POLR3H

Summary

POLR3H (RNA polymerase III subunit H, HGNC:30349) is a protein-coding gene on chromosome 22q13.2, encoding DNA-directed RNA polymerase III subunit RPC8 (Q9Y535). DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. It is a common-essential gene (DepMap: required in 99.8% of cancer cell lines).

Enables DNA-directed RNA polymerase activity. Involved in transcription by RNA polymerase III. Located in centrosome and nucleoplasm. Part of RNA polymerase III complex.

Source: NCBI Gene 171568 — RefSeq curated summary.

At a glance

• Gene–disease (curated): primary ovarian failure (Moderate, GenCC) — +1 more curated relationship
• GWAS associations: 6
• Clinical variants (ClinVar): 67 total — 1 likely-pathogenic
• Phenotypes (HPO): 25
• Cancer dependency (DepMap): dependent in 99.8% of screened cell lines (common-essential)
• MANE Select transcript: NM_001018050

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:30349
Approved symbol	POLR3H
Name	RNA polymerase III subunit H
Location	22q13.2
Locus type	gene with protein product
Status	Approved
Aliases	RPC8, KIAA1665, C25
Ensembl gene	ENSG00000100413
Ensembl biotype	protein_coding
OMIM	619801
Entrez	171568

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 10 protein_coding, 3 nonsense_mediated_decay, 1 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000337566, ENST00000355209, ENST00000396504, ENST00000407461, ENST00000420561, ENST00000431534, ENST00000432789, ENST00000442616, ENST00000483837, ENST00000878619, ENST00000878620, ENST00000878621, ENST00000878622, ENST00000878623, ENST00000953962

RefSeq mRNA: 5 — MANE Select: NM_001018050 NM_001018050, NM_001018052, NM_001282884, NM_001282885, NM_138338

CCDS: CCDS14018, CCDS33651

Canonical transcript exons

ENST00000355209 — 6 exons

Exon	Start	End
ENSE00001702547	41543991	41544470
ENSE00001845392	41525799	41529336
ENSE00003474642	41540699	41540795
ENSE00003512791	41532659	41532745
ENSE00003525820	41532094	41532157
ENSE00003526190	41530687	41530888

Expression profiles

Bgee: expression breadth ubiquitous, 232 present calls, max score 94.75.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 19.6798 / max 121.3010, expressed in 1808 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
194366	17.1073	1795
194364	1.4675	775
194365	1.1050	742

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
prefrontal cortex	UBERON:0000451	94.75	gold quality
anterior cingulate cortex	UBERON:0009835	94.61	gold quality
right frontal lobe	UBERON:0002810	94.12	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.02	gold quality
nucleus accumbens	UBERON:0001882	93.66	gold quality
caudate nucleus	UBERON:0001873	93.58	gold quality
putamen	UBERON:0001874	93.41	gold quality
amygdala	UBERON:0001876	93.36	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	92.29	gold quality
neocortex	UBERON:0001950	92.09	gold quality
frontal cortex	UBERON:0001870	92.00	gold quality
hypothalamus	UBERON:0001898	91.86	gold quality
cortical plate	UBERON:0005343	91.15	gold quality
gastrocnemius	UBERON:0001388	90.92	gold quality
muscle of leg	UBERON:0001383	90.74	gold quality
cerebral cortex	UBERON:0000956	90.44	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	90.36	gold quality
forebrain	UBERON:0001890	90.33	gold quality
ventricular zone	UBERON:0003053	90.09	gold quality
sural nerve	UBERON:0015488	89.95	gold quality
substantia nigra	UBERON:0002038	89.74	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	89.53	gold quality
brain	UBERON:0000955	89.51	gold quality
stromal cell of endometrium	CL:0002255	89.43	gold quality
left adrenal gland cortex	UBERON:0035825	88.99	gold quality
left adrenal gland	UBERON:0001234	88.96	gold quality
right coronary artery	UBERON:0001625	88.88	gold quality
spinal cord	UBERON:0002240	88.85	gold quality
right adrenal gland	UBERON:0001233	88.75	gold quality
right adrenal gland cortex	UBERON:0035827	88.48	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-MTAB-9543	yes	40.01
E-ANND-3	yes	17.33
E-CURD-112	yes	13.96

