CRYGD

Summary

CRYGD (crystallin gamma D, HGNC:2411) is a protein-coding gene on chromosome 2q33.3, encoding Gamma-crystallin D (P07320). Crystallins are the dominant structural components of the vertebrate eye lens. It is a selective cancer dependency (DepMap: 24.3% of cell lines).

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. Gamma-crystallins are a homogeneous group of highly symmetrical, monomeric proteins typically lacking connecting peptides and terminal extensions. They are differentially regulated after early development. Four gamma-crystallin genes (gamma-A through gamma-D) and three pseudogenes (gamma-E, gamma-F, gamma-G) are tandemly organized in a genomic segment as a gene cluster. Whether due to aging or mutations in specific genes, gamma-crystallins have been involved in cataract formation.

Source: NCBI Gene 1421 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cataract 4 multiple types (Definitive, GenCC) — +6 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 85 total — 6 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 9
• Druggable target: yes
• Cancer dependency (DepMap): dependent in 24.3% of screened cell lines
• MANE Select transcript: NM_006891

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2411
Approved symbol	CRYGD
Name	crystallin gamma D
Location	2q33.3
Locus type	gene with protein product
Status	Approved
Ensembl gene	ENSG00000118231
Ensembl biotype	protein_coding
OMIM	123690
Entrez	1421

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000264376

RefSeq mRNA: 1 — MANE Select: NM_006891 NM_006891

CCDS: CCDS2378

Canonical transcript exons

ENST00000264376 — 3 exons

Exon	Start	End
ENSE00000796728	208121607	208121945
ENSE00001072759	208124465	208124524
ENSE00002505339	208124112	208124354

Expression profiles

Bgee: expression breadth broad, 60 present calls, max score 91.39.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 1.1104 / max 1797.4362, expressed in 51 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
33427	1.0810	43
202554	0.0294	9

Top tissues by expression

110 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	91.39	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	82.93	gold quality
ventricular zone	UBERON:0003053	82.21	gold quality
cortical plate	UBERON:0005343	81.24	gold quality
ganglionic eminence	UBERON:0004023	78.36	gold quality
lens of camera-type eye	UBERON:0000965	74.18	silver quality
left ovary	UBERON:0002119	68.62	gold quality
ovary	UBERON:0000992	67.39	gold quality
hypothalamus	UBERON:0001898	66.24	gold quality
substantia nigra	UBERON:0002038	63.79	gold quality
prefrontal cortex	UBERON:0000451	62.91	gold quality
temporal lobe	UBERON:0001871	62.28	gold quality
amygdala	UBERON:0001876	62.28	gold quality
anterior cingulate cortex	UBERON:0009835	62.27	gold quality
right ovary	UBERON:0002118	61.13	gold quality
cerebral cortex	UBERON:0000956	59.99	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	59.71	gold quality
frontal cortex	UBERON:0001870	59.69	gold quality
Brodmann (1909) area 9	UBERON:0013540	59.18	gold quality
eye	UBERON:0000970	58.59	silver quality
primary visual cortex	UBERON:0002436	57.67	gold quality
putamen	UBERON:0001874	57.48	gold quality
Ammon’s horn	UBERON:0001954	57.19	gold quality
bone marrow	UBERON:0002371	56.55	gold quality
caudate nucleus	UBERON:0001873	56.21	gold quality
right frontal lobe	UBERON:0002810	55.93	gold quality
brain	UBERON:0000955	53.26	gold quality
superior frontal gyrus	UBERON:0002661	49.53	gold quality
nucleus accumbens	UBERON:0001882	49.43	gold quality
bone marrow cell	CL:0002092	49.31	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.03

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): FOS, JUN, MAF, MAFB

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 24.3% of screened cell lines.

