HARS2

Summary

HARS2 (histidyl-tRNA synthetase 2, mitochondrial, HGNC:4817) is a protein-coding gene on chromosome 5q31.3, encoding Histidine–tRNA ligase, mitochondrial (P49590). Mitochondrial aminoacyl-tRNA synthetase that catalyzes the ATP-dependent ligation of histidine to the 3’-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (His-AMP).

Aminoacyl-tRNA synthetases are a class of enzymes that charge tRNAs with their cognate amino acids. The protein encoded by this gene is an enzyme belonging to the class II family of aminoacyl-tRNA synthetases. Functioning in the synthesis of histidyl-transfer RNA, the enzyme plays an accessory role in the regulation of protein biosynthesis. The gene is located in a head-to-head orientation with HARS on chromosome five, where the homologous genes likely share a bidirectional promoter. Mutations in this gene are associated with the pathogenesis of Perrault syndrome, which involves ovarian dysgenesis and sensorineural hearing loss. Alternative splicing results in multiple transcript variants of this gene.

Source: NCBI Gene 23438 — RefSeq curated summary.

At a glance

• Gene–disease (curated): Perrault syndrome 2 (Strong, GenCC) — +1 more curated relationship
• GWAS associations: 3
• Clinical variants (ClinVar): 292 total — 6 pathogenic, 17 likely-pathogenic
• Phenotypes (HPO): 1
• MANE Select transcript: NM_012208

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:4817
Approved symbol	HARS2
Name	histidyl-tRNA synthetase 2, mitochondrial
Location	5q31.3
Locus type	gene with protein product
Status	Approved
Aliases	HO3, HARSR
Ensembl gene	ENSG00000112855
Ensembl biotype	protein_coding
OMIM	600783
Entrez	23438

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 19 protein_coding, 4 nonsense_mediated_decay, 3 retained_intron, 2 protein_coding_CDS_not_defined

ENST00000230771, ENST00000448069, ENST00000502303, ENST00000503873, ENST00000506318, ENST00000508522, ENST00000509299, ENST00000510104, ENST00000511913, ENST00000513688, ENST00000513912, ENST00000520095, ENST00000642452, ENST00000642752, ENST00000642970, ENST00000643996, ENST00000645065, ENST00000645749, ENST00000646468, ENST00000647484, ENST00000879976, ENST00000879977, ENST00000879978, ENST00000926031, ENST00000926032, ENST00000926033, ENST00000926034, ENST00000943806

RefSeq mRNA: 5 — MANE Select: NM_012208 NM_001278731, NM_001278732, NM_001363535, NM_001363536, NM_012208

CCDS: CCDS4238, CCDS64267, CCDS87329, CCDS87330

Canonical transcript exons

ENST00000230771 — 13 exons

Exon	Start	End
ENSE00000766340	140696943	140697070
ENSE00001127564	140697932	140698078
ENSE00001127570	140697569	140697685
ENSE00001127576	140697164	140697406
ENSE00001127592	140696521	140696614
ENSE00002504905	140696103	140696201
ENSE00003462230	140693935	140694054
ENSE00003487927	140695738	140695845
ENSE00003498671	140694185	140694280
ENSE00003503759	140693591	140693665
ENSE00003791699	140695508	140695633
ENSE00003816603	140698493	140699305
ENSE00003824968	140691455	140691756

Expression profiles

Bgee: expression breadth ubiquitous, 272 present calls, max score 93.00.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.2562 / max 221.2611, expressed in 1822 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
58929	12.8330	1813
58930	7.1097	1631
58931	1.1693	723
58932	0.1441	40

