CRYM

Summary

CRYM (crystallin mu, HGNC:2418) is a protein-coding gene on chromosome 16p12.2, encoding Ketimine reductase mu-crystallin (Q14894). Catalyzes the NAD(P)H-dependent reduction of imine double bonds of a number of cyclic ketimine substrates, including sulfur-containing cyclic ketimines.

Crystallins are separated into two classes: taxon-specific and ubiquitous. The former class is also called phylogenetically-restricted crystallins. The latter class constitutes the major proteins of vertebrate eye lens and maintains the transparency and refractive index of the lens. This gene encodes a taxon-specific crystallin protein that binds NADPH and has sequence similarity to bacterial ornithine cyclodeaminases. The encoded protein does not perform a structural role in lens tissue, and instead it binds thyroid hormone for possible regulatory or developmental roles. Mutations in this gene have been associated with autosomal dominant non-syndromic deafness.

Source: NCBI Gene 1428 — RefSeq curated summary.

At a glance

• Gene–disease (curated): autosomal dominant nonsyndromic hearing loss (Supportive, GenCC) — +2 more curated relationships
• GWAS associations: 1
• Clinical variants (ClinVar): 150 total
• Phenotypes (HPO): 5
• MANE Select transcript: NM_001376256

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:2418
Approved symbol	CRYM
Name	crystallin mu
Location	16p12.2
Locus type	gene with protein product
Status	Approved
Aliases	DFNA40
Ensembl gene	ENSG00000103316
Ensembl biotype	protein_coding
OMIM	123740
Entrez	1428

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 11 protein_coding, 2 retained_intron, 1 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined

ENST00000219599, ENST00000543948, ENST00000570401, ENST00000571358, ENST00000571666, ENST00000572113, ENST00000572914, ENST00000574448, ENST00000574787, ENST00000576703, ENST00000903144, ENST00000903145, ENST00000903146, ENST00000934987, ENST00000934988

RefSeq mRNA: 2 — MANE Select: NM_001376256 NM_001376256, NM_001888

CCDS: CCDS10597

Canonical transcript exons

ENST00000572914 — 8 exons

Exon	Start	End
ENSE00001140785	21277431	21277584
ENSE00001523595	21258521	21258845
ENSE00002651029	21278082	21278290
ENSE00003584255	21275532	21275594
ENSE00003594729	21262037	21262158
ENSE00003608583	21261254	21261338
ENSE00003623018	21269790	21269891
ENSE00003675398	21267554	21267737

Expression profiles

Bgee: expression breadth ubiquitous, 252 present calls, max score 99.26.

FANTOM5 (CAGE): breadth broad, TPM avg 4.1780 / max 394.7564, expressed in 611 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
156719	1.7267	241
156720	1.3245	270
156724	0.6267	234
156718	0.2765	89
156723	0.1394	12
156721	0.0843	47

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cortical plate	UBERON:0005343	99.26	gold quality
cerebellar vermis	UBERON:0004720	98.97	gold quality
frontal pole	UBERON:0002795	98.88	gold quality
cerebellar cortex	UBERON:0002129	98.53	gold quality
paraflocculus	UBERON:0005351	98.53	gold quality
cerebellar hemisphere	UBERON:0002245	98.52	gold quality
right hemisphere of cerebellum	UBERON:0014890	98.46	gold quality
cerebellum	UBERON:0002037	98.43	gold quality
Brodmann (1909) area 10	UBERON:0013541	97.94	gold quality
orbitofrontal cortex	UBERON:0004167	97.84	gold quality
apex of heart	UBERON:0002098	97.82	gold quality
nucleus accumbens	UBERON:0001882	97.65	gold quality
Brodmann (1909) area 9	UBERON:0013540	97.47	gold quality
prefrontal cortex	UBERON:0000451	97.34	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	97.20	gold quality
right frontal lobe	UBERON:0002810	97.18	gold quality
nasal cavity epithelium	UBERON:0005384	97.11	gold quality
frontal cortex	UBERON:0001870	96.97	gold quality
cardiac muscle of right atrium	UBERON:0003379	96.82	gold quality
left ventricle myocardium	UBERON:0006566	96.66	gold quality
myocardium	UBERON:0002349	96.54	gold quality
caudate nucleus	UBERON:0001873	96.53	gold quality
middle temporal gyrus	UBERON:0002771	96.32	gold quality
heart right ventricle	UBERON:0002080	96.30	gold quality
Brodmann (1909) area 46	UBERON:0006483	96.23	gold quality
neocortex	UBERON:0001950	96.21	gold quality
cardiac ventricle	UBERON:0002082	96.20	gold quality
heart left ventricle	UBERON:0002084	96.19	gold quality
cardiac atrium	UBERON:0002081	96.07	gold quality
right atrium auricular region	UBERON:0006631	96.01	gold quality

Single-cell (SCXA)

Detected in 5 experiment(s), a significant marker in 5.

