CRYAA

Summary

CRYAA (crystallin alpha A, HGNC:2388) is a protein-coding gene on chromosome 21q22.3, encoding Alpha-crystallin A chain (P02489). Contributes to the transparency and refractive index of the lens.

Mammalian lens crystallins are divided into alpha, beta, and gamma families. Alpha crystallins are composed of two gene products: alpha-A and alpha-B, for acidic and basic, respectively. Alpha crystallins can be induced by heat shock and are members of the small heat shock protein (HSP20) family. They act as molecular chaperones although they do not renature proteins and release them in the fashion of a true chaperone; instead they hold them in large soluble aggregates. Post-translational modifications decrease the ability to chaperone. These heterogeneous aggregates consist of 30-40 subunits; the alpha-A and alpha-B subunits have a 3:1 ratio, respectively. Two additional functions of alpha crystallins are an autokinase activity and participation in the intracellular architecture. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. Alpha-A and alpha-B gene products are differentially expressed; alpha-A is preferentially restricted to the lens and alpha-B is expressed widely in many tissues and organs. Defects in this gene cause autosomal dominant congenital cataract (ADCC).

Source: NCBI Gene 1409 — RefSeq curated summary.

At a glance

• Gene–disease (curated): cataract 9 multiple types (Definitive, GenCC) — +5 more curated relationships
• GWAS associations: 11
• Clinical variants (ClinVar): 118 total — 6 pathogenic, 3 likely-pathogenic
• Phenotypes (HPO): 16
• Druggable target: yes
• MANE Select transcript: NM_000394

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2388
Approved symbol	CRYAA
Name	crystallin alpha A
Location	21q22.3
Locus type	gene with protein product
Status	Approved
Aliases	HSPB4
Ensembl gene	ENSG00000160202
Ensembl biotype	protein_coding
OMIM	123580
Entrez	1409

Gene structure

Transcript identifiers

Ensembl transcripts: 5 — 3 protein_coding, 1 retained_intron, 1 protein_coding_CDS_not_defined

ENST00000291554, ENST00000398132, ENST00000398133, ENST00000468016, ENST00000482775

RefSeq mRNA: 3 — MANE Select: NM_000394 NM_000394, NM_001320719, NM_001363766

CCDS: CCDS13695, CCDS86989

Canonical transcript exons

ENST00000291554 — 3 exons

Exon	Start	End
ENSE00001050530	43169008	43169288
ENSE00003462823	43172071	43172805
ENSE00003509055	43170517	43170639

Expression profiles

Bgee: expression breadth broad, 42 present calls, max score 89.14.

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
adult mammalian kidney	UBERON:0000082	89.14	gold quality
right lobe of liver	UBERON:0001114	79.98	gold quality
liver	UBERON:0002107	79.73	gold quality
kidney	UBERON:0002113	77.03	gold quality
metanephros cortex	UBERON:0010533	61.11	gold quality
cortex of kidney	UBERON:0001225	60.32	gold quality
bone marrow cell	CL:0002092	47.00	gold quality
duodenum	UBERON:0002114	40.75	gold quality
prefrontal cortex	UBERON:0000451	39.84	gold quality
primary visual cortex	UBERON:0002436	38.84	gold quality
temporal lobe	UBERON:0001871	37.38	gold quality
bone marrow	UBERON:0002371	37.28	gold quality
colonic epithelium	UBERON:0000397	37.20	gold quality
amygdala	UBERON:0001876	37.10	gold quality
frontal cortex	UBERON:0001870	36.91	gold quality
granulocyte	CL:0000094	36.67	gold quality
ventricular zone	UBERON:0003053	36.48	gold quality
cortical plate	UBERON:0005343	36.47	gold quality
Ammon’s horn	UBERON:0001954	36.33	gold quality
anterior cingulate cortex	UBERON:0009835	35.94	gold quality
caudate nucleus	UBERON:0001873	35.87	gold quality
cerebral cortex	UBERON:0000956	35.83	gold quality
ganglionic eminence	UBERON:0004023	35.49	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	34.03	gold quality
right frontal lobe	UBERON:0002810	33.97	gold quality
nucleus accumbens	UBERON:0001882	33.88	gold quality
putamen	UBERON:0001874	33.69	gold quality
skeletal muscle tissue	UBERON:0001134	33.38	gold quality
tonsil	UBERON:0002372	32.65	gold quality
brain	UBERON:0000955	32.54	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	43.13
E-MTAB-7316	yes	32.03
E-ANND-3	no	0.46