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

82 targeting POLR3H, 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-4673	100.00	66.64	1490
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-29A-3P	100.00	73.11	1835
HSA-MIR-29B-3P	100.00	73.18	1833
HSA-MIR-29C-3P	100.00	73.15	1833
HSA-MIR-4476	100.00	68.18	2030
HSA-MIR-6876-5P	100.00	67.68	2126
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-MIR-4514	99.99	67.10	1870
HSA-MIR-4645-5P	99.98	65.81	1284
HSA-MIR-8073	99.86	65.21	1118
HSA-MIR-221-5P	99.86	65.45	1052
HSA-MIR-659-3P	99.85	70.69	1620
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-4319	99.76	69.83	2586
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-92A-2-5P	99.75	67.01	2164
HSA-MIR-5004-5P	99.68	66.63	1294
HSA-MIR-3202	99.66	67.70	2737
HSA-MIR-6887-3P	99.66	67.83	1778
HSA-MIR-6715B-5P	99.64	69.63	1420
HSA-MIR-4708-3P	99.51	67.99	870
HSA-MIR-4688	99.48	64.68	828
HSA-MIR-6743-5P	99.48	63.60	721
HSA-MIR-542-3P	99.34	67.58	1270
HSA-MIR-4685-5P	99.25	65.99	1563
HSA-MIR-6837-5P	99.25	65.47	1632
HSA-MIR-3922-3P	99.25	64.96	1136
HSA-MIR-3176	99.25	64.35	954
HSA-MIR-6815-3P	99.13	68.98	1530

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.8% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 3)

• The authors demonstrate the interaction of both RNA polymerase I and III with hepatitis delta virus RNA, both in vitro and in human cells. (PMID:19246067)
• Findings reveal that RNA polymerase III-dependent EBER expression through induction of cellular transcription factors and add to the repertoire of EBNA1’s transcription-regulatory properties. (PMID:20843307)
• A pathogenic homozygous missense mutation (c.149A>G; p.Asp50Gly) in the POLR3H gene in two unrelated families with primary ovarian insufficiency was identified. (PMID:30830215)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	polr3h	ENSDARG00000102590
mus_musculus	Polr3h	ENSMUSG00000022476
rattus_norvegicus	Polr3h	ENSRNOG00000004471
drosophila_melanogaster	Polr3H	FBGN0036188
caenorhabditis_elegans		WBGENE00014111

Paralogs (2): POLR1F (ENSG00000105849), POLR2G (ENSG00000168002)

Protein

Protein identifiers

DNA-directed RNA polymerase III subunit RPC8 — Q9Y535 (reviewed: Q9Y535)

Alternative names: DNA-directed RNA polymerase III subunit H, RNA polymerase III subunit 22.9 kDa subunit

All UniProt accessions (4): Q9Y535, E7ERZ2, F8WDS5, F8WDV1

UniProt curated annotations — full annotation on UniProt →

Function. DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. Specific peripheric component of RNA polymerase III (Pol III) which synthesizes small non-coding RNAs including 5S rRNA, snRNAs, tRNAs and miRNAs from at least 500 distinct genomic loci. With CRCP/RPC9 forms a mobile stalk that protrudes from Pol III core and functions primarily in transcription initiation. Pol III plays a key role in sensing and limiting infection by intracellular bacteria and DNA viruses. Acts as nuclear and cytosolic DNA sensor involved in innate immune response. Can sense non-self dsDNA that serves as template for transcription into dsRNA. The non-self RNA polymerase III transcripts, such as Epstein-Barr virus-encoded RNAs (EBERs) induce type I interferon and NF-kappa-B through the RIG-I pathway.

Subunit / interactions. Component of the RNA polymerase III complex consisting of 17 subunits: a ten-subunit horseshoe-shaped catalytic core composed of POLR3A/RPC1, POLR3B/RPC2, POLR1C/RPAC1, POLR1D/RPAC2, POLR3K/RPC10, POLR2E/RPABC1, POLR2F/RPABC2, POLR2H/RPABC3, POLR2K/RPABC4 and POLR2L/RPABC5; a mobile stalk composed of two subunits POLR3H/RPC8 and CRCP/RPC9, protruding from the core and functioning primarily in transcription initiation; and additional subunits homologous to general transcription factors of the RNA polymerase II machinery, POLR3C/RPC3-POLR3F/RPC6-POLR3G/RPC7 heterotrimer required for transcription initiation and POLR3D/RPC4-POLR3E/RPC5 heterodimer involved in both transcription initiation and termination. Interacts with CRCP/RPC9. POLR3H/RPC8 and CRCP/RPC9 probably form a Pol III subcomplex.

