POLR3K

Summary

POLR3K (RNA polymerase III subunit K, HGNC:14121) is a protein-coding gene on chromosome 16p13.3, encoding DNA-directed RNA polymerase III subunit RPC10 (Q9Y2Y1). Core component of RNA polymerase III (Pol III) which synthesizes small non-coding RNAs using the four ribonucleoside triphosphates as substrates. It is a common-essential gene (DepMap: required in 99.1% of cancer cell lines).

This gene encodes a small essential subunit of RNA polymerase III, the polymerase responsible for synthesizing transfer and small ribosomal RNAs in eukaryotes. The carboxy-terminal domain of this subunit shares a high degree of sequence similarity to the carboxy-terminal domain of an RNA polymerase II elongation factor. This similarity in sequence is supported by functional studies showing that this subunit is required for proper pausing and termination during transcription. Pseudogenes of this gene are found on chromosomes 13 and 17.

Source: NCBI Gene 51728 — RefSeq curated summary.

At a glance

• Gene–disease (curated): leukodystrophy, hypomyelinating, 21 (Strong, GenCC)
• GWAS associations: 6
• Clinical variants (ClinVar): 27 total — 2 pathogenic
• Phenotypes (HPO): 25
• Cancer dependency (DepMap): dependent in 99.1% of screened cell lines (common-essential)
• MANE Select transcript: NM_016310

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14121
Approved symbol	POLR3K
Name	RNA polymerase III subunit K
Location	16p13.3
Locus type	gene with protein product
Status	Approved
Aliases	RPC11, C11
Ensembl gene	ENSG00000161980
Ensembl biotype	protein_coding
OMIM	606007
Entrez	51728

Gene structure

Transcript identifiers

Ensembl transcripts: 3 — 2 protein_coding, 1 retained_intron

ENST00000293860, ENST00000481810, ENST00000913642

RefSeq mRNA: 1 — MANE Select: NM_016310 NM_016310

CCDS: CCDS10395

Canonical transcript exons

ENST00000293860 — 3 exons

Exon	Start	End
ENSE00001061797	51558	51645
ENSE00001321652	53476	53608
ENSE00001326140	46407	47557

Expression profiles

Bgee: expression breadth ubiquitous, 277 present calls, max score 87.92.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 15.2376 / max 110.6306, expressed in 1791 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
155692	15.2376	1791

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	87.92	gold quality
prefrontal cortex	UBERON:0000451	86.99	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	86.91	gold quality
biceps brachii	UBERON:0001507	86.55	gold quality
diaphragm	UBERON:0001103	85.83	silver quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	85.38	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	85.26	gold quality
monocyte	CL:0000576	84.91	gold quality
leukocyte	CL:0000738	84.76	gold quality
mononuclear cell	CL:0000842	84.60	gold quality
anterior cingulate cortex	UBERON:0009835	84.07	gold quality
granulocyte	CL:0000094	84.04	gold quality
cingulate cortex	UBERON:0003027	84.00	gold quality
hindlimb stylopod muscle	UBERON:0004252	83.97	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	83.90	gold quality
frontal cortex	UBERON:0001870	83.63	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	83.58	gold quality
lymph node	UBERON:0000029	83.55	gold quality
neocortex	UBERON:0001950	83.23	gold quality
epithelium of bronchus	UBERON:0002031	83.15	gold quality
Brodmann (1909) area 9	UBERON:0013540	82.87	gold quality
nucleus accumbens	UBERON:0001882	82.85	gold quality
bronchus	UBERON:0002185	82.76	gold quality
embryo	UBERON:0000922	82.70	gold quality
right frontal lobe	UBERON:0002810	82.67	gold quality
vermiform appendix	UBERON:0001154	82.56	gold quality
right adrenal gland	UBERON:0001233	82.50	gold quality
triceps brachii	UBERON:0001509	82.45	gold quality
islet of Langerhans	UBERON:0000006	82.44	gold quality
bronchial epithelial cell	CL:0002328	82.21	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	yes	6.81