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): AP1, CREB1, E2F1, ERF, HIVEP1, JUN, MAF, MAFA, MAFB, PAX6, SMARCA5, TFAP2A, TFCP2, USF1

miRNA regulators (miRDB)

19 targeting CRYAA, 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-7110-3P	100.00	73.18	2486
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-7-5P	99.67	70.53	1809
HSA-MIR-6762-3P	99.66	66.94	1188
HSA-MIR-6828-5P	99.31	69.21	1433
HSA-MIR-485-5P	99.10	64.78	1889
HSA-MIR-6884-5P	99.10	64.50	1987
HSA-MIR-371A-5P	99.08	66.51	1914
HSA-MIR-6829-5P	98.86	65.12	1480
HSA-MIR-4716-5P	98.82	68.57	1168
HSA-MIR-6761-5P	98.71	68.03	1504
HSA-MIR-12114	98.70	63.45	730
HSA-MIR-6765-3P	97.83	64.59	1165
HSA-MIR-6893-3P	97.79	64.91	1238
HSA-MIR-370-3P	97.09	64.92	1221
HSA-MIR-3622A-3P	97.06	66.43	1000
HSA-MIR-3622B-3P	96.82	66.36	988
HSA-MIR-4509	96.19	65.80	900
HSA-MIR-6084	89.09	62.33	58

Literature-anchored findings (GeneRIF, showing 40)