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cerebellar hemisphere	UBERON:0002245	93.00	gold quality
right hemisphere of cerebellum	UBERON:0014890	92.96	gold quality
cerebellar cortex	UBERON:0002129	92.77	gold quality
apex of heart	UBERON:0002098	92.70	gold quality
granulocyte	CL:0000094	92.59	gold quality
mucosa of transverse colon	UBERON:0004991	92.59	gold quality
right adrenal gland cortex	UBERON:0035827	92.44	gold quality
rectum	UBERON:0001052	92.31	gold quality
right adrenal gland	UBERON:0001233	92.13	gold quality
right uterine tube	UBERON:0001302	92.09	gold quality
transverse colon	UBERON:0001157	92.06	gold quality
body of uterus	UBERON:0009853	92.01	gold quality
metanephros cortex	UBERON:0010533	91.84	gold quality
right ovary	UBERON:0002118	91.42	gold quality
left ovary	UBERON:0002119	91.40	gold quality
right lobe of thyroid gland	UBERON:0001119	91.38	gold quality
gastrocnemius	UBERON:0001388	91.32	gold quality
small intestine Peyer’s patch	UBERON:0003454	91.25	gold quality
left adrenal gland	UBERON:0001234	91.20	gold quality
tibial nerve	UBERON:0001323	91.20	gold quality
muscle of leg	UBERON:0001383	91.13	gold quality
cerebellum	UBERON:0002037	91.07	gold quality
spleen	UBERON:0002106	91.05	gold quality
left adrenal gland cortex	UBERON:0035825	90.97	gold quality
lower esophagus	UBERON:0013473	90.90	gold quality
lower esophagus muscularis layer	UBERON:0035833	90.90	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	90.88	gold quality
adenohypophysis	UBERON:0002196	90.82	gold quality
heart left ventricle	UBERON:0002084	90.74	gold quality
muscle layer of sigmoid colon	UBERON:0035805	90.74	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	3.16

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

44 targeting HARS2, 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-1184	99.99	68.19	1458
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-497-5P	99.92	71.83	2674
HSA-MIR-15A-5P	99.90	72.80	2787
HSA-MIR-15B-5P	99.90	72.78	2798
HSA-MIR-16-5P	99.90	72.80	2780
HSA-MIR-195-5P	99.90	72.81	2805
HSA-MIR-424-5P	99.89	71.90	2641
HSA-MIR-6838-5P	99.89	71.94	2690
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-139-5P	99.80	69.50	1399
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-6848-3P	99.64	66.49	885
HSA-MIR-216A-5P	99.50	68.02	1288
HSA-MIR-6833-5P	99.50	68.93	1161
HSA-MIR-519D-5P	99.41	69.30	2057
HSA-MIR-889-5P	99.41	68.75	1025
HSA-MIR-520A-5P	99.35	66.72	1632
HSA-MIR-525-5P	99.35	66.85	1615
HSA-MIR-520E-5P	99.27	68.90	1513
HSA-MIR-6843-3P	99.26	66.42	915
HSA-MIR-3125	99.14	68.49	2269
HSA-MIR-3916	98.99	68.04	2155
HSA-MIR-6859-5P	98.99	68.07	2049
HSA-MIR-606	98.72	67.34	960

Literature-anchored findings (GeneRIF, showing 7)

• This protein has been found differentially expressed in the anterior cingulate cortex in men patients with schizophrenia. (PMID:20381070)
• Mutations in mitochondrial histidyl tRNA synthetase HARS2 cause ovarian dysgenesis and sensorineural hearing loss of Perrault syndrome. (PMID:21464306)
• Novel HARS2 missense variants identified in individuals with sensorineural hearing impairment and Perrault syndrome. (PMID:31449985)
• Overexpression of mitochondrial histidyl-tRNA synthetase restores mitochondrial dysfunction caused by a deafness-associated tRNA(His) mutation. (PMID:31819004)
• A recurrent missense variant in HARS2 results in variable sensorineural hearing loss in three unrelated families. (PMID:31827252)
• Two novel likely pathogenic variants of HARS2 identified in a Chinese family with sensorineural hearing loss. (PMID:33228777)
• [Analysis of perrault syndrome caused by pathogenic variants in LARS2 and HARS2 genes]. (PMID:38186093)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	hars	ENSDARG00000003693
mus_musculus	Hars2	ENSMUSG00000019143
rattus_norvegicus	Zmat2	ENSRNOG00000016087
drosophila_melanogaster	HisRS	FBGN0027087
caenorhabditis_elegans		WBGENE00002001