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

19 targeting POLR3K, 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-3646	100.00	73.56	5283
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-7845-5P	99.88	64.88	771
HSA-MIR-12117	99.50	67.57	868
HSA-MIR-4672	99.50	71.58	2893
HSA-MIR-892C-5P	99.16	70.56	2116
HSA-MIR-4796-3P	99.08	68.38	1681
HSA-MIR-194-5P	99.01	69.65	1465
HSA-MIR-4801	98.96	69.42	2096
HSA-MIR-6754-3P	98.84	66.60	889
HSA-MIR-887-5P	98.82	65.90	1347
HSA-MIR-4731-3P	98.56	68.60	1860
HSA-MIR-3190-3P	97.61	66.95	1406
HSA-MIR-15A-3P	97.47	65.08	527
HSA-MIR-125B-2-3P	96.69	68.38	1210
HSA-MIR-3117-3P	95.96	67.82	473
HSA-MIR-8083	95.93	67.55	694

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 99.1% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 3)

• Changes in Maf1 expression affect Pol III-dependent transcription in human glioblastoma lines. (PMID:17499043)
• Results from a study on gene expression variability markers in early-stage human embryos shows that POLR3K is a putative expression variability marker for the 3-day, 8-cell embryo stage. (PMID:26288249)
• Cryo-EM structures of human RNA polymerase III in its unbound and transcribing states. (PMID:33558764)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	polr3k	ENSDARG00000037835
mus_musculus	Polr3k	ENSMUSG00000038628
rattus_norvegicus	Polr3k	ENSRNOG00000086796
drosophila_melanogaster	Polr3K	FBGN0061362
caenorhabditis_elegans		WBGENE00022309

Paralogs (2): POLR1H (ENSG00000066379), POLR2I (ENSG00000105258)

Protein

Protein identifiers

DNA-directed RNA polymerase III subunit RPC10 — Q9Y2Y1 (reviewed: Q9Y2Y1)

Alternative names: DNA-directed RNA polymerase III subunit K, RNA polymerase III 12.5 kDa subunit, RNA polymerase III subunit C11

All UniProt accessions (1): Q9Y2Y1

UniProt curated annotations — full annotation on UniProt →

Function. Core component of RNA polymerase III (Pol III) which synthesizes small non-coding RNAs using the four ribonucleoside triphosphates as substrates. Can mediate Pol I proofreading of the nascent RNA transcript. Anchors into the Pol III active site to constantly monitor transcription fidelity, cleaves mis-incorporated 5’-ribonucleotides and restarts the transcription process. Once Pol III reaches the poly(dT) termination signal, can induce Pol III clamp opening and transcription termination. Pol III plays an important role in sensing and limiting infection by intracellular bacteria and DNA viruses. Acts as a 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.

Subcellular location. Nucleus.

Disease relevance. Leukodystrophy, hypomyelinating, 21 (HLD21) [MIM:619310] An autosomal recessive neurodegenerative disorder characterized by global developmental delay, loss of motor, speech and cognitive milestones in the first decades of life, and diffuse hypomyelination of the white matter and atrophy of the cerebellum and corpus callosum observed on brain imaging. Clinical features include nystagmus, ataxia, dystonia, and spasticity. Other more variable features are feeding difficulties, poor overall growth with microcephaly, optic atrophy, and seizures. The disorder is progressive and may lead to premature death. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The TFIIS-type zinc-binding beta-ribbon domain contains an acidic hairpin motif (residues Asp-88, Glu-89) that likely coordinates the nucleophilic water and magnesium to cleave the scissile phosphodiester bond and release the mis-incorporated 5’-ribonucleotides.

Similarity. Belongs to the archaeal RpoM/eukaryotic RPA12/RPB9/RPC11 RNA polymerase family.