Literature-anchored findings (GeneRIF, showing 40)

• This the first report of a mutation in the Gamma-D crystallin gene (CRYGD) resulting in autosomal dominant congenital cerulean cataracts. (PMID:12676897)
• In gammaD-crystallin, methylation is exclusively at Cys 110, whereas in gammaC- and gammaB-crystallins, the principal methylation site is Cys 22 with minor methylation at Cys 79 (PMID:12876325)
• This study has identified an eighth type of cataract morphology associated with CRYGD and suggests that a CRYGD mutation may underlie the historically important “coralliform” cataract first reported in 1895. (PMID:15041957)
• It appearS to be caused by a missense mutation in the CRYGD gene, further supporting the notion that alterations to CRYG play an important factor in human cataract formation. (PMID:15064679)
• These results suggest that insolubility, rather than loss of stability, is the primary basis for human gammaD-crystallin P23T mutation-derived congenital cataracts. (PMID:15451671)
• The cataract-causing mutation proline23 to threonine does not exhibit any significant structural change relative to the native protein. However, in marked contrast to the native protein, the mutant shows a dramatically lowered solubility. (PMID:15709761)
• domain interface residues of the refolded C-td act as a nucleating center for refolding of the N-td (PMID:15722442)
• To our knowledge, this is the first example of phenotypic heterogeneity associated with the Arg 58 His CRYGD mutation. (PMID:16030500)
• Hydrophobic cluster residues of gammaD crystallin contribute to protein folding and protein stability. (PMID:16046626)
• The R36S mutation in CRYGD identified in this Chinese family caused a nuclear golden crystal cataract phenotype not described before. (PMID:16288201)
• interface deamidation decreases the thermodynamic stability of HgammaD-Crys and lowers the kinetic barrier to unfolding due to introduction of a negative charge into the domain interface (PMID:16891314)
• The backbone conformation of tryptophans in human gammaD-Crys may have evolved to enable the lens to become a very effective UV filter, while the efficient quenching provides an in situ mechanism to protect the tryptophans from photochemical degradation. (PMID:16981715)
• R36S mutation in CRYGD gene results in an autosomal dominant congenital cataract phenotype that is different from previous reports. This is the first report of congenital cataract caused by R36S mutation in CRYGD gene. (PMID:17217786)
• We identified a mutation in the CRYGD gene (P23S) of the gamma-crystallin gene cluster that is associated with a polymorphic congenital cataract that occurs with frequency of approximately 0.3% in a human population. (PMID:17564961)
• Five novel mutations in CRYAA, CRYGD, and GJA8 genes were detected in congenital cataract in association with microcornea (PMID:17724170)
• analysis of folding and stability of the isolated Greek key domains of the long-lived human lens proteins gammaD-crystallin and gammaS-crystallin (PMID:17905830)
• The liquid-liquid coexistence curve and the diffusivity of the P23V mutant human gammaD-crystallin is investigated. (PMID:17923670)
• The mutations in CRYGD were shown to cause changes in protein surface polarity, hydrophobicity, and spatial structure, contributing to protein deposition and cataract formation. (PMID:18041179)
• Novel mutation, c.494delG, in CRYGD associated with nuclear cataract. Hypothesized to impair nuclear transfiguration and degradation in lens fiber cell differentiation, leading to opacity formation during lens development. (PMID:18079686)
• Human gammaD-crystallin formed amyloid fibrils upon incubation at acid pH. (PMID:18253099)
• This is the first reported case of a congenital coralliform cataract phenotype associated with the mutation of Gly61Cys (P.G61C) in the CRYGD gene; it demonstrates a possible mechanism of action for the mutant gene. (PMID:18334953)
• Data show that a combination of energy transfer with electron transfer together with the high rigidity of the protein matrix around Trps, could protect HgammaD-Crys from excited-state reactions causing permanent covalent damage. (PMID:18795792)
• The structure of the cataract-causing P23T mutant of human gammaD-crystallin exhibits distinctive local conformational and dynamic changes (PMID:19216553)
• high-resolution NMR studies of human gammaD-crystallin and P23T was presented. (PMID:19275895)
• Fast charge transfer quenching is an evolved property of the gamma D-crystallin fold, probably protecting it from ultraviolet-induced photodamage. (PMID:19358562)
• Raman spectroscopy analysis shows that gamma D-crystallin mutant Arg14Cys protein forms aggregates even at pH 4.5; the lower pH enables monitoring of the evolution of disulfide cross-links with conformations around the CC-disulfide-CC dihedral angles. (PMID:19382745)
• Report a new nonsense mutation (Y56X) in CRYGD and a prev’ly reported missense mutation (R12C) in CRYAA associated with nuclear autosomal dominant congenital cataract in Brazilian families. A new polymorphism (S119S) in CRYGC was observed in one family. (PMID:19390652)
• This first report of p.P23T CRYGD mutation underlying cerulean cataract in the Saudi population strongly supports the mutation’s relation with the phenotype. (PMID:19633732)
• A novel R15S mutation in CRYGD caused congenital coralliform cataract in a Chinese family. (PMID:19668596)
• Data show that during thermal denaturation, the mutant proteins exhibited lowered thermal stability compared with WT. (PMID:19758984)
• Findings indicate that Glu135 and Arg142 of gammaD-crystallin are crucial for stabilizing its hydrophobic domain interface in native conformation, and disruption of charges on the gammaD-crystallin surface may lead to unfolding and subsequent aggregat’n. (PMID:19937657)
• Family having anterior polar coronary cataract that co-segregates with novel allele R77S of CRYGD in all affected members. (PMID:20508808)
• This work thus provides direct evidence of the dominant role played by net hydrophobic and anisotropic protein-protein interactions in the aggregation of the P23T cataract-associated gammaD-crystallin. (PMID:20553008)
• Data show a significant demixing of gammaD and betaB1 i.e., large difference of composition in the two coexisting phases. (PMID:20616077)
• The alphaB-crystallin oligomers formed long-lived stable complexes with their gammaD-crystallin substrates. (PMID:20621668)
• CRYGD gene mutation co-segregated with all autosomal dominant congenital nuclear cataract affected individuals and was not observed in either unaffected family members or in 200 normal unrelated individuals. (PMID:21031598)
• Cataract-associated mutant E107A of human gammaD-crystallin shows increased attraction to alpha-crystallin and enhanced light scattering (PMID:21173272)
• S130P point mutations of gammaD crystallin was the most resistant to aggregation, indicating a decrease of its intrinsic aggregation propensity. (PMID:21184609)
• The conformational features and aggregation properties of the mutant protein E107A human gammaD-crystallin (HGDC), associated with congenital nuclear cataract, were analyzed. (PMID:21197114)
• Two novel nonsynonymous variations and four reported variations in CRYAB, CRYGC, CRYGD, and GJA8, were observed. (PMID:21423869)