Experiment	Marker?	Max mean expression
E-GEOD-137537	yes	36.94
E-MTAB-7316	yes	23.37
E-MTAB-9388	yes	12.96
E-CURD-114	yes	12.27
E-ANND-3	yes	11.58

Regulation

Is transcription factor: no

Literature-anchored findings (GeneRIF, showing 17)

• Identification of CRYM as a candidate responsible for nonsyndromic deafness, through cDNA microarray analysis of human cochlear and vestibular tissues (PMID:12471561)
• up-regulation of mu-crystallin may play a specific and important role in pathogenesis of facioscapulohumeral muscular dystrophy (PMID:17451686)
• This protein has been found differentially expressed in the dorsolateral prefrontal cortex from patients with schizophrenia. (PMID:19110265)
• Using shotgun mass spectrometry, we found this protein differentially expressed in the dorsolateral prefrontal cortex from patients with schizophrenia. (PMID:19165527)
• CRYM is a novel androgen-regulated gene whose expression is elevated in prostate cancer but down-regulated in castration therapy-resistant tumors. (PMID:19353593)
• This is the first report linking hyperglycemia with thyroid hormone binding protein CRYM and suggests that the role of CRYM in diabetic complications should be further investigated. (PMID:20018174)
• This protein has been found differentially expressed in thalami from patients with schizophrenia. (PMID:20471030)
• Its enzyme function has been determined as a ketimine reductase in mammalian brain. (PMID:21332720)
• Its ketimine reductase activity is strongly inhibited by thyroid hormones. (PMID:21332720)
• The purified human mu-crystallin was confirmed to have ketimine reductase activity with a maximum specific activity similar to that of native ovine ketimine reductase (PMID:21332720)
• The expression of mu-crystallin was regulated through the AP-1 site in the promoter. (PMID:23508717)
• ketimine reductase is a key enzyme in the pipecolate pathway, which is the main lysine degradation pathway in the brain (PMID:25931162)
• These findings confirm that, mechanistically, ketimine reductase/CRYM acts as a classical imine reductase and may explain the finding of bound pyruvate in the crystallized protein. (PMID:26173510)
• Results suggest that mu-crystallin may play roles in development of cortical and hippocampal pyramidal cells in the early postnatal period, and in the later period, performs cell-specific functions in selected neuronal populations. (PMID:29603402)
• Thyroid and androgen receptor signaling are antagonized by mu-Crystallin in prostate cancer. (PMID:33034050)
• Gene expression patterns of CRYM and SIGLEC10 in Alzheimer’s disease: potential early diagnostic indicators. (PMID:38401023)
• Crym-positive striatal astrocytes gate perseverative behaviour. (PMID:38418885)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	crym	ENSDARG00000062817
mus_musculus	Crym	ENSMUSG00000030905
rattus_norvegicus	Crym	ENSRNOG00000061215
drosophila_melanogaster	CG4872	FBGN0030799

Protein

Protein identifiers

Ketimine reductase mu-crystallin — Q14894 (reviewed: Q14894)

Alternative names: 1-piperideine-2-carboxylate/1-pyrroline-2-carboxylate reductase, NADP-regulated thyroid-hormone-binding protein

All UniProt accessions (6): Q14894, I3L2W5, I3L325, I3L3J9, I3L3Y1, I3NI53

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the NAD(P)H-dependent reduction of imine double bonds of a number of cyclic ketimine substrates, including sulfur-containing cyclic ketimines. Under physiological conditions, it efficiently catalyzes delta(1)-piperideine-2-carboxylate (P2C) and delta(1)-pyrroline-2-carboxylate (Pyr2C) reduction, suggesting a central role in lysine and glutamate metabolism. Additional substrates are delta(2)-thiazoline-2-carboxylate (T2C), 3,4-dehydrothiomorpholine-3-carboxylate (AECK), and (R)-lanthionine ketimine (LK) that is reduced at very low rate compared to other substrates. Also catalyzes the NAD(P)H-dependent reduction of (S)-cystathionine ketimine (CysK).