• The R116C mutation in alpha A-crystallin diminishes its protective ability against stress-induced lens epithelial cell apoptosis (PMID:11756414)
• suppression of dithiothreitol-induced aggregation of abrin by alpha A-crystallin (PMID:12095619)
• The positive charge of a basic amino acid, (such as arginine or lysine) must be preserved at position 116 for the structural and functional integrity of alpha A-crystallin. (PMID:12369832)
• The regions of alpha A crystallin most affected by interaction with ATP are near putative substrate binding regions, as determined by hydrogen-deuterium exchange. (PMID:12501218)
• the SRLFDQFFG sequence region contributes to the oligomer dynamics in addition to the higher order assembly and structural stability, and is one of the critical motifs in structure-function regulation of alpha A- and alpha B-crystallin (PMID:14532291)
• accumulation and abnormal modification of alpha-crystallins might be implicated in the pathogenic mechanism of anterior polar cataracts. (PMID:15004872)
• both Asn residues (Asn-101 and Asn-123) are required for the structural integrity and chaperone function of alphaA-crystallin (PMID:15284238)
• results suggest that the presence of the alpha-crystallin domain and hydrophobic clefts on the protein surface, which correlate poorly with oligomeric size, are important for chaperone function (PMID:15382236)
• Using a cross-linker, close proximity of C termini of alpha A and alpha B crystallins was demonstrated. (PMID:15388868)
• the rate of subunit exchange is not the critical parameter in determining efficient chaperone behavior for alphaA-crystallin (PMID:15701626)
• isothermal titration calorimetric analysis of hydrophobicity and the chaperone-like function of alphaA- and alphaB-crystallin (PMID:15817465)
• May be involved in protection of hepatocytes from the toxic effects of high concentrations of bile acids (PMID:16012168)
• Based upon the unique finding of the mutation and the expression of CRYAA in the lens, this R21L mutation in the CRYAA is considered to be causative for the dominant cataract phenotype. (PMID:16453125)
• Mutations in alphaA-crystallin activate substrate binding (PMID:16531622)
• Positive charges on R21, R49, and R103 are important determinants of chaperone function of alphaA-crystallin & suggest that chemical modification of arginine residues may play a role in protein aggregation during lens aging & cataract formation. (PMID:16584192)
• Mapping a locus for syndromal cataract (cataract-microcornea syndrome) on 21q22.3. (CRYAA) (PMID:16735993)
• results indicate only slight decreased efficiency and increased distance between two probes for the R116C alphaA and R120G alphaB mutations despite conformational changes (PMID:16751613)
• Proper orientation of residues contributing to RS-1 and RS-2 sites in alphaB-crystallin is important for homooligomerization and optimal subunit interaction with alphaA-crystallin. (PMID:16760894)
• G98R mutation in alphaA-crystallin results in altered folding and becomes aggregation-prone leading to formation of large oligomers lacking chaperone function. (PMID:17149363)
• alpha A-crystallin is more stable to gamma irradiation than alpha B-crystallin (PMID:17258947)
• This study indicates that an Arg116Cys mutation in the CRYAA gene could be associated with an unusual phenotype in affected individuals. (PMID:17296897)
• characterization of the formation of amyloid fibrils by human alphaB-crystallin in detail, and also that of alphaA-crystallin and the disease-related mutant R120G alphaB-crystallin (PMID:17662998)
• Five novel mutations in CRYAA, CRYGD, and GJA8 genes were detected in congenital cataract in association with microcornea (PMID:17724170)
• mixed oligomers of wild-type and G98R alphaA-crystallin exhibit properties dominated by those of the mutant protein in structural aspects, oligomeric size, urea-induced unfolding and, more importantly, the chaperone activity (PMID:17900621)
• The presence of an intact C-terminus is essential for the formation of fully integrated heteroaggregates with equal proportion of alphaA and alphaB subunits. (PMID:17909943)
• R54C is the second reported recessive CRYAA mutation associated with congenital cataract and the first with described morphology. punctuate lenticular opacities in carriers and congenital total white cataract with microcornea in homozygotes. (PMID:17937925)
• Presbyopia may be the result of a loss of alpha-crystallin coupled with progressive heat-induced denaturation of structural proteins in the lens during the first five decades of life. (PMID:17973972)
• 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)
• this is the first knock-in mouse model for a crystallin mutation causing hereditary human cataract and establishes that alphaA-R49C promotes protein insolubility and cell death in vivo. (PMID:18056999)
• Bivalent zinc specifically interacts with alpha-crystallin with a dissociation constant in the submillimolar range. (PMID:18095658)
• G98R mutation causes conformational changes that makes the complexes the mutant protein forms with certain substrates prone to precipitattion, suggesting an etiology of cataract in individuals with this mutation. (PMID:18199971)
• With the exception of iris coloboma, the clinical features (cataracts, microcornea and/or corneal opacity) in all six previously reported families with mutations in the CRYAA gene were found in this family (PMID:18302245)
• These results suggest that the changes in the structure and function of the alpha-crystallin complex and cytotoxicity are vital factors in the pathogenesis of congenital cataract linked to the P20S mutation in the alphaB-crystallin. (PMID:18343237)
• Findings support the hypothesis that positively charged guanidino group on arginine residues keeps the chaperone function of alphaA-crystallin in check and that methylglyoxal neutralizes this charge to restore and enhance chaperone function. (PMID:18344542)
• Sequencing of CRYAA revealed a novel heterozygous G>A transition (c.346G>A) in exon 3 that cosegregated with the disease phenotype and results in a conservative substitution of Arg to His at codon 116 (PMID:18407550)
• structures close to Asp58 and Asp151 residues in the protein affect the rate constant of Asp racemization and the size and chaperone function of alpha A-crystallin (PMID:18477484)
• This study was aimed to investigate the effect of AGE crosslinks on the chaperone activity of alpha-crystallin. (PMID:18521724)
• BB is the most susceptible to gamma-irradiation and that alpha B-crystallin forms a more stable aggregate than alpha A-crystallin under normal conditions. (PMID:18639655)
• Results describe the selective copper binding, redox silencing, and cytoprotective effects of the small heat shock proteins alphaA- and alphaB-crystallin. (PMID:18692065)
• the decrease in the solubility of the alphaA-R49C mutant protein was due to an increase in its hydrophobicity and supra-aggregation of alphaA-crystallin that leads to cataract formation. (PMID:18700785)

Cross-species orthologs

21 orthologs

Organism	Symbol	Gene ID
danio_rerio	cryaa	ENSDARG00000053502
mus_musculus	Cryaa	ENSMUSG00000024041
rattus_norvegicus	Cryaa	ENSRNOG00000047175
drosophila_melanogaster	Hsp22	FBGN0001223
drosophila_melanogaster	Hsp23	FBGN0001224
drosophila_melanogaster	Hsp26	FBGN0001225
drosophila_melanogaster	Hsp67Ba	FBGN0001227
drosophila_melanogaster	Hsp67Bc	FBGN0001229
drosophila_melanogaster	l(2)efl	FBGN0011296
drosophila_melanogaster	CG14207	FBGN0031037
caenorhabditis_elegans		WBGENE00002011
caenorhabditis_elegans		WBGENE00002015
caenorhabditis_elegans		WBGENE00002016
caenorhabditis_elegans		WBGENE00002017
caenorhabditis_elegans		WBGENE00002018
caenorhabditis_elegans		WBGENE00002019
caenorhabditis_elegans		WBGENE00002020
caenorhabditis_elegans		WBGENE00002023
caenorhabditis_elegans		WBGENE00008591
caenorhabditis_elegans		WBGENE00008592
caenorhabditis_elegans	hsp-12.1	WBGENE00011906