Paralogs (1): HARS1 (ENSG00000170445)

Protein

Protein identifiers

Histidine–tRNA ligase, mitochondrial — P49590 (reviewed: P49590)

Alternative names: Histidine–tRNA ligase-like, Histidyl-tRNA synthetase

All UniProt accessions (10): A0A2R8Y3N3, A0A2R8Y4X6, A0A2R8Y5E8, A0A2R8Y5P7, A0A2R8Y6I1, B4DQ67, P49590, D6R9M5, D6RB22, D6RJE6

UniProt curated annotations — full annotation on UniProt →

Function. Mitochondrial aminoacyl-tRNA synthetase that catalyzes the ATP-dependent ligation of histidine to the 3’-end of its cognate tRNA, via the formation of an aminoacyl-adenylate intermediate (His-AMP).

Subunit / interactions. Homodimer.

Subcellular location. Mitochondrion.

Tissue specificity. A high level expression is seen in the heart, kidney and skeletal muscle while a lower level expression is seen in the brain and liver.

Disease relevance. Perrault syndrome 2 (PRLTS2) [MIM:614926] An autosomal recessive, sex-influenced disorder characterized by sensorineural deafness in both males and females and ovarian dysgenesis in females. Affected females have primary amenorrhea, streak gonads, and infertility, whereas affected males show normal pubertal development and are fertile. The disease is caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the class-II aminoacyl-tRNA synthetase family.

Isoforms (2)

UniProt ID	Names	Canonical?
P49590-1	1	yes
P49590-2	2

RefSeq proteins (5): NP_001265660, NP_001265661, NP_001350464, NP_001350465, NP_036340* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004154	Anticodon-bd	Domain
IPR004516	HisRS/HisZ	Family
IPR006195	aa-tRNA-synth_II	Domain
IPR015807	His-tRNA-ligase	Family
IPR033656	HisRS_anticodon	Domain
IPR036621	Anticodon-bd_dom_sf	Homologous_superfamily
IPR041715	HisRS-like_core	Domain
IPR045864	aa-tRNA-synth_II/BPL/LPL	Homologous_superfamily

Pfam: PF03129, PF13393

Enzyme classification (BRENDA):

• EC 6.1.1.21 — histidine-tRNA ligase (BRENDA: 37 organisms, 53 substrates, 38 inhibitors, 81 Km, 64 kcat entries)

Substrate kinetics (BRENDA)

13 substrates with measured Km, best-characterized 13. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
TRNAHIS	—	19
ATP	0.0442–1.763	17
HIS	0.0006–0.08	15
L-HISTIDINE	0.008–0.6872	7
SYNTHETIC TRNAHIS A-1	0.001–0.0063	4
SYNTHETIC TRNAHIS G-1	0.0012–0.0178	4
WILD-TYPE FULL LENGTH TRNAHIS G-1	0.0003–0.015	4
RNA MICROHELIX	0.0038–0.124	2
TRNAHISCUA	0.0055–0.013	2
U73TRNAHISGUG	0.0003–0.0016	2
L-HIS	0.0005	1
TRNAHISII	—	1
WILD TYPE TRNAHIS	—	0

Catalyzed reactions (Rhea), 1 shown:

• tRNA(His) + L-histidine + ATP = L-histidyl-tRNA(His) + AMP + diphosphate + H(+) (RHEA:17313)

UniProt features (18 total): sequence variant 7, binding site 6, modified residue 2, transit peptide 1, chain 1, splice variant 1

Structure

Experimental structures (PDB)

0 structures.