RefSeq proteins (1): NP_057394* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001222	Znf_TFIIS	Domain
IPR001529	Zn_ribbon_RPB9	Domain
IPR012164	Rpa12/Rpb9/Rpc10/TFS	Family
IPR019761	DNA-dir_RNA_pol-M_15_CS	Conserved_site
IPR034014	Zn_ribbon_RPC11_C	Domain

Pfam: PF01096, PF02150

UniProt features (28 total): strand 10, binding site 8, turn 3, zinc finger region 2, sequence variant 2, chain 1, helix 1, short sequence motif 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-Q9Y2Y1-F1	85.14	0.13

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 (8): 98; 102; 5; 8; 25; 28; 69; 72

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: 254 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_DN, GSE18804_SPLEEN_MACROPHAGE_VS_TUMORAL_MACROPHAGE_DN, ELVIDGE_HYPOXIA_DN, REACTOME_RNA_POLYMERASE_III_TRANSCRIPTION_INITIATION_FROM_TYPE_3_PROMOTER, REACTOME_RNA_POLYMERASE_III_TRANSCRIPTION_TERMINATION, BUYTAERT_PHOTODYNAMIC_THERAPY_STRESS_DN, REACTOME_INNATE_IMMUNE_SYSTEM, REACTOME_RNA_POLYMERASE_III_CHAIN_ELONGATION, GOBP_DNA_TEMPLATED_TRANSCRIPTION_TERMINATION, GRAESSMANN_APOPTOSIS_BY_SERUM_DEPRIVATION_DN, GRAESSMANN_RESPONSE_TO_MC_AND_SERUM_DEPRIVATION_DN, GOBP_TRANSCRIPTION_BY_RNA_POLYMERASE_III, KEGG_CYTOSOLIC_DNA_SENSING_PATHWAY, GOLDRATH_ANTIGEN_RESPONSE, WEI_MYCN_TARGETS_WITH_E_BOX

GO Biological Process (5): transcription by RNA polymerase III (GO:0006383), innate immune response (GO:0045087), defense response to virus (GO:0051607), immune system process (GO:0002376), DNA-templated transcription (GO:0006351)

GO Molecular Function (5): nucleic acid binding (GO:0003676), DNA-directed RNA polymerase activity (GO:0003899), zinc ion binding (GO:0008270), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (5): nucleoplasm (GO:0005654), RNA polymerase III complex (GO:0005666), 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	2
binding	2
cellular anatomical structure	2
DNA-templated transcription	1
immune response	1
defense response to symbiont	1
defense response	1
response to virus	1
biological_process	1
gene expression	1
5’-3’ RNA polymerase activity	1
transition metal ion binding	1
cation binding	1
nuclear lumen	1
DNA-directed RNA polymerase complex	1
nuclear protein-containing complex	1
cytoplasm	1
RNA polymerase complex	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

2138 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POLR3K	POLR3B	Q9NW08	955
POLR3K	TCEA1	P23193	902
POLR3K	POLR3D	P05423	883
POLR3K	POLR2E	P19388	876
POLR3K	POLR3A	O14802	866
POLR3K	POLI	Q9UNA4	831
POLR3K	POLR2L	P52436	823
POLR3K	POLR1C	O15160	822
POLR3K	POLR3F	Q9H1D9	816
POLR3K	GTF2F1	P35269	814
POLR3K	POLR3C	Q9BUI4	813
POLR3K	POLR2H	P52434	810
POLR3K	POLR3G	O15318	802
POLR3K	POLR2I	P36954	798
POLR3K	POLR1D	P0DPB6	797

IntAct

53 interactions, top by confidence:

A	B	Type	Score
POLR2E	POLR3A	psi-mi:“MI:0914”(association)	0.870
POLR2E	POLR3A	psi-mi:“MI:0915”(physical association)	0.870
POLR3GL	POLR3A	psi-mi:“MI:0914”(association)	0.730
POLR2E	MED19	psi-mi:“MI:0914”(association)	0.730
POLR3D	POLR3A	psi-mi:“MI:0914”(association)	0.640
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
POLR2L	POLR3A	psi-mi:“MI:0914”(association)	0.640
SDCBP	POLR3K	psi-mi:“MI:0915”(physical association)	0.560
TRIM69	POLR3K	psi-mi:“MI:0915”(physical association)	0.560
CENPP	POLR3K	psi-mi:“MI:0915”(physical association)	0.560
PIH1D1	POLR3A	psi-mi:“MI:0914”(association)	0.530
POLR3H	POLR3A	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
Ruvbl1	AAR2	psi-mi:“MI:0914”(association)	0.350
POLR2F	BDP1	psi-mi:“MI:0914”(association)	0.350
POLR3E	BDP1	psi-mi:“MI:0914”(association)	0.350
RFPL4B	KRBA1	psi-mi:“MI:0914”(association)	0.350
POLR1C	POLR3A	psi-mi:“MI:0914”(association)	0.350
POLR3E	POLR3A	psi-mi:“MI:0914”(association)	0.350
GPN3	POLR3A	psi-mi:“MI:0914”(association)	0.350
TUBGCP4	SPTLC1	psi-mi:“MI:0914”(association)	0.350

BioGRID (141): POLR3K (Affinity Capture-MS), POLR3K (Affinity Capture-MS), POLR3K (Affinity Capture-MS), POLR3K (Affinity Capture-MS), POLR1C (Co-fractionation), POLR3D (Co-fractionation), POLR3K (Co-fractionation), POLR3K (Co-fractionation), POLR3K (Co-fractionation), POLR3K (Co-fractionation), POLR3K (Co-fractionation), POLR3K (Co-fractionation), POLR3K (Co-fractionation), POLR3K (Synthetic Growth Defect), POLR3K (Synthetic Growth Defect)

ESM2 similar proteins: A2XIP9, A4IFR3, O13868, O13896, O24473, O74635, P10711, P23193, P27999, P37164, P37165, P38861, P48598, P53803, P60002, P60003, Q08DS5, Q09817, Q0VA16, Q148K0, Q15560, Q21230, Q29RL9, Q2M2S7, Q32LB0, Q3TWF6, Q3ZBC0, Q4KLL0, Q54KR5, Q5EB92, Q5RC82, Q63871, Q6FS48, Q6GPP0, Q6MFY5, Q755B3, Q75LU5, Q791N7, Q8LEF3, Q8LHP0

Diamond homologs: O13896, O27369, O29033, O75764, P07273, P10711, P20232, P23193, P23881, P36958, P49373, Q04307, Q07271, Q29RL9, Q2KI09, Q2M2S7, Q4KLL0, Q56254, Q58548, Q5JF34, Q5UQS8, Q980K2, Q9CQZ7, Q9P9I8, Q9Y2Y1, Q9ZVH8, B0UYI1, F4J4Y5, P0C8F5, P0C8F6, P0C8F7, P0C8F8, P27948, P52652, Q148K0, Q15560, Q3US16, Q54YG9, Q63799, Q6GZP4

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
POLR3K	“form complex”	“RNA Polymerase III”	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 36 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	14	341.6×	8e-34
RNA Polymerase III Transcription Termination	14	267.4×	4e-32
RNA Polymerase III Transcription Initiation From Type 2 Promoter	15	244.0×	2e-33
RNA Polymerase III Transcription Initiation From Type 1 Promoter	15	235.3×	3e-33
RNA Polymerase III Transcription Initiation From Type 3 Promoter	15	235.3×	3e-33
RNA Polymerase III Transcription Initiation	15	193.8×	8e-32
RNA Polymerase III Transcription	15	188.2×	1e-31
RNA Polymerase III Abortive And Retractive Initiation	15	160.7×	2e-30

GO biological processes:

GO term	Partners	Fold	FDR
transcription by RNA polymerase III	5	123.5×	2e-08
defense response to virus	6	13.4×	8e-05
transcription by RNA polymerase II	5	11.4×	7e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	2
Likely pathogenic	0
Uncertain significance	18
Likely benign	4
Benign	1