Cross-species orthologs

0 orthologs

Paralogs (14): CRYBG3 (ENSG00000080200), CRYBB3 (ENSG00000100053), CRYBB1 (ENSG00000100122), CRYBA1 (ENSG00000108255), CRYBG1 (ENSG00000112297), CRYGN (ENSG00000127377), CRYGC (ENSG00000163254), CRYBA2 (ENSG00000163499), CRYGA (ENSG00000168582), CRYBG2 (ENSG00000176092), CRYGB (ENSG00000182187), CRYBA4 (ENSG00000196431), CRYGS (ENSG00000213139), CRYBB2 (ENSG00000244752)

Protein

Protein identifiers

Gamma-crystallin D — P07320 (reviewed: P07320)

Alternative names: Gamma-D-crystallin, Gamma-crystallin 4

All UniProt accessions (2): P07320, A0A140CTX7

UniProt curated annotations — full annotation on UniProt →

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

Subunit / interactions. Monomer.

Disease relevance. Cataract 4, multiple types (CTRCT4) [MIM:115700] 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. CTRCT4 includes crystalline aculeiform, congenital cerulean and non-nuclear polymorphic cataracts, among others. Crystalline aculeiform cataract is characterized by fiberglass-like or needle-like crystals projecting in different directions, through or close to the axial region of the lens. Non-nuclear polymorphic cataract is a partial opacity with variable location between the fetal nucleus of the lens and the equator. The fetal nucleus is normal. The opacities are irregular and look similar to a bunch of grapes and may be present simultaneously in different lens layers. Congenital 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. 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_008822* (*=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 (47 total): strand 15, sequence variant 14, helix 5, domain 4, mutagenesis site 3, turn 3, initiator methionine 1, chain 1, region of interest 1

Structure

Experimental structures (PDB)

16 structures.

