POLD4

Summary

POLD4 (DNA polymerase delta 4, accessory subunit, HGNC:14106) is a protein-coding gene on chromosome 11q13.2, encoding DNA polymerase delta subunit 4 (Q9HCU8). As a component of the tetrameric DNA polymerase delta complex (Pol-delta4), plays a role in high fidelity genome replication and repair.

This gene encodes the smallest subunit of DNA polymerase delta. DNA polymerase delta possesses both polymerase and 3’ to 5’ exonuclease activity and plays a critical role in DNA replication and repair. The encoded protein enhances the activity of DNA polymerase delta and plays a role in fork repair and stabilization through interactions with the DNA helicase Bloom syndrome protein. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 57804 — RefSeq curated summary.

At a glance

• GWAS associations: 5
• Clinical variants (ClinVar): 1 total
• Druggable target: yes
• MANE Select transcript: NM_021173

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:14106
Approved symbol	POLD4
Name	DNA polymerase delta 4, accessory subunit
Location	11q13.2
Locus type	gene with protein product
Status	Approved
Aliases	p12, POLDS
Ensembl gene	ENSG00000175482
Ensembl biotype	protein_coding
OMIM	611525
Entrez	57804

Gene structure

Transcript identifiers

Ensembl transcripts: 13 — 7 protein_coding, 6 retained_intron

ENST00000312419, ENST00000524743, ENST00000528087, ENST00000529000, ENST00000529704, ENST00000530584, ENST00000531239, ENST00000532830, ENST00000533429, ENST00000534515, ENST00000539074, ENST00000542982, ENST00000944954

RefSeq mRNA: 2 — MANE Select: NM_021173 NM_001256870, NM_021173

CCDS: CCDS58149, CCDS8158

Canonical transcript exons

ENST00000312419 — 4 exons

Exon	Start	End
ENSE00001213808	67353303	67353546
ENSE00003655650	67352691	67352802
ENSE00003672983	67352988	67353077
ENSE00003841909	67350772	67352019

Expression profiles

Bgee: expression breadth ubiquitous, 138 present calls, max score 98.71.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 82.5918 / max 651.2332, expressed in 1826 samples.

FANTOM5 promoters (6 alternative TSS)

Promoter ID	TPM avg	Samples expressed
120896	75.7631	1826
120895	6.2272	1321
120897	0.4080	209
120893	0.1140	42
120899	0.0457	19
120898	0.0338	9

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
mucosa of transverse colon	UBERON:0004991	98.71	gold quality
right lobe of liver	UBERON:0001114	97.71	gold quality
granulocyte	CL:0000094	97.70	gold quality
lower esophagus mucosa	UBERON:0035834	97.69	gold quality
duodenum	UBERON:0002114	97.58	gold quality
vermiform appendix	UBERON:0001154	97.31	gold quality
lymph node	UBERON:0000029	97.22	gold quality
descending thoracic aorta	UBERON:0002345	97.07	gold quality
blood	UBERON:0000178	97.06	gold quality
left coronary artery	UBERON:0001626	97.01	gold quality
small intestine Peyer’s patch	UBERON:0003454	97.01	gold quality
right coronary artery	UBERON:0001625	96.90	gold quality
small intestine	UBERON:0002108	96.87	gold quality
spleen	UBERON:0002106	96.81	gold quality
transverse colon	UBERON:0001157	96.76	gold quality
liver	UBERON:0002107	96.71	gold quality
thoracic aorta	UBERON:0001515	96.65	gold quality
ascending aorta	UBERON:0001496	96.61	gold quality
body of pancreas	UBERON:0001150	96.58	gold quality
popliteal artery	UBERON:0002250	96.55	gold quality
tibial artery	UBERON:0007610	96.55	gold quality
leukocyte	CL:0000738	96.49	gold quality
monocyte	CL:0000576	96.41	gold quality
esophagus mucosa	UBERON:0002469	96.38	gold quality
body of stomach	UBERON:0001161	96.09	gold quality
right atrium auricular region	UBERON:0006631	95.99	gold quality
adult mammalian kidney	UBERON:0000082	95.74	gold quality
mucosa of stomach	UBERON:0001199	95.71	gold quality
prostate gland	UBERON:0002367	95.68	gold quality
esophagus	UBERON:0001043	95.55	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-CURD-114	yes	57.16
E-CURD-122	yes	18.76
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