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P49590-F1	88.44	0.74

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 (6): 131–133; 158; 174; 178; 327; 331–332

Post-translational modifications (2): 67, 444

Function

Pathways and Gene Ontology

Reactome pathways

4 pathways

ID	Pathway
R-HSA-379726	Mitochondrial tRNA aminoacylation
R-HSA-379724	tRNA Aminoacylation
R-HSA-392499	Metabolism of proteins
R-HSA-72766	Translation

MSigDB gene sets: 148 (showing top): GOBP_AMINO_ACID_ACTIVATION, MORF_MBD4, YAGI_AML_WITH_INV_16_TRANSLOCATION, MORF_RAB5A, LFA1_Q6, SHEPARD_CRASH_AND_BURN_MUTANT_UP, GOBP_TRNA_METABOLIC_PROCESS, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_MITOCHONDRIAL_TRANSLATION, MORF_PSMC2, GOBP_TRANSLATION, MORF_SKP1A, MORF_ATOX1, MORF_PPP6C, MODULE_110

GO Biological Process (4): translation (GO:0006412), tRNA aminoacylation for protein translation (GO:0006418), histidyl-tRNA aminoacylation (GO:0006427), mitochondrial translation (GO:0032543)

GO Molecular Function (7): RNA binding (GO:0003723), histidine-tRNA ligase activity (GO:0004821), ATP binding (GO:0005524), nucleotide binding (GO:0000166), aminoacyl-tRNA ligase activity (GO:0004812), protein binding (GO:0005515), ligase activity (GO:0016874)

GO Cellular Component (3): mitochondrion (GO:0005739), mitochondrial matrix (GO:0005759), cytoplasm (GO:0005737)

Reactome top-level categories

Rollup of top-3 pathways:

Category	Pathways
tRNA Aminoacylation	1
Translation	1
Metabolism of proteins	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
translation	2
mitochondrion	2
peptidyltransferase activity	1
translational initiation	1
translational elongation	1
translational termination	1
macromolecule biosynthetic process	1
protein metabolic process	1
protein biosynthetic process	1
tRNA aminoacylation	1
tRNA aminoacylation for protein translation	1
mitochondrial gene expression	1
nucleic acid binding	1
aminoacyl-tRNA ligase activity	1
adenyl ribonucleotide binding	1
purine ribonucleoside triphosphate binding	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
ligase activity, forming carbon-oxygen bonds	1
catalytic activity, acting on a tRNA	1
binding	1
catalytic activity	1
cytoplasm	1
intracellular membrane-bounded organelle	1
intracellular organelle lumen	1
intracellular anatomical structure	1
cellular anatomical structure	1

Protein interactions and networks

STRING

2326 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
HARS2	GARS1	P41250	960
HARS2	HMOX2	P30519	924
HARS2	AARS1	P49588	841
HARS2	TARS3	A2RTX5	820
HARS2	NARS2	Q96I59	816
HARS2	TARS2	Q9BW92	813
HARS2	TARS1	P26639	813
HARS2	YARS1	P54577	811
HARS2	YARS2	Q9Y2Z4	810
HARS2	IARS2	Q9NSE4	810
HARS2	WARS2	Q9UGM6	807
HARS2	LARS2	Q15031	796
HARS2	MARS1	P56192	794
HARS2	MARS2	Q96GW9	794
HARS2	KARS1	Q15046	794
HARS2	IARS1	P41252	794

IntAct

152 interactions, top by confidence:

A	B	Type	Score
PRKAB1	PRKAB2	psi-mi:“MI:0914”(association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
HSPD1	NUDT19	psi-mi:“MI:0914”(association)	0.710
IMP3	MPHOSPH10	psi-mi:“MI:0914”(association)	0.670
LYRM4	NDUFAB1	psi-mi:“MI:0914”(association)	0.640
NDUFS7	NDUFS8	psi-mi:“MI:0914”(association)	0.640
STX7	SNAP23	psi-mi:“MI:0914”(association)	0.640
HARS2	HSPD1	psi-mi:“MI:0914”(association)	0.610
AGTRAP	HARS2	psi-mi:“MI:0915”(physical association)	0.560
HARS2	AGTRAP	psi-mi:“MI:0915”(physical association)	0.560
gag	EEF1E1	psi-mi:“MI:0914”(association)	0.560
FAM174A	BLTP3B	psi-mi:“MI:0914”(association)	0.530
CD79A	METTL15	psi-mi:“MI:0914”(association)	0.530
LAMP3	METTL15	psi-mi:“MI:0914”(association)	0.530
OTC	RTL8C	psi-mi:“MI:0914”(association)	0.530
LRP1	NME4	psi-mi:“MI:0914”(association)	0.530
YBEY	NME4	psi-mi:“MI:0914”(association)	0.530
ATP5F1D	NDUFB5	psi-mi:“MI:0914”(association)	0.530
NRBP1	TBC1D4	psi-mi:“MI:0914”(association)	0.530

BioGRID (225): HARS2 (Affinity Capture-MS), AGTRAP (Two-hybrid), HARS2 (Affinity Capture-RNA), HARS2 (Affinity Capture-RNA), HARS2 (Affinity Capture-RNA), HARS2 (Affinity Capture-MS), GARS (Co-fractionation), HARS2 (Co-fractionation), HARS2 (Co-fractionation), HARS2 (Affinity Capture-MS), HARS2 (Affinity Capture-MS), HARS2 (Affinity Capture-MS), HARS2 (Affinity Capture-MS), HARS (Affinity Capture-MS), HARS2 (Affinity Capture-MS)

ESM2 similar proteins: A2RTX5, A4QP75, A5D7V9, A6QNM8, A6QPU5, D3ZX08, F4IFC5, O04630, O43011, O95363, P07178, P12081, P26639, P34183, P36776, P49590, P70076, Q0V9S0, Q2KI84, Q3KRD0, Q3UQ84, Q3ZBV8, Q4R816, Q59HJ6, Q5M7W7, Q5R4R2, Q5R5E5, Q5XHY5, Q61035, Q66HG3, Q68FW7, Q6AYQ3, Q6E6B4, Q6PI48, Q86AS6, Q8BGQ7, Q8BGV0, Q8BIP0, Q8BLY2, Q8CFI5

Diamond homologs: A0M0E2, A1B3C5, A1RUZ2, A1UTY3, A3MTI8, A4WIN2, A5D7V9, A5F9R5, A5VTT4, A6KXA6, A6LIF7, A8LKA5, A9MDU4, A9WXP3, B0R6V2, B0U3B6, B1L6B4, B1YCS2, B2FPL6, B2I5Y4, B2J5J5, B2SCY7, B2SKP3, B2UUV2, B3QII5, B4STN3, B5Z8I6, B5ZRD0, B6JN30, B6YS23, B8DU04, B8ER30, B9J9Y1, B9KU51, C0RKC7, C5CCH4, E9QI36, O58028, P12081, P49590

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 191 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Mitochondrial ribosome-associated quality control	8	7.5×	7e-03

GO biological processes:

GO term	Partners	Fold	FDR
mitochondrial large ribosomal subunit assembly	5	29.2×	6e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	6
Likely pathogenic	17
Uncertain significance	144
Likely benign	82
Benign	11

Top pathogenic / likely-pathogenic (23)