Subcellular location. Nucleus.

Similarity. Belongs to the eukaryotic RPB7/RPC8 RNA polymerase subunit family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9Y535-1	1	yes
Q9Y535-2	2

RefSeq proteins (5): NP_001018060, NP_001018062, NP_001269813, NP_001269814, NP_612211 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR004519	RNAP_E/RPC8	Family
IPR005576	Rpb7-like_N	Domain
IPR012340	NA-bd_OB-fold	Homologous_superfamily
IPR013238	RNA_pol_III_Rbc25	Domain
IPR036898	RNA_pol_Rpb7-like_N_sf	Homologous_superfamily
IPR045113	Rpb7-like	Family

Pfam: PF03876, PF08292

UniProt features (25 total): strand 14, helix 4, turn 3, chain 1, region of interest 1, compositionally biased region 1, splice variant 1

Structure

Experimental structures (PDB)

29 structures.

PDB	Method	Resolution (Å)
7AE1	ELECTRON MICROSCOPY	2.8
9K39	ELECTRON MICROSCOPY	2.8
7D58	ELECTRON MICROSCOPY	2.9
9K36	ELECTRON MICROSCOPY	2.9
9K2G	ELECTRON MICROSCOPY	3
9K3U	ELECTRON MICROSCOPY	3
7AE3	ELECTRON MICROSCOPY	3.1
7D59	ELECTRON MICROSCOPY	3.1
9K38	ELECTRON MICROSCOPY	3.1
9FSO	ELECTRON MICROSCOPY	3.28
7A6H	ELECTRON MICROSCOPY	3.3
9LXN	ELECTRON MICROSCOPY	3.3
7DU2	ELECTRON MICROSCOPY	3.35
9FSP	ELECTRON MICROSCOPY	3.39
7AEA	ELECTRON MICROSCOPY	3.4
8IUH	ELECTRON MICROSCOPY	3.4
7DN3	ELECTRON MICROSCOPY	3.5
9K3V	ELECTRON MICROSCOPY	3.5
9LKT	ELECTRON MICROSCOPY	3.5
9FSQ	ELECTRON MICROSCOPY	3.51
7FJI	ELECTRON MICROSCOPY	3.6
7FJJ	ELECTRON MICROSCOPY	3.6
9LXO	ELECTRON MICROSCOPY	3.6
9FSR	ELECTRON MICROSCOPY	3.76
8ITY	ELECTRON MICROSCOPY	3.9
7AST	ELECTRON MICROSCOPY	4
8IUE	ELECTRON MICROSCOPY	4.1
9FSS	ELECTRON MICROSCOPY	4.14
9K3B	ELECTRON MICROSCOPY	4.8

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9Y535-F1	88.56	0.77

Function

Pathways and Gene Ontology

Reactome pathways

12 pathways

ID	Pathway
R-HSA-1834949	Cytosolic sensors of pathogen-associated DNA
R-HSA-73780	RNA Polymerase III Chain Elongation
R-HSA-73980	RNA Polymerase III Transcription Termination
R-HSA-749476	RNA Polymerase III Abortive And Retractive Initiation
R-HSA-76061	RNA Polymerase III Transcription Initiation From Type 1 Promoter
R-HSA-76066	RNA Polymerase III Transcription Initiation From Type 2 Promoter
R-HSA-76071	RNA Polymerase III Transcription Initiation From Type 3 Promoter
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-74158	RNA Polymerase III Transcription
R-HSA-74160	Gene expression (Transcription)
R-HSA-76046	RNA Polymerase III Transcription Initiation