PDB	Method	Resolution (Å)
1H4A	X-RAY DIFFRACTION	1.15
6W5B	X-RAY DIFFRACTION	1.15
6ETC	X-RAY DIFFRACTION	1.2
6WCY	X-RAY DIFFRACTION	1.2
1HK0	X-RAY DIFFRACTION	1.25
7P53	X-RAY DIFFRACTION	1.57
4GR7	X-RAY DIFFRACTION	1.7
9G3W	X-RAY DIFFRACTION	1.8
8BD0	X-RAY DIFFRACTION	2
8BPI	X-RAY DIFFRACTION	2
8Q3L	X-RAY DIFFRACTION	2.1
6ETA	X-RAY DIFFRACTION	2.2
2G98	X-RAY DIFFRACTION	2.2
4JGF	X-RAY DIFFRACTION	2.5
2KFB	SOLUTION NMR
2KLJ	SOLUTION SCATTERING, SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P07320-F1	96.45	0.94

Functional residue map

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

Mutagenesis-validated functional residues (3):

Position	Phenotype
24–25	no effect on solubility.
24	no effect on solubility.
24	slightly reduces solubility.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 99 (showing top): GOBP_LENS_FIBER_CELL_DIFFERENTIATION, GOBP_EPITHELIUM_DEVELOPMENT, TSENG_IRS1_TARGETS_UP, AAAYRNCTG_UNKNOWN, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_SENSORY_PERCEPTION_OF_LIGHT_STIMULUS, WTGAAAT_UNKNOWN, GOBP_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, HP1SITEFACTOR_Q6, GOBP_SENSORY_PERCEPTION, GOBP_SENSORY_ORGAN_DEVELOPMENT, MODULE_287, LEE_CALORIE_RESTRICTION_MUSCLE_UP, MCCLUNG_COCAIN_REWARD_4WK, GOBP_CELLULAR_RESPONSE_TO_REACTIVE_OXYGEN_SPECIES

GO Biological Process (4): lens development in camera-type eye (GO:0002088), visual perception (GO:0007601), cellular response to reactive oxygen species (GO:0034614), lens fiber cell differentiation (GO:0070306)

GO Molecular Function (2): structural constituent of eye lens (GO:0005212), protein binding (GO:0005515)

GO Cellular Component (2): nucleus (GO:0005634), cytoplasm (GO:0005737)

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
response to reactive oxygen species	1
cellular response to oxidative stress	1
cellular response to oxygen-containing compound	1
lens development in camera-type eye	1
epithelial cell differentiation	1
structural molecule activity	1
binding	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

468 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CRYGD	BFSP2	Q13515	938
CRYGD	GJA8	P48165	937
CRYGD	GJA3	Q9Y6H8	931
CRYGD	PITX3	O75364	846
CRYGD	TRNT1	Q96Q11	832
CRYGD	CRYAA	P02489	829
CRYGD	GCNT2	Q8N0V5	748
CRYGD	TMEM114	B3SHH9	745
CRYGD	BFSP1	Q12934	741
CRYGD	CRYAB	P02511	736
CRYGD	HSF4	Q9ULV5	716
CRYGD	MAF	O75444	709
CRYGD	LIM2	P55344	669
CRYGD	GALK1	P51570	667
CRYGD	MIP	P30301	626

IntAct

12 interactions, top by confidence:

A	B	Type	Score
CEP20	OFD1	psi-mi:“MI:0914”(association)	0.710
Cryab	CRYGD	psi-mi:“MI:0407”(direct interaction)	0.560
CRYGD	Cryaa	psi-mi:“MI:0407”(direct interaction)	0.560
Cryaa	CRYGD	psi-mi:“MI:0407”(direct interaction)	0.560
CRYGD	CRYGD	psi-mi:“MI:0407”(direct interaction)	0.440
PTPN22	CRYGD	psi-mi:“MI:0915”(physical association)	0.400
EMCN	PLEKHG3	psi-mi:“MI:0914”(association)	0.350
CRYGD	ACTA2	psi-mi:“MI:0914”(association)	0.350
IL10	VGF	psi-mi:“MI:0914”(association)	0.350
ZNF385C	CRYGD	psi-mi:“MI:0914”(association)	0.350