Variant ID	HGVS	Classification
2085053	NM_012208.4(HARS2):c.229del (p.Ile77fs)	Pathogenic
2964113	NM_012208.4(HARS2):c.243_244insCTTT (p.Ile82fs)	Pathogenic
3601170	NM_012208.4(HARS2):c.928del (p.Tyr309_Leu310insTer)	Pathogenic
3658901	NM_012208.4(HARS2):c.13G>T (p.Gly5Ter)	Pathogenic
4692851	NM_012208.4(HARS2):c.586_587del (p.Met196fs)	Pathogenic
982371	NM_012208.4(HARS2):c.647G>A (p.Arg216Gln)	Pathogenic
1185123	NM_012208.4(HARS2):c.399+1G>A	Likely pathogenic
1185124	NM_012208.4(HARS2):c.1403G>C (p.Gly468Ala)	Likely pathogenic
214544	NM_012208.4(HARS2):c.633+1G>A	Likely pathogenic
2446360	NM_012208.4(HARS2):c.1273C>T (p.Arg425Trp)	Likely pathogenic
2917271	NM_012208.4(HARS2):c.1091A>G (p.Tyr364Cys)	Likely pathogenic
3242247	NM_012208.4(HARS2):c.1012G>A (p.Glu338Lys)	Likely pathogenic
3601169	NM_012208.4(HARS2):c.281A>G (p.Asp94Gly)	Likely pathogenic
3659534	NM_012208.4(HARS2):c.1197+1G>C	Likely pathogenic
3687534	NM_012208.4(HARS2):c.634-1G>T	Likely pathogenic
3693493	NM_012208.4(HARS2):c.183+1G>T	Likely pathogenic
3774952	NM_012208.4(HARS2):c.634-2A>C	Likely pathogenic
39620	NM_012208.4(HARS2):c.598C>G (p.Leu200Val)	Likely pathogenic
633638	NM_012208.4(HARS2):c.137T>A (p.Leu46Gln)	Likely pathogenic
633639	NM_012208.4(HARS2):c.980G>A (p.Arg327Gln)	Likely pathogenic
633640	NM_012208.4(HARS2):c.259C>T (p.Arg87Cys)	Likely pathogenic
635271	NM_012208.4(HARS2):c.828delinsGTATCCCTAGTATTTCTACTA (p.Gly276_Gly277insTyrProTer)	Likely pathogenic
635273	NM_012208.4(HARS2):c.72C>A (p.Cys24Ter)	Likely pathogenic

SpliceAI

0 predictions. Top by Δscore:

AlphaMissense

3308 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:140697359:A:C	S384R	0.995
5:140697361:C:A	S384R	0.995
5:140697361:C:G	S384R	0.995
5:140695521:G:C	R138P	0.994
5:140695622:T:C	F172L	0.994
5:140695624:C:A	F172L	0.994
5:140695624:C:G	F172L	0.994
5:140695577:T:A	W157R	0.993
5:140695577:T:C	W157R	0.993
5:140695518:C:A	A137D	0.991
5:140695581:G:C	R158P	0.990
5:140697285:C:A	A359D	0.990
5:140695780:G:C	A190P	0.988
5:140697284:G:C	A359P	0.988
5:140697612:T:A	V414E	0.988
5:140697297:G:C	R363P	0.987
5:140697666:T:C	L432P	0.987
5:140695631:T:C	C175R	0.986
5:140697291:G:A	G361D	0.986
5:140698056:G:C	R480P	0.985
5:140695786:T:C	C192R	0.984
5:140693935:G:C	G62R	0.983
5:140694264:T:A	L128H	0.983
5:140695751:C:A	A180D	0.983
5:140694020:C:A	A90E	0.982
5:140695520:C:A	R138S	0.982
5:140697349:T:G	C380W	0.982
5:140697606:T:A	V412E	0.980
5:140697645:G:C	R425P	0.980
5:140695557:G:C	R150P	0.979

dbSNP variants (sampled 300 via entrez): RS1000790166 (5:140694973 G>A), RS1001045341 (5:140692496 T>C), RS1001211465 (5:140691804 A>G), RS1001584317 (5:140692303 A>C,G), RS1001631468 (5:140694395 A>G), RS1002068908 (5:140689617 G>A,C), RS1002247720 (5:140696102 G>T), RS1002387717 (5:140698926 C>A,T), RS1002481235 (5:140699446 A>G), RS1003054286 (5:140695373 G>A,C), RS1003070382 (5:140691133 C>A,G,T), RS1003515075 (5:140690776 G>A), RS1003955431 (5:140690485 T>C), RS1004477314 (5:140694789 G>A), RS1004597170 (5:140694423 G>A)

