Two-hybrid), CRYBB2 (Two-hybrid), CRYAA (Affinity Capture-Western), CRYAB (Affinity Capture-Western), CRYBB2 (Affinity Capture-Western), CRYBB2 (Two-hybrid), CRYBB2 (Two-hybrid), HSPB1 (Affinity Capture-Western), CRYBB2 (Two-hybrid)

ESM2 similar proteins: A2IBH5, A2IBY7, A3KGF7, A4D1Z8, A8MX76, E7F9T0, F6Q2R9, O88644, O89040, P02522, P02523, P02524, P07318, P07530, P13943, P19141, P26998, P43320, P49221, P50281, P53672, P53674, P53690, P55165, P62696, P62697, P62698, Q007T1, Q05714, Q10739, Q2LEC2, Q3UW68, Q4V8Q1, Q5BK10, Q5EF38, Q5RES1, Q6J756, Q6MZZ7, Q91318, Q91320

Diamond homologs: A2IBH5, A2IBY7, A2ICR5, A3RLD7, A3RLD8, A3RLE1, A3RLE2, A4L9I8, A4L9I9, A4QNB6, D3ZEG1, F6Q2R9, O35486, P02522, P02523, P02524, P02525, P02526, P02527, P02528, P02529, P02530, P02531, P04342, P04344, P04345, P05813, P06504, P07315, P07316, P07317, P07318, P07320, P07530, P08209, P0C5E9, P10042, P10043, P10065, P10066

SIGNOR signaling

5 interactions.

A	Effect	B	Mechanism
CRYBB2	up-regulates	Maintenance_of_lens_transparency
CRYBB2	“up-regulates activity”	CRYBB3	binding
CRYBB2	“up-regulates activity”	CRYBB1	binding
CRYBB2	“up-regulates activity”	CRYBB2	binding
CRYAA	“up-regulates activity”	CRYBB2	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	7
Uncertain significance	72
Likely benign	29
Benign	27

Top pathogenic / likely-pathogenic (13)

Variant ID	HGVS	Classification
16949	NM_000496.3(CRYBB2):c.463C>T (p.Gln155Ter)	Pathogenic
16950	NM_000496.3(CRYBB2):c.471C>T (p.Pro157=)	Pathogenic
1708137	NM_000496.3(CRYBB2):c.470C>T (p.Pro157Leu)	Pathogenic
252952	NM_000496.3(CRYBB2):c.563G>T (p.Arg188Leu)	Pathogenic
280142	NM_000496.3(CRYBB2):c.563G>A (p.Arg188His)	Pathogenic
4278000	NM_000496.3(CRYBB2):c.54+1G>A	Pathogenic
1210343	NM_000496.3(CRYBB2):c.173C>T (p.Pro58Leu)	Likely pathogenic
1803265	NM_000496.3(CRYBB2):c.427T>C (p.Ser143Pro)	Likely pathogenic
217330	NM_000496.3(CRYBB2):c.556T>C (p.Ser186Pro)	Likely pathogenic
3897839	NM_000496.3(CRYBB2):c.230G>T (p.Gly77Val)	Likely pathogenic
463969	NM_000496.3(CRYBB2):c.161T>G (p.Val54Gly)	Likely pathogenic
463971	NM_000496.3(CRYBB2):c.551T>G (p.Val184Gly)	Likely pathogenic
952559	NM_000496.3(CRYBB2):c.446G>T (p.Gly149Val)	Likely pathogenic

SpliceAI

695 predictions. Top by Δscore:

Variant	Effect	Δscore
22:25221484:G:GA	donor_loss	1.0000
22:25221485:T:G	donor_loss	1.0000
22:25225032:GGACC:G	donor_gain	1.0000
22:25225033:GACC:G	donor_gain	1.0000
22:25225033:GACCG:G	donor_gain	1.0000
22:25225035:CC:C	donor_gain	1.0000
22:25225037:G:GG	donor_gain	1.0000
22:25227847:T:G	acceptor_gain	1.0000
22:25229431:A:AG	acceptor_gain	1.0000
22:25229434:A:AG	acceptor_gain	1.0000
22:25229434:AG:A	acceptor_gain	1.0000
22:25229435:G:GA	acceptor_gain	1.0000
22:25229435:GG:G	acceptor_gain	1.0000
22:25229435:GGA:G	acceptor_gain	1.0000
22:25229435:GGAC:G	acceptor_gain	1.0000
22:25229435:GGACA:G	acceptor_gain	1.0000
22:25229566:TGCA:T	donor_gain	1.0000
22:25229567:GCAG:G	donor_gain	1.0000
22:25229574:GGCAC:G	donor_gain	1.0000
22:25229575:GCAC:G	donor_gain	1.0000
22:25229575:GCACG:G	donor_gain	1.0000
22:25229576:CAC:C	donor_gain	1.0000
22:25229577:AC:A	donor_gain	1.0000
22:25229579:GT:G	donor_loss	1.0000
22:25229579:GTAA:G	donor_gain	1.0000
22:25229580:T:G	donor_loss	1.0000
22:25229583:G:GG	donor_gain	1.0000
22:25219665:TGGT:T	donor_loss	0.9900
22:25219667:G:GC	donor_loss	0.9900
22:25219667:G:GG	donor_gain	0.9900