Subunit / interactions. Homodimer. Binds the thyroid hormone triiodothyronine (T3); T3 binding inhibits enzymatic activity.

Subcellular location. Cytoplasm.

Tissue specificity. Expressed in neural tissues, muscle and kidney. Expressed in the inner ear.

Disease relevance. Deafness, autosomal dominant, 40 (DFNA40) [MIM:616357] A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. The disease is caused by variants affecting the gene represented in this entry.

Activity regulation. Inhibited by thyroid hormones triiodothyronine (T3) and thyroxine (T4).

Similarity. Belongs to the ornithine cyclodeaminase/mu-crystallin family.

RefSeq proteins (2): NP_001363185, NP_001879 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR003462	ODC_Mu_crystall	Family
IPR023401	ODC_N	Homologous_superfamily
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily

Pfam: PF02423

Enzyme classification (BRENDA):

• EC 1.5.1.21 — 1-piperideine-2-carboxylate/1-pyrroline-2-carboxylate reductase (NADPH) (BRENDA: 12 organisms, 42 substrates, 16 inhibitors, 17 Km, 6 kcat entries)
• EC 1.5.1.25 — thiomorpholine-carboxylate dehydrogenase (BRENDA: 6 organisms, 36 substrates, 27 inhibitors, 15 Km, 4 kcat entries)

Substrate kinetics (BRENDA)

20 substrates with measured Km, best-characterized 15. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
DELTA1-PIPERIDEINE-2-CARBOXYLATE	0.23–1.6	3
NADPH	0.034–0.14	3
NADH	0.015–0.26	3
NADP+	0.034–0.14	2
CYSTATHIONINE KETIMINE	3–10	2
LANTHIONINE KETIMINE	0.47–1.17	2
S-AMINOETHYLCYSTEINE KETIMINE	0.077–0.24	2
1-PIPERIDEINE-2-CARBOXYLATE	1.57	1
1-PYRROLINE-(4R)-HYDROXY-2-CARBOXYLATE	0.835	1
1-PYRROLINE-2-CARBOXYLATE	0.447	1
DELTA1-PYRROLINE-5-CARBOXYLATE	0.4	1
DIGLUTAMATE	0.28	1
L-PIPECOLATE	34.8	1
L-PROLINE	18.5	1
TRANS-3-HYDROXY-L-PROLINE	132	1

Catalyzed reactions (Rhea), 10 shown:

• (3R)-1,4-thiomorpholine-3-carboxylate + NADP(+) = 3,4-dehydrothiomorpholine-3-carboxylate + NADPH + 2 H(+) (RHEA:12500)
• (3R)-1,4-thiomorpholine-3-carboxylate + NAD(+) = 3,4-dehydrothiomorpholine-3-carboxylate + NADH + 2 H(+) (RHEA:12504)
• L-pipecolate + NADP(+) = Delta(1)-piperideine-2-carboxylate + NADPH + H(+) (RHEA:12524)
• L-proline + NADP(+) = 1-pyrroline-2-carboxylate + NADPH + H(+) (RHEA:20317)
• L-proline + NAD(+) = 1-pyrroline-2-carboxylate + NADH + H(+) (RHEA:20321)
• L-pipecolate + NAD(+) = Delta(1)-piperideine-2-carboxylate + NADH + H(+) (RHEA:30807)
• (S)-cystathionine ketimine + NADH + 2 H(+) = (3R,5S)-2,3,5,6,7-pentahydro-1,4-thiazepine-3,5-dicarboxylate + NAD(+) (RHEA:68032)
• (S)-cystathionine ketimine + NADPH + 2 H(+) = (3R,5S)-2,3,5,6,7-pentahydro-1,4-thiazepine-3,5-dicarboxylate + NADP(+) (RHEA:68036)
• (R)-lanthionine ketimine + NADPH + 2 H(+) = (3R,5R)-1,4-thiomorpholine-3,5-dicarboxylate + NADP(+) (RHEA:68040)
• Delta(2)-thiazoline-2-carboxylate + NADPH + 2 H(+) = L-thiazolidine-2-carboxylate + NADP(+) (RHEA:68072)

UniProt features (53 total): binding site 17, helix 15, strand 14, sequence variant 3, turn 3, chain 1

Structure

Experimental structures (PDB)

1 structures.