MSigDB gene sets: 159 (showing top): REACTOME_RNA_POLYMERASE_III_TRANSCRIPTION_INITIATION_FROM_TYPE_3_PROMOTER, REACTOME_RNA_POLYMERASE_III_TRANSCRIPTION_TERMINATION, REACTOME_INNATE_IMMUNE_SYSTEM, CCAWYNNGAAR_UNKNOWN, REACTOME_RNA_POLYMERASE_III_CHAIN_ELONGATION, GOBP_DNA_TEMPLATED_TRANSCRIPTION_TERMINATION, GOBP_TRANSCRIPTION_BY_RNA_POLYMERASE_III, GOCC_MICROTUBULE_ORGANIZING_CENTER, KEGG_CYTOSOLIC_DNA_SENSING_PATHWAY, GOBP_DEFENSE_RESPONSE_TO_OTHER_ORGANISM, MARTIN_VIRAL_GPCR_SIGNALING_UP, GOCC_CENTROSOME, GOBP_DNA_TEMPLATED_TRANSCRIPTION_INITIATION, CYTAGCAAY_UNKNOWN, KEGG_PURINE_METABOLISM

GO Biological Process (8): nucleobase-containing compound metabolic process (GO:0006139), transcription by RNA polymerase III (GO:0006383), transcription initiation at RNA polymerase III promoter (GO:0006384), innate immune response (GO:0045087), defense response to virus (GO:0051607), immune system process (GO:0002376), DNA-templated transcription (GO:0006351), DNA-templated transcription initiation (GO:0006352)

GO Molecular Function (3): DNA binding (GO:0003677), DNA-directed RNA polymerase activity (GO:0003899), protein binding (GO:0005515)

GO Cellular Component (6): nucleoplasm (GO:0005654), RNA polymerase III complex (GO:0005666), centrosome (GO:0005813), cytosol (GO:0005829), DNA-directed RNA polymerase complex (GO:0000428), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-5 pathways:

Category	Pathways
RNA Polymerase III Transcription	4
RNA Polymerase III Transcription Initiation	3
Innate Immune System	1
Immune System	1
Gene expression (Transcription)	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
RNA biosynthetic process	3
DNA-templated transcription	2
cellular anatomical structure	2
primary metabolic process	1
DNA-templated transcription initiation	1
transcription by RNA polymerase III	1
immune response	1
defense response to symbiont	1
defense response	1
response to virus	1
biological_process	1
gene expression	1
nucleic acid binding	1
5’-3’ RNA polymerase activity	1
binding	1
nuclear lumen	1
DNA-directed RNA polymerase complex	1
nuclear protein-containing complex	1
centriole	1
microtubule organizing center	1
cytoplasm	1
RNA polymerase complex	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

1382 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POLR3H	POLR3F	Q9H1D9	901
POLR3H	POLR3E	Q9NVU0	848
POLR3H	POLR3D	P05423	838
POLR3H	POLR3C	Q9BUI4	818
POLR3H	POLR3B	Q9NW08	816
POLR3H	POLR3G	O15318	804
POLR3H	CRCP	O75575	800
POLR3H	POLR3A	O14802	782
POLR3H	POLR3K	Q9Y2Y1	781
POLR3H	POLR3GL	Q9BT43	732
POLR3H	POLR1D	P0DPB6	720
POLR3H	PLAC8	Q9NZF1	717
POLR3H	C12orf57	Q99622	665
POLR3H	POLR1C	O15160	593
POLR3H	TBL1XR1	Q9BZK7	578

IntAct

57 interactions, top by confidence:

A	B	Type	Score
POLR2E	POLR3A	psi-mi:“MI:0915”(physical association)	0.870
POLR2E	POLR3A	psi-mi:“MI:0914”(association)	0.870
CDK2	CCNB2	psi-mi:“MI:0914”(association)	0.860
POLR2E	MED19	psi-mi:“MI:0914”(association)	0.730
POLR3GL	POLR3A	psi-mi:“MI:0914”(association)	0.730
POLR3E	POLR3A	psi-mi:“MI:0914”(association)	0.730
POLR2L	RCCD1	psi-mi:“MI:0914”(association)	0.640
POLR3K	POLR3A	psi-mi:“MI:0914”(association)	0.640
POLR2F	POLR3A	psi-mi:“MI:0914”(association)	0.640
POLR3D	POLR3A	psi-mi:“MI:0914”(association)	0.640
ATPAF2	POLR3H	psi-mi:“MI:0915”(physical association)	0.560
ELAVL2	IGF2BP3	psi-mi:“MI:0914”(association)	0.530
GPN3	POLR3A	psi-mi:“MI:0914”(association)	0.530
POLR1C	POLR3A	psi-mi:“MI:0914”(association)	0.530
GPN1	POLR3A	psi-mi:“MI:0914”(association)	0.530
POLR3H	POLR3A	psi-mi:“MI:0914”(association)	0.530
POLR3H	UBE2M	psi-mi:“MI:0914”(association)	0.530
ELAVL2	CASC3	psi-mi:“MI:0914”(association)	0.530
POLR1D	POLR3A	psi-mi:“MI:0914”(association)	0.530
PCNA	POLR3H	psi-mi:“MI:0915”(physical association)	0.370
POLR2F	BDP1	psi-mi:“MI:0914”(association)	0.350