AlphaMissense

1362 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
22:25227854:T:A	W59R	0.999
22:25227854:T:C	W59R	0.999
22:25227932:T:A	W85R	0.999
22:25227932:T:C	W85R	0.999
22:25231605:T:A	W151R	0.999
22:25231605:T:C	W151R	0.999
22:25231716:C:A	R188S	0.999
22:25231717:G:C	R188P	0.999
22:25225014:T:C	S51P	0.998
22:25225018:T:A	V52D	0.998
22:25227861:G:A	G61D	0.998
22:25229575:G:A	G149D	0.998
22:25229575:G:T	G149V	0.998
22:25231635:G:A	G161R	0.998
22:25231635:G:C	G161R	0.998
22:25231635:G:T	G161W	0.998
22:25231636:G:A	G161E	0.998
22:25231636:G:T	G161V	0.998
22:25231710:T:C	S186P	0.998
22:25231719:C:A	R189S	0.998
22:25227914:T:G	Y79D	0.997
22:25229520:A:C	S131R	0.997
22:25229522:C:A	S131R	0.997
22:25229522:C:G	S131R	0.997
22:25229556:T:C	S143P	0.997
22:25229574:G:C	G149R	0.997
22:25231607:G:C	W151C	0.997
22:25231607:G:T	W151C	0.997
22:25231609:T:A	V152D	0.997
22:25231612:G:A	G153D	0.997

dbSNP variants (sampled 300 via entrez): RS1000041601 (22:25219245 T>A,C), RS1000181058 (22:25228984 A>G), RS1000195414 (22:25223498 T>C), RS1000429832 (22:25225356 C>T), RS1000637683 (22:25228909 CGTGT>C,CGT,CGTGTGT), RS1000701414 (22:25229027 T>C), RS1000708702 (22:25215049 A>G), RS1000772167 (22:25209804 T>A), RS1000932501 (22:25214787 T>C), RS1000983634 (22:25225218 C>G), RS1001045779 (22:25220289 G>T), RS1001057660 (22:25215227 A>C), RS1001312632 (22:25228823 A>G), RS1001321919 (22:25226373 G>A), RS1001363080 (22:25228416 T>G)

Disease associations

OMIM: gene MIM:123620 | disease phenotypes: MIM:601547

GenCC curated gene-disease

Disease	Classification	Inheritance
cataract 3 multiple types	Definitive	Autosomal dominant
cataract - microcornea syndrome	Supportive	Autosomal dominant
early-onset posterior subcapsular cataract	Supportive	Autosomal dominant
pulverulent cataract	Supportive	Autosomal dominant
early-onset sutural cataract	Supportive	Autosomal dominant
cerulean cataract	Supportive	Autosomal dominant
early-onset nuclear cataract	Supportive	Autosomal dominant
total early-onset cataract	Supportive	Autosomal dominant

Mondo (8): cataract 3 multiple types (MONDO:0011104), cataract - microcornea syndrome (MONDO:0015300), early-onset posterior subcapsular cataract (MONDO:0018610), pulverulent cataract (MONDO:0011430), early-onset sutural cataract (MONDO:0020372), cerulean cataract (MONDO:0020374), early-onset nuclear cataract (MONDO:0020376), total early-onset cataract (MONDO:0021548)

Orphanet (1): Cataract-microcornea syndrome (Orphanet:1377)

HPO phenotypes

12 total (12 of 12 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000482	Microcornea
HP:0000518	Cataract
HP:0000519	Developmental cataract
HP:0000545	Myopia
HP:0000612	Iris coloboma
HP:0000639	Nystagmus
HP:0001131	Corneal dystrophy
HP:0007957	Corneal opacity
HP:0007976	Cerulean cataract
HP:0010695	Sutural cataract
HP:0010698	Nuclear pulverulent cataract

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST009028_20	Adverse response to drug	7.000000e-08

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0009658	adverse effect

MeSH disease descriptors (5)

Descriptor	Name	Tree numbers
C538287	Cataract microcornea syndrome (supp.)
C563333	Cataract, Age-Related Nuclear (supp.)
C563294	Cataract, Congenital, Cerulean Type, 2 (supp.)
C565133	Cataract, Coppock-Like (supp.)
C537955	Cerulean cataract (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4296284 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

22 total (human), top 22 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
uranyl acetate	affects expression	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
sodium arsenite	increases expression	1
potassium chromate(VI)	affects cotreatment, increases expression	1
epigallocatechin gallate	affects cotreatment, increases expression	1
chromium hexavalent ion	increases expression	1
CGP 52608	affects binding, increases reaction	1
theaflavin-3,3’-digallate	affects expression	1
Resveratrol	affects cotreatment, decreases expression	1
Acetaminophen	increases expression	1
Benzo(a)pyrene	increases methylation	1
Cocaine	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Rotenone	decreases expression	1
Silicon Dioxide	increases expression	1
Tobacco Smoke Pollution	increases expression	1
Tretinoin	decreases expression	1
Tunicamycin	increases expression	1
Uranium	affects expression	1
Aflatoxin B1	decreases methylation	1
Cadmium Chloride	increases expression	1
Thapsigargin	increases expression	1

ChEMBL screening assays

9 unique, capped per target: 9 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4201167	Binding	Inhibition of beta-crystallin B2 V187E mutant (unknown origin)-induced intracellular protein aggregation expressed in human HeLa cells or HLE-B3 cells at 4 uM incubated for 6 to 8 hrs by fluorescence microscopy relative to untreated control	Synthesis, Evaluation, and Structure-Activity Relationship Study of Lanosterol Derivatives To Reverse Mutant-Crystallin-Induced Protein Aggregation. — J Med Chem

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT06068348	Not specified	ACTIVE_NOT_RECRUITING	Liquid Biopsy Collection Study