PDB	Method	Resolution (Å)
2I99	X-RAY DIFFRACTION	2.6

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14894-F1	96.06	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.

Ligand- & substrate-binding residues (17): 47; 170; 173; 205; 206; 226; 228; 257; 292; 82; 92; 119 …

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-71064	Lysine catabolism

MSigDB gene sets: 190 (showing top): GOBP_PHENOL_CONTAINING_COMPOUND_METABOLIC_PROCESS, GOBP_SENSORY_PERCEPTION_OF_MECHANICAL_STIMULUS, GOBP_ALPHA_AMINO_ACID_METABOLIC_PROCESS, GOBP_REGULATION_OF_HORMONE_LEVELS, GOBP_HORMONE_TRANSPORT, GOBP_THYROID_HORMONE_METABOLIC_PROCESS, HERNANDEZ_ABERRANT_MITOSIS_BY_DOCETACEL_2NM_DN, MODULE_66, MARTINEZ_RB1_TARGETS_DN, HOSHIDA_LIVER_CANCER_SUBCLASS_S3, GOBP_ORGANIC_ACID_CATABOLIC_PROCESS, GOBP_ORGANIC_ACID_METABOLIC_PROCESS, GOBP_SMALL_MOLECULE_CATABOLIC_PROCESS, MODULE_88, GOBP_SENSORY_PERCEPTION

GO Biological Process (5): negative regulation of transcription by RNA polymerase II (GO:0000122), obsolete lysine catabolic process (GO:0006554), sensory perception of sound (GO:0007605), thyroid hormone metabolic process (GO:0042403), thyroid hormone transport (GO:0070327)

GO Molecular Function (10): transcription corepressor activity (GO:0003714), protein homodimerization activity (GO:0042803), delta1-piperideine-2-carboxylate reductase activity (GO:0047125), thiomorpholine-carboxylate dehydrogenase activity (GO:0047127), pyrroline-2-carboxylate reductase activity (GO:0050241), NADP binding (GO:0050661), thyroid hormone binding (GO:0070324), protein binding (GO:0005515), oxidoreductase activity (GO:0016491), hormone binding (GO:0042562)

GO Cellular Component (6): nucleus (GO:0005634), cytoplasm (GO:0005737), mitochondrion (GO:0005739), peroxisomal matrix (GO:0005782), cytosol (GO:0005829), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Metabolism of amino acids and derivatives	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
oxidoreductase activity, acting on the CH-NH group of donors, NAD or NADP as acceptor	3
negative regulation of DNA-templated transcription	2
binding	2
intracellular membrane-bounded organelle	2
cellular anatomical structure	2
cytoplasm	2
regulation of transcription by RNA polymerase II	1
transcription by RNA polymerase II	1
sensory perception of mechanical stimulus	1
modified amino acid metabolic process	1
phenol-containing compound metabolic process	1
hormone metabolic process	1
hormone transport	1
transcription coregulator activity	1
identical protein binding	1
protein dimerization activity	1
adenyl nucleotide binding	1
hormone binding	1
catalytic activity	1
intracellular anatomical structure	1
peroxisome	1
microbody lumen	1
extracellular vesicle	1

Protein interactions and networks

STRING

1784 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CRYM	CRYBB1	P53674	629
CRYM	LBHD1	Q9BQE6	557
CRYM	SLC16A2	P36021	556
CRYM	CRYBA1	P05813	548
CRYM	L3HYPDH	Q96EM0	545
CRYM	CRYZL1	O95825	530
CRYM	MYH9	P35579	521
CRYM	SLC16A10	Q8TF71	510
CRYM	PMM1	Q92871	497
CRYM	CSNK1D	P48730	496
CRYM	GJB3	O75712	472
CRYM	HMOX2	P30519	470
CRYM	TMC1	Q8TDI8	470
CRYM	SLC17A8	Q8NDX2	459
CRYM	TTR	P02766	456

IntAct

17 interactions, top by confidence:

A	B	Type	Score
CRYM	OPTN	psi-mi:“MI:0915”(physical association)	0.560
CRYM	TERF1	psi-mi:“MI:0915”(physical association)	0.510
CRYM	NSF	psi-mi:“MI:0915”(physical association)	0.400
CRYM	ADRB2	psi-mi:“MI:0915”(physical association)	0.370
C7orf25	CRYM	psi-mi:“MI:0915”(physical association)	0.370
CRYM	CDC37	psi-mi:“MI:0915”(physical association)	0.370
PPP1CA	ACO2	psi-mi:“MI:0914”(association)	0.350
RNF126	CAPN15	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350
RNF126	GET3	psi-mi:“MI:0914”(association)	0.350
FCGR2B	FCGR2A	psi-mi:“MI:0914”(association)	0.350
TERF1	CRYM	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (13): CRYM (Affinity Capture-MS), CRYM (Affinity Capture-MS), TG (Reconstituted Complex), CRYM (Two-hybrid), CRYM (Affinity Capture-MS), CRYM (Affinity Capture-MS), CRYM (Affinity Capture-MS), NSF (Affinity Capture-MS), CRYM (Affinity Capture-MS), DYNC1H1 (Cross-Linking-MS (XL-MS)), CRYM (Two-hybrid), CRYM (Two-hybrid), CRYM (Two-hybrid)

ESM2 similar proteins: A0A0U4AHM6, F2Z678, K4BW79, O00097, O13309, O19053, O23939, O54983, O94038, O97764, P00330, P00331, P06525, P07246, P07754, P08843, P0DXJ3, P11415, P12711, P12886, P13603, P19854, P20369, P38113, P39451, P41747, P43067, P47199, P48977, P49383, P49384, P49385, P54202, P80467, Q07288, Q08257, Q0MVN8, Q14894, Q28488, Q2KHX6

Diamond homologs: A1B196, A9AKH1, O54983, P55665, P58338, P58339, Q0B953, Q14894, Q28488, Q2KHX6, Q485R8, Q9FLY0, Q9HDZ0, Q9QYU4, V5YW53, A1B8Z0, O28608, Q59701, P09773, Q2G1N2, Q59175, Q63FA5, Q6HMS8, Q73CR9, Q81HB0, Q88H32, Q8FVE4, Q8YCY1, Q60172, Q54304

SIGNOR signaling

0 interactions.

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	62
Likely benign	40
Benign	28

Top pathogenic / likely-pathogenic (0)

SpliceAI

1582 predictions. Top by Δscore:

Variant	Effect	Δscore
16:21249727:CTA:C	acceptor_loss	1.0000
16:21249728:TA:T	acceptor_loss	1.0000
16:21249729:A:AG	acceptor_gain	1.0000
16:21249729:AGAG:A	acceptor_gain	1.0000
16:21249729:AGAGG:A	acceptor_gain	1.0000
16:21249730:G:GG	acceptor_gain	1.0000
16:21249730:GA:G	acceptor_gain	1.0000
16:21249730:GAGG:G	acceptor_gain	1.0000
16:21249730:GAGGG:G	acceptor_gain	1.0000
16:21262031:CCTCA:C	donor_loss	1.0000
16:21262032:CTCAC:C	donor_loss	1.0000
16:21262033:TCA:T	donor_loss	1.0000
16:21262034:CAC:C	donor_loss	1.0000
16:21262035:A:AC	donor_gain	1.0000
16:21262035:AC:A	donor_gain	1.0000
16:21262035:ACC:A	donor_gain	1.0000
16:21262036:C:CC	donor_gain	1.0000
16:21262036:CC:C	donor_gain	1.0000
16:21262036:CCC:C	donor_gain	1.0000
16:21262037:C:A	donor_gain	1.0000
16:21262077:T:TA	donor_gain	1.0000
16:21262156:CAG:C	acceptor_gain	1.0000
16:21262157:AGC:A	acceptor_loss	1.0000
16:21262158:GC:G	acceptor_loss	1.0000
16:21262159:C:CC	acceptor_gain	1.0000
16:21262159:CTAA:C	acceptor_loss	1.0000
16:21269783:GACTT:G	donor_loss	1.0000
16:21269784:ACTTA:A	donor_loss	1.0000
16:21269785:CTTA:C	donor_loss	1.0000
16:21269786:TTA:T	donor_loss	1.0000