BioGRID (191): POLR3H (Affinity Capture-MS), POLR3H (Affinity Capture-MS), POLR3H (Affinity Capture-MS), POLR3H (Co-fractionation), POLR3H (Co-fractionation), POLR3H (Co-fractionation), POLR3H (Co-fractionation), POLR3H (Co-fractionation), POLR3H (Co-fractionation), POLR3H (Co-fractionation), POLR3H (Co-fractionation), POLR3H (Co-fractionation), POLR3H (Co-fractionation), POLR3H (Affinity Capture-MS), POLR3H (Affinity Capture-MS)

ESM2 similar proteins: A6QRA1, B0VZR4, B3MGZ0, B4HQJ2, F4IFF3, J9VR81, O13867, O14459, O23617, O59821, O65041, O65595, O94285, P05198, P18562, P20459, P20460, P22200, P34087, P35718, P46228, P56286, P68101, P68102, Q16974, Q16WA6, Q1JPL4, Q2T9X1, Q32NH8, Q54P04, Q55GQ6, Q5R493, Q5ZLX2, Q6GL89, Q6ZWX6, Q7QJW7, Q7ZTK4, Q8BLR2, Q8LE42, Q96A23

Diamond homologs: O94285, P34087, P35718, Q2T9X1, Q557J3, Q9D2C6, Q9Y535, B8YB57, Q980A3

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
POLR3H	“form complex”	“RNA Polymerase III”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 37 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
RNA Polymerase III Chain Elongation	16	327.5×	7e-40
RNA Polymerase III Transcription Termination	16	256.3×	6e-37
RNA Polymerase III Transcription Initiation From Type 2 Promoter	18	245.6×	1e-40
RNA Polymerase III Transcription Initiation From Type 1 Promoter	18	236.8×	1e-40
RNA Polymerase III Transcription Initiation From Type 3 Promoter	18	236.8×	1e-40
RNA Polymerase III Transcription Initiation	18	195.0×	1e-38
RNA Polymerase III Transcription	18	189.5×	2e-38
RNA Polymerase III Abortive And Retractive Initiation	18	161.7×	7e-37

GO biological processes:

GO term	Partners	Fold	FDR
transcription by RNA polymerase III	7	153.2×	2e-12
positive regulation of innate immune response	5	75.2×	2e-07
positive regulation of interferon-beta production	6	67.2×	1e-08
defense response to virus	8	15.8×	7e-07
transcription by RNA polymerase II	6	12.1×	1e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	1
Uncertain significance	42
Likely benign	11
Benign	2

Top pathogenic / likely-pathogenic (1)

Variant ID	HGVS	Classification
242873	NM_001098.3(ACO2):c.2338_2339del (p.Gln780fs)	Likely pathogenic

SpliceAI

1959 predictions. Top by Δscore:

Variant	Effect	Δscore
22:41526248:A:AG	acceptor_gain	1.0000
22:41526249:C:G	acceptor_gain	1.0000
22:41526252:A:AG	acceptor_gain	1.0000
22:41526253:C:G	acceptor_gain	1.0000
22:41526255:A:AG	acceptor_gain	1.0000
22:41526256:C:G	acceptor_gain	1.0000
22:41526257:CCAA:C	acceptor_loss	1.0000
22:41526259:A:AG	acceptor_gain	1.0000
22:41526259:AAG:A	acceptor_gain	1.0000
22:41526260:A:AG	acceptor_gain	1.0000
22:41526260:A:T	acceptor_loss	1.0000
22:41526261:G:GG	acceptor_gain	1.0000
22:41526261:GGTC:G	acceptor_gain	1.0000
22:41526261:GGTCA:G	acceptor_gain	1.0000
22:41526415:G:GT	donor_gain	1.0000
22:41526451:AAGGT:A	donor_loss	1.0000
22:41526454:G:GA	donor_loss	1.0000
22:41526455:T:G	donor_loss	1.0000
22:41527283:GACA:G	acceptor_loss	1.0000
22:41527285:CA:C	acceptor_loss	1.0000
22:41527286:A:AG	acceptor_gain	1.0000
22:41527286:AGAAA:A	acceptor_loss	1.0000
22:41527287:G:GC	acceptor_loss	1.0000
22:41527287:G:GG	acceptor_gain	1.0000
22:41527287:GA:G	acceptor_gain	1.0000
22:41527287:GAA:G	acceptor_gain	1.0000
22:41527287:GAAA:G	acceptor_gain	1.0000
22:41527287:GAAAC:G	acceptor_gain	1.0000
22:41527418:ACGGT:A	donor_loss	1.0000
22:41527420:GGT:G	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000382133 (22:41531821 C>G), RS1000539187 (22:41543601 A>C), RS1000636763 (22:41546565 C>T), RS1000720501 (22:41526812 A>G), RS1000801099 (22:41536207 A>C,G), RS1000935867 (22:41532150 T>C), RS1000939798 (22:41536409 T>C), RS1001144862 (22:41537415 G>A), RS1001227068 (22:41527022 C>G,T), RS1001481839 (22:41531100 A>C,G), RS1001500668 (22:41537790 T>A,C), RS1001526966 (22:41541792 A>T), RS1001630420 (22:41545286 G>A), RS1001806407 (22:41534708 A>G), RS1001829280 (22:41538370 C>T)

Disease associations

OMIM: gene MIM:619801 | disease phenotypes: MIM:614559

GenCC curated gene-disease

Disease	Classification	Inheritance
primary ovarian failure	Moderate	Autosomal recessive
46 XX gonadal dysgenesis	Supportive	Autosomal dominant

Mondo (4): infantile cerebellar-retinal degeneration (MONDO:0013802), optic atrophy (MONDO:0003608), 46 XX gonadal dysgenesis (MONDO:0009299), primary ovarian failure (MONDO:0005387)

Orphanet (1): Infantile cerebellar-retinal degeneration (Orphanet:313850)

HPO phenotypes

25 total (25 of 25 shown, HPO-id order):

HPO	Term
HP:0000062	Ambiguous genitalia
HP:0000133	Gonadal dysgenesis
HP:0000144	Decreased fertility
HP:0000252	Microcephaly
HP:0000365	Hearing impairment
HP:0000786	Primary amenorrhea
HP:0000823	Delayed puberty
HP:0000837	Increased circulating gonadotropin level
HP:0000869	Secondary amenorrhea
HP:0000938	Osteopenia
HP:0001166	Arachnodactyly
HP:0001251	Ataxia
HP:0001939	Abnormality of metabolism/homeostasis
HP:0002206	Pulmonary fibrosis
HP:0002225	Sparse pubic hair
HP:0002750	Delayed skeletal maturation
HP:0004322	Short stature
HP:0004349	Reduced bone mineral density
HP:0005625	Osteoporosis of vertebrae
HP:0008209	Premature ovarian insufficiency
HP:0008214	Decreased serum estradiol
HP:0008684	Aplasia/hypoplasia of the uterus
HP:0009888	Abnormality of secondary sexual hair
HP:0010311	Aplasia/Hypoplasia of the breasts
HP:0010464	Streak ovary

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST004946_20	Schizophrenia	1.000000e-12
GCST005232_52	Neuroticism	3.000000e-18
GCST008522_45	Bitter alcoholic beverage consumption	7.000000e-09
GCST008811_1	Alcohol consumption (drinks per week)	7.000000e-10
GCST010002_83	Refractive error	2.000000e-27
GCST010143_2	Meat-related diet	4.000000e-08