Paralogs (8): HSPB6 (ENSG00000004776), HSPB1 (ENSG00000106211), CRYAB (ENSG00000109846), HSPB8 (ENSG00000152137), HSPB3 (ENSG00000169271), HSPB2 (ENSG00000170276), HSPB7 (ENSG00000173641), HSPB9 (ENSG00000260325)

Protein

Protein identifiers

Alpha-crystallin A chain — P02489 (reviewed: P02489)

Alternative names: Heat shock protein beta-4, Heat shock protein family B member 4

All UniProt accessions (3): P02489, A0A8C8KJZ9, E7EWH7

UniProt curated annotations — full annotation on UniProt →

Function. Contributes to the transparency and refractive index of the lens. In its oxidized form (absence of intramolecular disulfide bond), acts as a chaperone, preventing aggregation of various proteins under a wide range of stress conditions. Required for the correct formation of lens intermediate filaments as part of a complex composed of BFSP1, BFSP2 and CRYAA.

Subunit / interactions. Heteropolymer composed of three CRYAA and one CRYAB subunits. Inter-subunit bridging via zinc ions enhances stability, which is crucial as there is no protein turn over in the lens. Can also form homodimers and homotetramers (dimers of dimers) which serve as the building blocks of homooligomers. Within homooligomers, the zinc-binding motif is created from residues of 3 different molecules. His-100 and Glu-102 from one molecule are ligands of the zinc ion, and His-107 and His-154 residues from additional molecules complete the site with tetrahedral coordination geometry. Part of a complex required for lens intermediate filament formation composed of BFSP1, BFSP2 and CRYAA.

Subcellular location. Cytoplasm. Nucleus.

Tissue specificity. Expressed in the eye lens (at protein level).

Post-translational modifications. O-glycosylated; contains N-acetylglucosamine side chains. Deamidation of Asn-101 in lens occurs mostly during the first 30 years of age, followed by a small additional amount of deamidation (approximately 5%) during the next approximately 38 years, resulting in a maximum of approximately 50% deamidation during the lifetime of the individual. Phosphorylation on Ser-122 seems to be developmentally regulated. Absent in the first months of life, it appears during the first 12 years of human lifetime. The relative amount of phosphorylated form versus unphosphorylated form does not change over the lifetime of the individual. Acetylation at Lys-70 may increase chaperone activity. Undergoes age-dependent proteolytical cleavage at the C-terminus. Alpha-crystallin A(1-172) is the most predominant form produced most rapidly during the first 12 years of age and after this age is present in approximately 50% of the lens molecules. In young individuals and during the first approximately 30 years of life, less than half molecules contain an intramolecular disulfide bond (oxidized form), while in the remaining fraction the cysteines are in the free sulfhydryl form (reduced form). With aging, the amount of oxidized form increases up to 90% and it becomes a major constituent of high molecular weight aggregates, concomitant with an age-dependent loss of its chaperone activity. The reduced form is undetectable in cataractous lenses.

Disease relevance. Alpha-crystallin A 1-172 is found at nearly twofold higher levels in diabetic lenses than in age-matched control lenses. Cataract 9, multiple types (CTRCT9) [MIM:604219] 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. In general, the more posteriorly located and dense an opacity, the greater the impact on visual function. CTRCT9 includes nuclear, zonular central nuclear, anterior polar, cortical, embryonal, anterior subcapsular, fan-shaped, and total cataracts, among others. In some cases cataract is associated with microcornea without any other systemic anomaly or dysmorphism. Microcornea is defined by a corneal diameter inferior to 10 mm in both meridians in an otherwise normal eye. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the small heat shock protein (HSP20) family.

RefSeq proteins (4): NP_000385, NP_001300979, NP_001307648, NP_001350695 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001436	Alpha-crystallin/sHSP_animal	Family
IPR002068	A-crystallin/Hsp20_dom	Domain
IPR003090	Alpha-crystallin_N	Domain
IPR008978	HSP20-like_chaperone	Homologous_superfamily
IPR055269	Alpha-crystallin/HSP_16	Family

Pfam: PF00011, PF00525

UniProt features (50 total): sequence variant 20, modified residue 11, chain 4, site 4, binding site 4, sequence conflict 2, glycosylation site 1, disulfide bond 1, domain 1, mutagenesis site 1, region of interest 1

Structure

Experimental structures (PDB)

5 structures.