BioGRID (20): LIMA1 (Affinity Capture-MS), CRYGD (Affinity Capture-MS), LRRFIP2 (Affinity Capture-MS), NEXN (Affinity Capture-MS), ACTA2 (Affinity Capture-MS), ACTBL2 (Affinity Capture-MS), CRYGD (Affinity Capture-MS), PPP1R9A (Affinity Capture-MS), FLII (Affinity Capture-MS), CRYGD (Affinity Capture-MS), CRYGD (Affinity Capture-MS), CRYGD (Affinity Capture-MS), CRYGD (Two-hybrid), CRYGD (Two-hybrid), CRYGD (Two-hybrid)

ESM2 similar proteins: A2IBY7, A3RLD7, A3RLD8, A3RLE1, A4L9I8, O35486, P02527, P02528, P02529, P02530, P02531, P04342, P04344, P04345, P06504, P07315, P07316, P07320, P08209, P0C5E9, P10065, P10066, P10067, P10068, P10112, P11844, P22914, P23005, P26444, P48646, P48647, P48649, P49152, P53673, P55164, P55940, P55941, Q03740, Q06254, Q06255

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

2 interactions.

A	Effect	B	Mechanism
CRYGD	up-regulates	Maintenance_of_lens_transparency
CRYAB	“up-regulates activity”	CRYGD	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	5
Uncertain significance	39
Likely benign	6
Benign	21

Top pathogenic / likely-pathogenic (11)

Variant ID	HGVS	Classification
16937	NM_006891.4(CRYGD):c.43C>T (p.Arg15Cys)	Pathogenic
16938	NM_006891.4(CRYGD):c.176G>A (p.Arg59His)	Pathogenic
16939	NM_006891.4(CRYGD):c.109C>A (p.Arg37Ser)	Pathogenic
16941	NM_006891.4(CRYGD):c.470G>A (p.Trp157Ter)	Pathogenic
16942	NM_006891.4(CRYGD):c.70C>T (p.Pro24Ser)	Pathogenic
574060	NM_006891.4(CRYGD):c.418C>T (p.Arg140Ter)	Pathogenic
1300288	NM_006891.4(CRYGD):c.51T>G (p.Tyr17Ter)	Likely pathogenic
191146	NM_006891.4(CRYGD):c.134T>C (p.Leu45Pro)	Likely pathogenic
1994732	NM_006891.4(CRYGD):c.154T>C (p.Ser52Pro)	Likely pathogenic
2580739	NM_006891.4(CRYGD):c.110G>C (p.Arg37Pro)	Likely pathogenic
2772706	NM_006891.4(CRYGD):c.161_163del (p.Leu54del)	Likely pathogenic

SpliceAI

194 predictions. Top by Δscore:

Variant	Effect	Δscore
2:208121956:C:CT	acceptor_gain	1.0000
2:208121957:A:T	acceptor_gain	1.0000
2:208124108:TCA:T	donor_loss	1.0000
2:208124109:CACG:C	donor_loss	1.0000
2:208124110:A:AC	donor_gain	1.0000
2:208124110:A:T	donor_loss	1.0000
2:208124111:C:CA	donor_gain	1.0000
2:208124111:CG:C	donor_gain	1.0000
2:208124111:CGT:C	donor_gain	1.0000
2:208124111:CGTG:C	donor_gain	1.0000
2:208124111:CGTGG:C	donor_gain	1.0000
2:208121941:CCAGA:C	acceptor_gain	0.9900
2:208121942:CAGA:C	acceptor_gain	0.9900
2:208121942:CAGAC:C	acceptor_gain	0.9900
2:208121961:A:AC	acceptor_gain	0.9900
2:208121961:A:C	acceptor_gain	0.9900
2:208124105:TACT:T	donor_loss	0.9900
2:208124106:A:AC	donor_gain	0.9900
2:208124107:C:CC	donor_gain	0.9900
2:208121946:C:CC	acceptor_gain	0.9800
2:208121956:C:T	acceptor_gain	0.9800
2:208124107:CTCA:C	donor_gain	0.9800
2:208121944:GA:G	acceptor_gain	0.9700
2:208121946:C:A	acceptor_loss	0.9700
2:208121943:AGA:A	acceptor_gain	0.9600
2:208121950:C:CT	acceptor_gain	0.9600
2:208121954:C:CT	acceptor_gain	0.9500
2:208121955:C:CT	acceptor_gain	0.9300
2:208121951:G:T	acceptor_gain	0.9100
2:208122913:G:C	donor_gain	0.8900