EFO canonical traits (3, from GWAS)

EFO ID	Trait name
EFO:0007660	neuroticism measurement
EFO:0010092	bitter alcoholic beverage consumption measurement
EFO:0008111	diet measurement

MeSH disease descriptors (3)

Descriptor	Name	Tree numbers
D023961	Gonadal Dysgenesis, 46,XX	C12.050.351.875.253.064.249; C12.050.351.875.253.309.193; C12.200.706.316.064.249; C12.200.706.316.309.193; C12.800.316.064.249; C12.800.316.309.193; C16.131.939.316.064.249; C16.131.939.316.309.193; C19.391.119.064.249; C19.391.119.309.193
D009896	Optic Atrophy	C10.292.700.225; C11.640.451
D016649	Primary Ovarian Insufficiency	C12.050.351.500.056.630.750; C12.100.250.056.630.750; C19.391.630.750

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, increases expression	3
perfluorooctanoic acid	decreases expression	2
Particulate Matter	increases expression	2
GSK-J4	decreases expression	1
alpha-pinene	affects cotreatment, affects expression, increases abundance	1
mono-(2-ethylhexyl)phthalate	increases abundance, increases methylation	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	affects cotreatment, decreases expression	1
ferrous chloride	decreases expression	1
methacrylaldehyde	affects cotreatment, affects expression, increases abundance	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
perfluorooctane sulfonic acid	decreases expression	1
perfluoro-n-nonanoic acid	decreases expression	1
K 7174	decreases expression	1
perfluorohexanesulfonic acid	decreases expression	1
abrine	decreases expression	1
bisphenol S	affects cotreatment, decreases expression	1
Bortezomib	decreases expression	1
Acrolein	affects cotreatment, affects expression, increases abundance	1
Air Pollutants	affects expression, increases abundance, affects cotreatment	1
Carbamazepine	affects expression	1
Dexamethasone	affects cotreatment, decreases expression	1
Diethylhexyl Phthalate	increases abundance, increases methylation	1
Doxorubicin	decreases expression	1
Estradiol	increases expression	1
Ethyl Methanesulfonate	decreases expression	1
Hydrogen Peroxide	affects cotreatment, decreases expression	1
Indomethacin	affects cotreatment, decreases expression	1