PDB	Method	Resolution (Å)
9U4L	ELECTRON MICROSCOPY	3.7
6T1R	ELECTRON MICROSCOPY	9.8
9MTZ	SOLUTION NMR
9MU0	SOLUTION NMR
9MYQ	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P02489-F1	74.60	0.41

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 (4): 1 (susceptible to oxidation); 18 (susceptible to oxidation); 34 (susceptible to oxidation); 138 (susceptible to oxidation)

Ligand- & substrate-binding residues (4): 100; 102; 107; 154

Post-translational modifications (11): 1, 6, 45, 50, 70, 90, 99, 101, 122, 123, 147

Disulfide bonds (1): 131–142

Glycosylation sites (1): 162

Mutagenesis-validated functional residues (1):

Position	Phenotype
123	impairs chaperone activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 172 (showing top): MORF_RAGE, GOBP_LENS_FIBER_CELL_DIFFERENTIATION, GOBP_EPITHELIUM_DEVELOPMENT, GOBP_EPITHELIAL_CELL_DEVELOPMENT, GOBP_GROWTH, GAUSSMANN_MLL_AF4_FUSION_TARGETS_A_UP, MORF_ESR1, MODULE_16, GOBP_PEPTIDE_METABOLIC_PROCESS, GOBP_ANIMAL_ORGAN_MORPHOGENESIS, GOBP_PROTEIN_MATURATION, GOBP_NEGATIVE_REGULATION_OF_TRANSPORT, GOBP_SULFUR_COMPOUND_BIOSYNTHETIC_PROCESS, GOBP_EMBRYONIC_CAMERA_TYPE_EYE_MORPHOGENESIS, GOBP_EMBRYONIC_ORGAN_MORPHOGENESIS

GO Biological Process (24): response to hypoxia (GO:0001666), lens development in camera-type eye (GO:0002088), glutathione biosynthetic process (GO:0006750), mitochondrion organization (GO:0007005), actin filament organization (GO:0007015), microtubule-based process (GO:0007017), tubulin complex assembly (GO:0007021), visual perception (GO:0007601), response to heat (GO:0009408), negative regulation of gene expression (GO:0010629), positive regulation of cell growth (GO:0030307), negative regulation of intracellular transport (GO:0032387), protein refolding (GO:0042026), response to hydrogen peroxide (GO:0042542), negative regulation of apoptotic process (GO:0043066), embryonic camera-type eye morphogenesis (GO:0048596), protein stabilization (GO:0050821), apoptotic process involved in morphogenesis (GO:0060561), response to UV-A (GO:0070141), lens fiber cell morphogenesis (GO:0070309), lens morphogenesis in camera-type eye (GO:0002089), glutathione metabolic process (GO:0006749), apoptotic process (GO:0006915), camera-type eye development (GO:0043010)

GO Molecular Function (6): structural molecule activity (GO:0005198), structural constituent of eye lens (GO:0005212), identical protein binding (GO:0042802), metal ion binding (GO:0046872), obsolete unfolded protein binding (GO:0051082), protein binding (GO:0005515)

GO Cellular Component (5): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), protein-containing complex (GO:0032991)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	3
response to stress	2
response to decreased oxygen levels	1
camera-type eye development	1
anatomical structure development	1
glutathione metabolic process	1
nonribosomal peptide biosynthetic process	1
modified amino acid biosynthetic process	1
sulfur compound biosynthetic process	1
organelle organization	1
actin cytoskeleton organization	1
supramolecular fiber organization	1
cellular process	1
protein-containing complex assembly	1
sensory perception of light stimulus	1
response to temperature stimulus	1
gene expression	1
regulation of gene expression	1
negative regulation of macromolecule biosynthetic process	1
regulation of cell growth	1
cell growth	1
positive regulation of growth	1
positive regulation of cellular process	1
regulation of intracellular transport	1
intracellular transport	1
negative regulation of cellular process	1
negative regulation of transport	1
protein folding	1
response to reactive oxygen species	1
apoptotic process	1
regulation of apoptotic process	1
negative regulation of programmed cell death	1
embryonic camera-type eye development	1
embryonic eye morphogenesis	1
camera-type eye morphogenesis	1
regulation of protein stability	1
anatomical structure morphogenesis	1
apoptotic process involved in development	1
response to UV	1
cell morphogenesis	1