AlphaMissense

890 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:21277530:C:A	K75N	0.996
16:21277530:C:G	K75N	0.996
16:21277570:A:G	M62T	0.994
16:21275548:G:A	S124F	0.993
16:21275562:T:A	R119S	0.993
16:21275562:T:G	R119S	0.993
16:21278113:G:T	R47S	0.993
16:21275557:G:T	A121D	0.992
16:21275575:A:T	I115K	0.992
16:21277569:C:A	M62I	0.992
16:21277569:C:G	M62I	0.992
16:21277569:C:T	M62I	0.992
16:21275539:G:T	A127D	0.991
16:21277433:C:G	A108P	0.991
16:21277532:T:C	K75E	0.991
16:21275548:G:T	S124Y	0.989
16:21275563:C:G	R119T	0.988
16:21275575:A:C	I115R	0.988
16:21277444:C:A	G104V	0.988
16:21277540:A:G	L72P	0.987
16:21269863:A:G	L139P	0.986
16:21275584:C:T	G112E	0.986
16:21277532:T:G	K75Q	0.986
16:21275546:C:G	A125P	0.985
16:21278160:A:G	L31P	0.985
16:21269887:A:G	L131P	0.984
16:21275555:C:G	A122P	0.984
16:21275560:G:A	T120I	0.983
16:21275572:G:A	T116I	0.983
16:21277462:A:G	L98P	0.983

dbSNP variants (sampled 300 via entrez): RS1000045633 (16:21272266 T>C), RS1000063085 (16:21262756 C>T), RS1000093621 (16:21293079 AAT>A), RS1000162667 (16:21290138 C>G,T), RS1000308100 (16:21281885 T>G), RS1000330458 (16:21276706 G>A), RS1000368868 (16:21283845 A>C,G), RS1000423976 (16:21282198 A>G), RS1000498640 (16:21304108 A>G), RS1000525843 (16:21288713 T>C), RS1000590792 (16:21282022 T>A,C), RS1000686635 (16:21275141 C>T), RS1000708342 (16:21268494 G>A), RS1000717573 (16:21283746 A>G), RS1000717587 (16:21275901 G>C,T)

Disease associations

OMIM: gene MIM:123740 | disease phenotypes: MIM:616357

GenCC curated gene-disease

Disease	Classification	Inheritance
autosomal dominant nonsyndromic hearing loss	Supportive	Autosomal dominant
autosomal dominant nonsyndromic hearing loss 40	Limited	Unknown

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
nonsyndromic genetic hearing loss	Limited	AD

Mondo (2): autosomal dominant nonsyndromic hearing loss 40 (MONDO:0014603), autosomal dominant nonsyndromic hearing loss (MONDO:0019587)

Orphanet (1): Rare autosomal dominant non-syndromic sensorineural deafness type DFNA (Orphanet:90635)

HPO phenotypes

5 total (5 of 5 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000407	Sensorineural hearing impairment
HP:0001249	Intellectual disability
HP:0001751	Abnormal vestibular function
HP:0011463	Childhood onset

GWAS associations

1 associations (top):

Study	Trait	p-value
GCST003226_4	Pelvic organ prolapse	4.000000e-07

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases expression	5
Benzo(a)pyrene	affects methylation, decreases expression, increases expression, increases methylation	4
Silicon Dioxide	decreases expression, increases expression	3
entinostat	increases expression, affects cotreatment	2
Phenylmercuric Acetate	affects cotreatment, decreases expression	2
Smoke	decreases expression	2
Tobacco Smoke Pollution	affects expression, decreases expression	2
Tretinoin	increases expression	2
Cyclosporine	decreases expression, increases expression	2
sotorasib	affects cotreatment, decreases expression	1
propionaldehyde	increases expression	1
pirinixic acid	increases expression, affects binding, increases activity	1
ethyl-p-hydroxybenzoate	decreases expression	1
tris(2-butoxyethyl) phosphate	affects expression	1
sodium arsenite	increases expression	1
butyraldehyde	increases expression	1
pentanal	increases expression	1
perfluoro-n-nonanoic acid	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	decreases expression, affects cotreatment, increases expression	1
perfluorohexanesulfonic acid	increases expression	1
2,2’,4,4’,5-brominated diphenyl ether	decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, increases expression, decreases expression	1
archazolid B	increases expression	1
enzalutamide	decreases expression, increases reaction	1
licochalcone B	increases expression	1
bisphenol S	decreases methylation	1
trametinib	affects cotreatment, decreases expression	1
NVP-BKM120	affects cotreatment, decreases expression	1
Temozolomide	decreases expression	1

Clinical trials (associated diseases)

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