Top pathogenic / likely-pathogenic (2)

Variant ID	HGVS	Classification
1065610	NM_016310.5(POLR3K):c.121C>T (p.Arg41Trp)	Pathogenic
2499507	NM_016310.5(POLR3K):c.322G>T (p.Asp108Tyr)	Pathogenic

SpliceAI

438 predictions. Top by Δscore:

Variant	Effect	Δscore
16:51552:TCTTA:T	donor_loss	1.0000
16:51553:CTTAC:C	donor_loss	1.0000
16:51554:TTACC:T	donor_loss	1.0000
16:51555:TACC:T	donor_loss	1.0000
16:51556:A:T	donor_loss	1.0000
16:51557:C:CA	donor_loss	1.0000
16:51557:CCTG:C	donor_gain	1.0000
16:51644:ACCTA:A	acceptor_loss	1.0000
16:51646:CTAA:C	acceptor_loss	1.0000
16:51556:A:AC	donor_gain	0.9900
16:51557:C:CC	donor_gain	0.9900
16:51642:TTAC:T	acceptor_gain	0.9900
16:51646:C:CC	acceptor_gain	0.9900
16:51647:T:C	acceptor_loss	0.9900
16:53470:TCCCA:T	donor_loss	0.9900
16:53471:CCCAC:C	donor_loss	0.9900
16:53472:CCAC:C	donor_loss	0.9900
16:53473:CA:C	donor_loss	0.9900
16:53474:A:C	donor_loss	0.9900
16:53475:CC:C	donor_loss	0.9900
16:47553:CGACT:C	acceptor_gain	0.9800
16:51641:GTTAC:G	acceptor_gain	0.9800
16:51643:TAC:T	acceptor_gain	0.9800
16:53476:C:G	donor_loss	0.9800
16:47556:CT:C	acceptor_gain	0.9700
16:53540:T:TA	donor_gain	0.9700
16:47558:C:CC	acceptor_gain	0.9600
16:51650:C:CT	acceptor_gain	0.9600
16:47557:TCTG:T	acceptor_gain	0.9500
16:51644:AC:A	acceptor_gain	0.9400

AlphaMissense

709 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
16:47495:C:G	D88H	0.999
16:47520:G:C	F79L	0.999
16:47520:G:T	F79L	0.999
16:47522:A:G	F79L	0.999
16:51580:C:A	W59C	0.999
16:51580:C:G	W59C	0.999
16:47439:C:A	W106C	0.998
16:47439:C:G	W106C	0.998
16:47475:G:C	F94L	0.998
16:47475:G:T	F94L	0.998
16:47477:A:G	F94L	0.998
16:47494:T:A	D88V	0.998
16:47508:C:A	Q83H	0.998
16:47508:C:G	Q83H	0.998
16:51582:A:G	W59R	0.998
16:51582:A:T	W59R	0.998
16:47441:A:G	W106R	0.997
16:47441:A:T	W106R	0.997
16:47482:G:A	T92I	0.997
16:47490:C:A	E89D	0.997
16:47490:C:G	E89D	0.997
16:47495:C:A	D88Y	0.997
16:47497:G:T	A87E	0.997
16:47552:A:G	C69R	0.997
16:53514:A:G	C25R	0.997
16:47467:C:G	C97S	0.996
16:47468:A:G	C97R	0.996
16:47468:A:T	C97S	0.996
16:47491:T:A	E89V	0.996
16:47492:C:T	E89K	0.996

dbSNP variants (sampled 300 via entrez): RS1000268642 (16:54809 C>G,T), RS1000789770 (16:49781 A>C), RS1001032004 (16:54278 A>G), RS1001400177 (16:55006 A>C,G,T), RS1001463169 (16:54071 G>A,C,T), RS1001860029 (16:51879 G>A), RS1001969779 (16:48942 G>A,C), RS1002108361 (16:54354 G>T), RS1002291140 (16:51733 T>C), RS1002565896 (16:54202 C>T), RS1002919182 (16:48246 C>G), RS1003163172 (16:53175 C>T), RS1003572117 (16:52945 GGTGGC>G), RS1004020760 (16:48928 T>G), RS1004240654 (16:47196 G>C)