Disease associations

OMIM: gene MIM:600783 | disease phenotypes: MIM:614504, MIM:614926, MIM:233400

GenCC curated gene-disease

Disease	Classification	Inheritance
Perrault syndrome 2	Strong	Autosomal recessive
Perrault syndrome	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
Perrault syndrome 2	Limited	AR

Mondo (5): Usher syndrome type 3B (MONDO:0013788), Perrault syndrome 2 (MONDO:0013972), Perrault syndrome (MONDO:0017312), PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome (MONDO:1060108), sensorineural hearing loss disorder (MONDO:0020678)

Orphanet (4): Perrault syndrome (Orphanet:2855), Perrault syndrome type 2 (Orphanet:642976), PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome (Orphanet:438213), PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome due to a point mutation (Orphanet:438216)

HPO phenotypes

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

HPO	Term
HP:0000407	Sensorineural hearing impairment

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST006803_54	Schizophrenia	8.000000e-07
GCST010146_22	Serum immune biomarker levels	7.000000e-09
GCST90011899_62	Aspartate aminotransferase levels	2.000000e-08

EFO canonical traits (2, from GWAS)

EFO ID	Trait name
EFO:0004872	inflammatory biomarker measurement
EFO:0004736	aspartate aminotransferase measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, decreases methylation	3
Acetaminophen	affects cotreatment, decreases expression	2
Air Pollutants	increases oxidation, decreases expression, affects cotreatment, increases abundance	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Particulate Matter	decreases expression, increases abundance	2
aristolochic acid I	increases expression	1
FR900359	increases phosphorylation	1
bisphenol F	affects cotreatment, decreases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
bisphenol A	affects cotreatment, decreases expression	1
beta-lapachone	decreases expression, increases expression	1
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	increases expression	1
manganese chloride	increases abundance, increases expression	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
Resveratrol	affects cotreatment, increases expression	1
Arsenic Trioxide	decreases reaction, affects binding	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Vehicle Emissions	increases abundance, decreases expression	1
Benzene	increases expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1
Lipopolysaccharides	affects cotreatment, decreases expression	1
Manganese	increases abundance, increases expression	1
Ozone	affects cotreatment, increases oxidation, increases abundance	1
Plant Extracts	affects cotreatment, increases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT01655212	PHASE3	TERMINATED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment in a Randomized Controlled Trial
NCT02005822	PHASE3	COMPLETED	Congenital Cytomegalovirus: Efficacy of Antiviral Treatment
NCT03374514	PHASE3	UNKNOWN	Cochlear Electrical Impedance and the Effect of Topical Dexamethasone on Cochlear Implant Surgery
NCT02497690	PHASE2	COMPLETED	Effectiveness of Therapy Via Telemedicine Following Cochlear Implants
NCT03107871	PHASE2	ACTIVE_NOT_RECRUITING	Randomized Controlled Trial of Valganciclovir for Cytomegalovirus Infected Hearing Impaired Infants
NCT04120116	PHASE2	COMPLETED	FX-322 in Adults With Stable Sensorineural Hearing Loss
NCT05061758	PHASE2	WITHDRAWN	A Trial of LY3056480 in Patients With SNLH