Protein interactions and networks

STRING

804 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CRYAA	CRYBB2	P43320	956
CRYAA	CRYGS	P22914	945
CRYAA	CRYBA1	P05813	943
CRYAA	CRYGA	P11844	932
CRYAA	CRYBA4	P53673	878
CRYAA	CRYBB3	P26998	870
CRYAA	LIM2	P55344	854
CRYAA	CRYBB1	P53674	847
CRYAA	CRYGC	P07315	835
CRYAA	CRYGD	P07320	829
CRYAA	GJA8	P48165	827
CRYAA	GJA3	Q9Y6H8	812
CRYAA	CRYGB	P07316	788
CRYAA	BFSP1	Q12934	749
CRYAA	BFSP2	Q13515	742

IntAct

406 interactions, top by confidence:

A	B	Type	Score
CRYAB	CRYAA	psi-mi:“MI:0915”(physical association)	0.970
CRYAA	CRYAB	psi-mi:“MI:0407”(direct interaction)	0.970
CRYAB	CRYAA	psi-mi:“MI:0407”(direct interaction)	0.970
CRYAA	CRYAB	psi-mi:“MI:0915”(physical association)	0.970
CRYAA	CRYAA	psi-mi:“MI:0915”(physical association)	0.930
CRYAA	CRYAA	psi-mi:“MI:0407”(direct interaction)	0.930
CRYAA	GORASP2	psi-mi:“MI:0915”(physical association)	0.840
GORASP2	CRYAA	psi-mi:“MI:0915”(physical association)	0.840
CRYAA	HSPB1	psi-mi:“MI:0915”(physical association)	0.810
SDCBP	CRYAA	psi-mi:“MI:0915”(physical association)	0.780
CRYAA	NTAQ1	psi-mi:“MI:0915”(physical association)	0.780
SPG21	CRYAA	psi-mi:“MI:0915”(physical association)	0.780

BioGRID (254): CRYAA (Two-hybrid), CRYAB (Two-hybrid), SDCBP (Two-hybrid), GORASP2 (Two-hybrid), SPG21 (Two-hybrid), WDYHV1 (Two-hybrid), CRYAA (Reconstituted Complex), CRYAB (Reconstituted Complex), CRYAA (Reconstituted Complex), CRYBA1 (Reconstituted Complex), CRYAB (Reconstituted Complex), CRYBA1 (FRET), CRYAB (FRET), CRYAA (Two-hybrid), CRYAB (Reconstituted Complex)

ESM2 similar proteins: O12984, O12988, O73919, O93591, P02470, P02472, P02474, P02475, P02476, P02478, P02479, P02480, P02482, P02483, P02484, P02485, P02486, P02487, P02488, P02489, P02492, P02493, P02494, P02498, P02499, P02501, P02502, P02503, P02504, P02505, P02506, P02508, P06904, P23928, P68280, P68281, P68282, P68283, P68284, P68285

Diamond homologs: A5JV83, O14558, P02487, P02488, P02489, P02507, P02510, P02511, P02512, P04120, P04792, P05811, P06581, P06582, P14602, P15991, P23927, P23928, P30218, P30219, P34696, P35385, P41316, P42929, P42930, P42931, P82147, P97541, Q00649, Q04757, Q05557, Q05713, Q148F8, Q1RI96, Q3T149, Q5EAC9, Q5ENY9, Q5R9K0, Q5RAB0, Q5S1U1

SIGNOR signaling

2 interactions.

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

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 103 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.

GO biological processes:

GO term	Partners	Fold	FDR
stress-activated MAPK cascade	5	39.0×	9e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	3
Uncertain significance	54
Likely benign	29
Benign	16

Top pathogenic / likely-pathogenic (9)

Variant ID	HGVS	Classification
16957	NM_000394.4(CRYAA):c.346C>T (p.Arg116Cys)	Pathogenic
16960	NM_000394.4(CRYAA):c.347G>A (p.Arg116His)	Pathogenic
521018	NM_000394.4(CRYAA):c.346C>A (p.Arg116Ser)	Pathogenic
68456	NM_000394.4(CRYAA):c.292G>A (p.Gly98Arg)	Pathogenic
68457	NM_000394.4(CRYAA):c.160C>T (p.Arg54Cys)	Pathogenic
68461	NM_000394.4(CRYAA):c.62G>A (p.Arg21Gln)	Pathogenic
16958	NM_000394.4(CRYAA):c.27G>A (p.Trp9Ter)	Likely pathogenic
217332	NM_000394.4(CRYAA):c.142T>G (p.Tyr48Asp)	Likely pathogenic
3731277	NM_000394.4(CRYAA):c.347G>T (p.Arg116Leu)	Likely pathogenic

SpliceAI

386 predictions. Top by Δscore:

Variant	Effect	Δscore
21:43169285:TGAGG:T	donor_loss	1.0000
21:43169286:GAG:G	donor_gain	1.0000
21:43169286:GAGGT:G	donor_loss	1.0000
21:43169287:AG:A	donor_gain	1.0000
21:43169287:AGG:A	donor_loss	1.0000
21:43169288:GG:G	donor_gain	1.0000
21:43169288:GGT:G	donor_loss	1.0000
21:43169289:G:GG	donor_gain	1.0000
21:43169289:GT:G	donor_loss	1.0000
21:43169290:T:A	donor_loss	1.0000
21:43170513:TCAG:T	acceptor_loss	1.0000
21:43170513:TCAGG:T	acceptor_loss	1.0000
21:43170514:CA:C	acceptor_loss	1.0000
21:43170516:G:GA	acceptor_loss	1.0000
21:43170635:GCCAG:G	donor_gain	1.0000
21:43170637:CAGG:C	donor_loss	1.0000
21:43170638:AGGTG:A	donor_loss	1.0000
21:43170639:GGTGA:G	donor_loss	1.0000
21:43170640:G:GG	donor_gain	1.0000
21:43170640:G:T	donor_loss	1.0000
21:43170640:GTGAG:G	donor_loss	1.0000
21:43169285:TGAG:T	donor_gain	0.9900
21:43169286:GAGG:G	donor_gain	0.9900
21:43170516:GGTTC:G	acceptor_gain	0.9900
21:43170621:A:T	donor_gain	0.9900
21:43170639:GGT:G	donor_gain	0.9900
21:43170640:GTG:G	donor_gain	0.9900
21:43172065:CTCCA:C	acceptor_loss	0.9900
21:43172066:TCCA:T	acceptor_loss	0.9900
21:43172067:CCAG:C	acceptor_loss	0.9900

AlphaMissense

1127 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
21:43170551:T:C	L75P	1.000
21:43170565:T:C	F80L	1.000
21:43170566:T:C	F80S	1.000
21:43170567:C:A	F80L	1.000
21:43170567:C:G	F80L	1.000
21:43170581:T:C	L85P	1.000
21:43170620:G:A	G98E	1.000
21:43172080:G:C	G108R	1.000
21:43172081:G:A	G108D	1.000
21:43172092:C:A	R112S	1.000
21:43172093:G:C	R112P	1.000
21:43172098:T:C	F114L	1.000
21:43172099:T:C	F114S	1.000
21:43172100:C:A	F114L	1.000
21:43172100:C:G	F114L	1.000
21:43172104:C:A	R116S	1.000
21:43172105:G:C	R116P	1.000
21:43172168:G:T	G137V	1.000
21:43172174:T:C	L139P	1.000
21:43170565:T:G	F80V	0.999
21:43170566:T:G	F80C	0.999
21:43170581:T:A	L85H	0.999
21:43170587:T:A	V87E	0.999
21:43170608:T:A	V94E	0.999
21:43170614:T:A	I96N	0.999
21:43170614:T:G	I96S	0.999
21:43170620:G:T	G98V	0.999
21:43170625:C:G	H100D	0.999
21:43172071:G:C	D105H	0.999
21:43172080:G:T	G108C	0.999

dbSNP variants (sampled 300 via entrez): RS1000647169 (21:43168394 C>T), RS1001849891 (21:43172750 G>A), RS1001920022 (21:43168755 A>C), RS1002054336 (21:43168913 C>T), RS1002219013 (21:43172574 G>A), RS1003733563 (21:43169823 C>A,T), RS1004065418 (21:43167151 A>G), RS1004772737 (21:43169871 T>G), RS1005740086 (21:43168095 A>C), RS1008190104 (21:43167252 C>T), RS1008350726 (21:43173111 G>GCCGGCA), RS1009759807 (21:43169490 G>T), RS1010141352 (21:43169698 A>G), RS1014443488 (21:43167729 G>A), RS1015579329 (21:43171055 G>A)

Disease associations

OMIM: gene MIM:123580 | disease phenotypes: MIM:604219

GenCC curated gene-disease

Disease	Classification	Inheritance
cataract 9 multiple types	Definitive	Autosomal recessive
cataract - microcornea syndrome	Supportive	Autosomal dominant
early-onset lamellar cataract	Supportive	Autosomal dominant
early-onset anterior polar cataract	Supportive	Autosomal dominant
early-onset nuclear cataract	Supportive	Autosomal dominant
total early-onset cataract	Supportive	Autosomal dominant