AlphaMissense

1147 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:208121807:A:G	W131R	0.985
2:208121807:A:T	W131R	0.985
2:208124237:A:G	W43R	0.981
2:208124237:A:T	W43R	0.981
2:208124328:G:C	F12L	0.974
2:208124328:G:T	F12L	0.974
2:208124330:A:G	F12L	0.974
2:208121805:C:A	W131C	0.967
2:208121805:C:G	W131C	0.967
2:208124159:A:G	W69R	0.967
2:208124159:A:T	W69R	0.967
2:208124254:C:G	R37P	0.966
2:208121729:A:G	W157R	0.965
2:208121729:A:T	W157R	0.965
2:208124230:A:T	L45H	0.962
2:208124353:A:G	I4T	0.962
2:208124324:C:G	G14R	0.960
2:208121831:A:G	S123P	0.957
2:208121813:C:G	G129R	0.956
2:208121876:C:G	D108H	0.955
2:208121929:A:G	I90T	0.955
2:208124235:C:A	W43C	0.955
2:208124235:C:G	W43C	0.955
2:208124261:A:G	S35P	0.955
2:208121803:A:T	V132D	0.954
2:208124324:C:A	G14C	0.953
2:208121921:A:C	Y93D	0.952
2:208124129:A:G	C79R	0.952
2:208124345:A:C	Y7D	0.952
2:208121777:C:G	G141R	0.949

dbSNP variants (sampled 300 via entrez): RS1000265125 (2:208124601 G>A), RS1000550292 (2:208126078 G>A,C), RS1000602695 (2:208125878 T>C), RS1000984475 (2:208122649 G>A,C), RS1001342044 (2:208125190 G>C,T), RS1001353423 (2:208122270 T>C), RS1001842627 (2:208122727 G>A,T), RS1003558326 (2:208122441 C>A), RS1003589280 (2:208124185 C>T), RS1003778185 (2:208124004 C>A,T), RS1004687085 (2:208125804 G>A), RS1005017654 (2:208124640 C>G,T), RS1005294848 (2:208121201 C>T), RS1005797722 (2:208121253 A>T), RS1006244693 (2:208121567 T>C)

Disease associations

OMIM: gene MIM:123690 | disease phenotypes: MIM:115700, MIM:614615

GenCC curated gene-disease

Disease	Classification	Inheritance
cataract 4 multiple types	Definitive	Autosomal dominant
cataract - microcornea syndrome	Supportive	Autosomal dominant
early-onset lamellar cataract	Supportive	Autosomal dominant
pulverulent cataract	Supportive	Autosomal dominant
cerulean cataract	Supportive	Autosomal dominant
coralliform cataract	Supportive	Autosomal dominant
early-onset nuclear cataract	Supportive	Autosomal dominant

Mondo (8): cataract 4 multiple types (MONDO:0007281), Joubert syndrome 17 (MONDO:0013824), cataract - microcornea syndrome (MONDO:0015300), early-onset lamellar cataract (MONDO:0018611), pulverulent cataract (MONDO:0011430), cerulean cataract (MONDO:0020374), (MONDO:0020375), early-onset nuclear cataract (MONDO:0020376)

Orphanet (2): Cataract-microcornea syndrome (Orphanet:1377), Isolated Joubert syndrome (Orphanet:475)

HPO phenotypes

9 total (9 of 9 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

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST011494_100	Daytime nap	3.000000e-12

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0007828	daytime rest measurement

MeSH disease descriptors (4)

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

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4296286 (SINGLE PROTEIN)

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

CTD chemical–gene interactions

10 total (human), top 10 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
ethyl-p-hydroxybenzoate	decreases expression	1
tris(2-carboxyethyl)phosphine	decreases oxidation	1
tebuconazole	decreases expression	1
CGP 52608	affects binding, increases reaction	1
copper-1,10-phenanthroline	affects folding, decreases stability, increases oxidation	1
Benzo(a)pyrene	affects methylation	1
Endosulfan	decreases expression	1
Antirheumatic Agents	increases expression	1
Glutathione Disulfide	increases oxidation	1
Acrylamide	decreases 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
CHEMBL4201169	Binding	Inhibition of gamma-crystallin D W43R 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)

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