NCT07364747	PHASE2	RECRUITING	Protective Effect of Acetylcysteine Against Cisplatinum-Induced Ototoxicity: A Randomized Controlled Trial
NCT02259595	PHASE1	COMPLETED	Study to Determine the Safety, Tolerability, and Pharmacokinetic Profile of HPN-07 and HPN-07 Plus NAC
NCT02693704	PHASE2/PHASE3	COMPLETED	Evaluation of a Binaural Spatialization Method for Hearing Aids
NCT02882477	PHASE2/PHASE3	UNKNOWN	Treatment of Wolfram Syndrome Type 2 With the Chelator Deferiprone and Incretin Based Therapy
NCT01267994	PHASE1/PHASE2	COMPLETED	A Clinical Trial of Anakinra for Steroid-Resistant Autoimmune Inner Ear Disease
NCT01902914	PHASE1/PHASE2	UNKNOWN	Effectiveness of P02 Digital Hearing Aids
NCT02038972	PHASE1/PHASE2	COMPLETED	Safety of Autologous Stem Cell Infusion for Children With Acquired Hearing Loss
NCT02616172	PHASE1/PHASE2	SUSPENDED	Autologous Bone Marrow Harvest and Transplant for Sensorineural Hearing Loss
NCT03616223	PHASE1/PHASE2	COMPLETED	FX-322 in Sensorineural Hearing Loss
NCT04129775	PHASE1/PHASE2	COMPLETED	OTO-413 in Subjects With Speech-in-Noise Hearing Impairment
NCT04462198	PHASE1/PHASE2	COMPLETED	Phase I/IIa Study Evaluating Safety and Efficacy of an Intratympanic Dose of PIPE-505 in Subjects With Hearing Loss
NCT07032038	PHASE1/PHASE2	NOT_YET_RECRUITING	First In Human Randomised Trial of Rincell-1 in Adults With a Cochlear Implant
NCT06025097	EARLY_PHASE1	COMPLETED	Intra-Tympanic Steroid With PRP Combination in Sensorineural Hearing Loss and Tinnitus.
NCT06707389	EARLY_PHASE1	NOT_YET_RECRUITING	Autologous Blood Monocyte Vesicles for the Treatment of Sudden Deafness
NCT07472023	EARLY_PHASE1	ENROLLING_BY_INVITATION	Regenerative Medicine and Stem Cell-Based Interventions for Inner Ear Trauma, Tinnitus, and Sensorineural Hearing Loss
NCT00023036	Not specified	COMPLETED	Clinical and Genetic Analysis of Enlarged Vestibular Aqueducts
NCT00023049	Not specified	COMPLETED	Genetic Analysis of Hereditary Disorders of Hearing and Balance
NCT00261768	Not specified	COMPLETED	Efficacy of Digital Noise Reduction Strategies: A Hearing Aid Trial
NCT00589511	Not specified	COMPLETED	Nucleus Freedom Cochlear Implant System Pediatric Post-approval Study
NCT00678899	Not specified	COMPLETED	Evaluation of the Nucleus Hybrid™ L24 Cochlear Implant System
NCT00787189	Not specified	COMPLETED	Study of Low Level Laser Therapy and Word Recognition in Hearing Impaired Individuals
NCT01184248	Not specified	COMPLETED	The Effect of Sound Stimulation on Pure-tone Hearing Threshold
NCT01434446	Not specified	COMPLETED	The Effect of Sound Stimulation on Hearing Ability
NCT01749592	Not specified	COMPLETED	Single-sided Deafness and Cochlear Implants
NCT01781039	Not specified	COMPLETED	Investigation of Anatomical Correlates of Speech Discrimination
NCT02082431	Not specified	COMPLETED	Determine the Incidence of Long QT Amongst a Large Cohort of Subjects Diagnosed With Unilateral or Bilateral Sensorineural Hearing Loss.
NCT02093806	Not specified	UNKNOWN	Clinical Applications of Round Window Imaging Anatomy in Cochlear Implant Surgery
NCT02252601	Not specified	UNKNOWN	Evaluation of the High Frequency Digit Triplet Test in Cystic Fibrosis
NCT02584361	Not specified	UNKNOWN	Cochlear Implant and Vestibular Function.
NCT02638883	Not specified	COMPLETED	Implantation of the Cochlear™ Nucleus® Hybrid S Round Window (S-RW) in Adults
NCT02689349	Not specified	COMPLETED	Esteem New Subject Enrollment Post Approval Study
NCT02698787	Not specified	COMPLETED	Fundamental Asynchronous Stimulus Timing Sound Coding Study
NCT02798783	Not specified	COMPLETED	Enlarged Vestibular Aqueduct Registry