Disease associations

OMIM: gene MIM:606007 | disease phenotypes: MIM:619310, MIM:619636

GenCC curated gene-disease

Disease	Classification	Inheritance
leukodystrophy, hypomyelinating, 21	Strong	Autosomal recessive

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
leukodystrophy, hypomyelinating, 21	Limited	AR

Mondo (2): leukodystrophy, hypomyelinating, 21 (MONDO:0030263), acromesomelic dysplasia 4 (MONDO:0030553)

Orphanet (0):

HPO phenotypes

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

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000028	Cryptorchidism
HP:0000044	Hypogonadotropic hypogonadism
HP:0000252	Microcephaly
HP:0000639	Nystagmus
HP:0000648	Optic atrophy
HP:0000668	Hypodontia
HP:0000750	Delayed speech and language development
HP:0001251	Ataxia
HP:0001259	Coma
HP:0001268	Mental deterioration
HP:0001272	Cerebellar atrophy
HP:0001332	Dystonia
HP:0001344	Absent speech
HP:0001508	Failure to thrive
HP:0001510	Growth delay
HP:0001946	Ketosis
HP:0002273	Tetraparesis
HP:0002305	Athetosis
HP:0003593	Infantile onset
HP:0007371	Corpus callosum atrophy
HP:0008872	Feeding difficulties in infancy
HP:0025336	Delayed ability to sit
HP:0033044	Motor regression
HP:0100660	Dyskinesia

GWAS associations

6 associations (top):

Study	Trait	p-value
GCST001873_3	Red blood cell traits	3.000000e-23
GCST001873_5	Red blood cell traits	9.000000e-48
GCST001873_6	Red blood cell traits	2.000000e-34
GCST001873_8	Red blood cell traits	4.000000e-22
GCST005951_12	Body mass index	5.000000e-11
GCST90002392_442	Mean corpuscular volume	2.000000e-15

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004509	hemoglobin measurement
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0004527	mean corpuscular hemoglobin
EFO:0004340	body mass index

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
sodium arsenite	decreases expression, increases expression	3
bisphenol A	decreases expression, increases expression	2
afuresertib	decreases expression	1
dicrotophos	decreases expression	1
lead acetate	affects cotreatment, decreases expression	1
tris(1,3-dichloro-2-propyl)phosphate	decreases expression	1
zinc protoporphyrin	decreases expression, affects cotreatment	1
cobaltous chloride	decreases expression	1
isobutyl alcohol	affects cotreatment, decreases expression, increases abundance	1
di-n-butylphosphoric acid	affects expression	1
2-palmitoylglycerol	increases expression	1
K 7174	decreases expression	1
erucylphospho-N,N,N-trimethylpropylammonium	decreases expression	1
abrine	decreases expression	1
2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine	increases response to substance, decreases expression	1
jinfukang	increases expression	1
NSC 689534	affects binding, decreases expression	1
Temozolomide	increases expression	1
Troglitazone	decreases expression	1
Atrazine	decreases expression	1
Copper	affects binding, decreases expression	1
Dichlorodiphenyl Dichloroethylene	increases expression	1
Gasoline	affects cotreatment, decreases expression, increases abundance	1
Hydrogen Peroxide	affects cotreatment, decreases expression	1
Oxygen	decreases expression	1
Piroxicam	decreases expression	1
Plant Extracts	decreases expression	1
Polycyclic Aromatic Hydrocarbons	affects cotreatment, decreases expression, increases abundance	1
Progesterone	decreases expression	1
Silicon Dioxide	increases expression	1

Clinical trials (associated diseases)

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