Mondo (7): cataract 9 multiple types (MONDO:0011413), congenital portosystemic shunt (MONDO:0018811), cataract - microcornea syndrome (MONDO:0015300), early-onset lamellar cataract (MONDO:0018611), early-onset anterior polar cataract (MONDO:0020373), early-onset nuclear cataract (MONDO:0020376), total early-onset cataract (MONDO:0021548)

Orphanet (2): Cataract-microcornea syndrome (Orphanet:1377), Congenital portosystemic shunt (Orphanet:480531)

HPO phenotypes

16 total (16 of 16 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000482	Microcornea
HP:0000486	Strabismus
HP:0000501	Glaucoma
HP:0000505	Visual impairment
HP:0000518	Cataract
HP:0000519	Developmental cataract
HP:0000545	Myopia
HP:0000568	Microphthalmia
HP:0000612	Iris coloboma
HP:0000639	Nystagmus
HP:0000646	Amblyopia
HP:0001131	Corneal dystrophy
HP:0007834	Progressive cataract
HP:0007957	Corneal opacity

GWAS associations

11 associations (top):

Study	Trait	p-value
GCST002498_3	Age-related nuclear cataracts	2.000000e-09
GCST004280_75	Diastolic blood pressure	4.000000e-13
GCST004776_28	Systolic blood pressure	2.000000e-09
GCST004777_59	Diastolic blood pressure	2.000000e-09
GCST006258_18	Diastolic blood pressure	1.000000e-11
GCST006259_24	Systolic blood pressure	3.000000e-14
GCST007094_138	Diastolic blood pressure	3.000000e-08
GCST007099_68	Systolic blood pressure	5.000000e-07
GCST009391_2135	Metabolite levels	2.000000e-07
GCST009391_433	Metabolite levels	8.000000e-07
GCST90013423_7	Age-related nuclear cataracts	3.000000e-16

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0006336	diastolic blood pressure
EFO:0006335	systolic blood pressure
EFO:0010384	phosphatidylcholine 38:2 measurement
EFO:0010385	phosphatidylcholine 38:3 measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
C538287	Cataract microcornea syndrome (supp.)
C563333	Cataract, Age-Related Nuclear (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4296283 (SINGLE PROTEIN)

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

ChEMBL bioactivities

1 potent at pChembl≥5 of 2 total, top 1 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
7.45	EC50	35.6	nM	CHEMBL4203007

PubChem BioAssay actives

2 with measured affinity, of 170 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(3S,5R,10S,13R,14R,17R)-17-[(2R)-6-hydroxy-6-methylheptan-2-yl]-4,4,10,13,14-pentamethyl-2,3,5,6,7,11,12,15,16,17-decahydro-1H-cyclopenta[a]phenanthren-3-ol	1386508: Induction of redissolving of aggregated alpha-crystallin A Y118D mutant (unknown origin) incubated for 24 hrs by ThT-fluorescence based assay	ec50	0.0356	uM

CTD chemical–gene interactions

23 total (human), top 23 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Dimethylnitrosamine	decreases expression	2
Zinc	decreases expression	2
Cyclosporine	decreases expression, increases expression	2
dicrotophos	increases expression	1
quinone	affects binding, affects folding	1
beryllium sulfate	decreases expression	1
2,3-dimethoxy-1,4-naphthoquinone	decreases expression	1
ICG 001	increases expression	1
Resveratrol	affects cotreatment, decreases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Cadmium	decreases expression	1
Chromium	decreases expression	1
Diethylhexyl Phthalate	decreases expression	1
Doxorubicin	decreases response to substance	1
Mercury	decreases expression	1
Plant Extracts	affects cotreatment, decreases expression	1
Potassium Dichromate	decreases expression	1
Silver	increases expression	1
Tetrachloroethylene	decreases expression	1
Urethane	decreases expression	1
Valproic Acid	decreases expression, increases methylation	1
Sertraline	increases expression	1

ChEMBL screening assays

25 unique, capped per target: 25 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4201166	Binding	Inhibition of alpha-crystallin A Y118D 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)

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

Trial	Phase	Status	Title
NCT06068348	Not specified	ACTIVE_NOT_RECRUITING	Liquid Biopsy Collection Study
NCT06041906	Not specified	ENROLLING_BY_INVITATION	International Registry of Congenital Portosystemic Shunt (IRCPSS)
NCT07314814	Not specified	NOT_YET_RECRUITING	Genetic Hallmarks of Patients With Congenital Portosystemic Shunts and Portopulmonary Hypertension