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT00417066	PHASE4	COMPLETED	Flexible GnRH Antagonist vs Flare up GnRH Agonist Protocol in Poor Responders
NCT00732693	PHASE4	COMPLETED	Evaluation of Physiologic and Standard Sex Steroid Replacement Regimens in Women With Premature Ovarian Failure
NCT00837616	PHASE4	COMPLETED	Estrogen Dosing in Turner Syndrome: Pharmacology and Metabolism
NCT01853501	PHASE4	UNKNOWN	Effects of ADSC Therapy in Women With POF
NCT02783937	PHASE4	COMPLETED	Filgrastim for Premature Ovarian Insufficiency
NCT03535480	PHASE4	UNKNOWN	Autologous Bone Marrow Stem Cell Ovarian Transplantation to Restore Ovarian Function in Premature Ovarian Failure
NCT00140998	PHASE3	COMPLETED	Estrogen Treatment (Oral vs. Patches) in Turner Syndrome
NCT00001951	PHASE2	COMPLETED	Hormone Replacement in Young Women With Premature Ovarian Failure
NCT00370019	PHASE2	WITHDRAWN	Effects of an Estrogen Replacement Therapy Skin Patch on Ovulation in Women With Premature Ovarian Failure
NCT00429494	PHASE2	COMPLETED	GnRH Analogue for Ovarian Function Preservation in Hematopoietic Stem Cell Transplantation Patients
NCT03816852	PHASE2	SUSPENDED	The Safety and Efficiency Study of Mesenchymal Stem Cell (19#iSCLife®-POI) in Premature Ovarian Insufficiency
NCT04536467	PHASE2	UNKNOWN	Prevention of Chemotherapy-Induced Ovarian Failure With Goserelin in Premenopausal Lymphoma Patients
NCT06117982	PHASE2	COMPLETED	The Impact of Granulocyte Colony Stimulating Factor on Premature Ovarian Insufficiency
NCT02912104	PHASE1	COMPLETED	A Therapeutic Trial of Human Amniotic Epithelial Cells Transplantation for Primary Ovarian Failure
NCT03178695	PHASE1	COMPLETED	Inovium Ovarian Rejuvenation Trials
NCT04815213	PHASE1	ACTIVE_NOT_RECRUITING	The Use of Expandeded Mesenchymal Stromal Cells (MSC) in Premature Ovarian Failure (POF) in Adult Humans
NCT05138367	PHASE1	COMPLETED	Effects of UCA-PSCs in Women With POF
NCT06132542	PHASE1	UNKNOWN	Autologous ADMSC Transplantation in Patients With POI
NCT01064505	PHASE1	COMPLETED	Safety Study of a Single IVT Injection of QPI-1007 in Chronic Optic Nerve Atrophy and Recent Onset NAION Patients
NCT05147701	PHASE1	RECRUITING	Safety of Cultured Allogeneic Adult Umbilical Cord Derived Mesenchymal Stem Cells for NAION
NCT00948857	PHASE2/PHASE3	TERMINATED	Dehydroepiandrosterone (DHEA) Treatment and Premature Ovarian Failure (POF)
NCT04031456	PHASE2/PHASE3	RECRUITING	Autologous PRP Infusion May Restore Ovarian Function and May Promote Folliculogenesis in POI Patients
NCT02043743	PHASE1/PHASE2	UNKNOWN	Autologous Stem Cells Transplantation in Patients With Idiopathic and Drug Induced Premature Ovarian Failure
NCT02062931	PHASE1/PHASE2	UNKNOWN	Autologous Mesenchymal Stem Cells Transplantation In Women With Premature Ovarian Failure
NCT02151890	PHASE1/PHASE2	COMPLETED	Pregnancy After Stem Cell Transplantation in Premature Ovarian Failure
NCT02372474	PHASE1/PHASE2	COMPLETED	It is a Real The First Baby Of Autologous Stem Cell Therapy in Premature Ovarian Failure
NCT02603744	PHASE1/PHASE2	UNKNOWN	Autologous Adipose Derived Mesenchymal Stromal Cells Transplantation in Women With Premature Ovarian Failure (POF)
NCT02644447	PHASE1/PHASE2	COMPLETED	Transplantation of HUC-MSCs With Injectable Collagen Scaffold for POF
NCT03069209	PHASE1/PHASE2	UNKNOWN	Autologous Bone Marrow-Derived Stem Cell Transplantation in Patients With Premature Ovarian Failure (POF)
NCT03985462	PHASE1/PHASE2	WITHDRAWN	Very Small Embryonic-like Stem Cells for Ovary
NCT04009473	PHASE1/PHASE2	UNKNOWN	Stem Cell Therapy and Growth Factor Ovarian in Vitro Activation
NCT04071574	PHASE1/PHASE2	COMPLETED	Comparative Study on the Efficacy of Ovarian Stimulation Protocols on the Success Rate of ICSI in Female Infertility
NCT04922398	PHASE1/PHASE2	UNKNOWN	Ovarian Injection of PRP (Platelet -Rich Plasma) Vs Normal Saline in Premature Ovarian Insufficiency
NCT05462379	PHASE1/PHASE2	ACTIVE_NOT_RECRUITING	Autologous Heterotopic Fresh Ovarian Graft in Woman With LACC Eligible for Pelvic Radiotherapy Treatment.
NCT06202547	PHASE1/PHASE2	UNKNOWN	Intra-ovarian Injection of MSC-EVs in Idiopathic Premature Ovarian Failure
NCT01129947	EARLY_PHASE1	WITHDRAWN	The Use of DHEA in Women With Premature Ovarian Failure
NCT05522634	EARLY_PHASE1	UNKNOWN	A Clinical Study of Chinese Herbal Compound TJAOA101 in the Treatment of Premature Ovarian Insufficiency
NCT07308327	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	The Influence of Gut Microbiota on Ovarian Function: A Single-center, Randomized,Double Blind, Parallel-controlled, Exploratory Clinical Trial
NCT00001275	Not specified	COMPLETED	Ovarian Follicle Function in Patients With Primary Ovarian Failure
NCT00001306	Not specified	COMPLETED	Steroid Therapy in Autoimmune Premature Ovarian Failure