30 targeting POLD4, 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-1252-5P	100.00	69.80	2774
HSA-MIR-6798-5P	100.00	65.77	699
HSA-MIR-7110-3P	100.00	73.18	2486
HSA-MIR-4534	99.99	66.58	1907
HSA-MIR-1-3P	99.93	72.35	1914
HSA-MIR-206	99.93	72.50	1893
HSA-MIR-613	99.91	71.50	1710
HSA-MIR-4731-5P	99.89	67.23	2537
HSA-MIR-765	99.84	68.24	2442
HSA-MIR-11181-3P	99.75	66.38	2205
HSA-MIR-6716-5P	99.56	68.62	1244
HSA-MIR-4441	99.49	66.56	3216
HSA-MIR-6727-3P	99.49	65.92	1333
HSA-MIR-504-3P	99.30	67.18	1745
HSA-MIR-133A-5P	99.28	69.13	941
HSA-MIR-544B	99.18	67.41	1632
HSA-MIR-4270	99.02	66.26	1987
HSA-MIR-4763-5P	98.75	63.89	854
HSA-MIR-4635	98.74	67.63	1339
HSA-MIR-3161	98.71	67.14	816
HSA-MIR-6754-5P	98.60	65.54	1627
HSA-MIR-5589-5P	98.34	64.82	1148
HSA-MIR-340-3P	98.11	68.25	679
HSA-MIR-4483	98.09	64.12	1642
HSA-MIR-6827-3P	98.08	72.27	651
HSA-MIR-596	97.48	63.13	469
HSA-MIR-3169	96.40	67.58	698
HSA-MIR-4749-3P	96.40	66.24	798
HSA-MIR-4529-3P	96.40	66.46	582
HSA-MIR-3918	96.13	64.65	1300

Literature-anchored findings (GeneRIF, showing 15)

• pol delta interacts with PCNA via at least two of its subunits, and p12 could play a role in stabilizing the overall pol delta-PCNA complex as well as pol delta itself (PMID:16510448)
• The DNA polymerase delta enzyme, as well as the isolated p12 subunit, stimulates the DNA helicase activity of Bloom’s syndrome helicase. (PMID:18682526)
• these results indicate that POLD4 is required for the in vitro pol delta activity, and that it functions in cell proliferation and maintenance of genomic stability of human cells. (PMID:19931513)
• Low POLD4 is associated with lung cancer. (PMID:20861182)
• The identification of RNF8 allows new insights into the integration of the control of p12 degradation by different DNA damage signaling pathways. (PMID:23233665)
• Data indicate that CRL4(Cdt2) regulates the degradation of the p12 subunit of Pol delta4. (PMID:23913683)
• ubiquitination of p12 through CRL4(Cdt2) and subsequent degradation form one mechanism by which a cell responds to DNA damage to inhibit fork progression. (PMID:24022480)
• Findings provide evidence for the novel concept that Pol delta3 has a role in lagging strand synthesis, and that both forms of Pol delta3 and 4 may participate in DNA replication in higher eukaryotic cells. (PMID:24035200)
• A parallel study of Pol delta4 and Pol delta3 in Okazaki fragment processing provides evidence for a role of Pol delta3 in DNA replication (PMID:24300032)
• the p12/Pol delta is a target as a nuclear substrate of mu-calpain in a calcium-triggered apoptosis and appears to be a potential marker in the study of the chemotherapy of cancer therapies. (PMID:24691096)
• Human Poldelta is a pentameric complex with a dimeric p12 subunit. RKR-mediated dimerization plays a vital role in p12 binding to PCNA and Poldelta5 architecture, and the phenomenon appears to be conserved throughout evolution. (PMID:30885984)
• The role in cellular processes (DNA replication, DNA repair, homologous recombination) and cell cycle regulation of 2 forms of human DNA polymerase delta: delta3 and delta4 was reviewed. (REVIEW) (PMID:31326365)
• Circular RNA circ_0026359 Enhances Cisplatin Resistance in Gastric Cancer via Targeting miR-1200/POLD4 Pathway. (PMID:32855967)
• Expression Profile, Molecular Association, and Clinical Significance of POLD4 in Glioblastoma. (PMID:37543966)
• POLD4 Promotes Glioma Cell Proliferation and Suppressive Immune Microenvironment: A Pan-Cancer Analysis Integrated with Experimental Validation. (PMID:37762224)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	pold4	ENSDARG00000079632
mus_musculus	Pold4	ENSMUSG00000024854
rattus_norvegicus	Pold4	ENSRNOG00000018765

Protein

Protein identifiers

DNA polymerase delta subunit 4 — Q9HCU8 (reviewed: Q9HCU8)

Alternative names: DNA polymerase delta subunit p12

All UniProt accessions (2): E9PL15, Q9HCU8

UniProt curated annotations — full annotation on UniProt →

Function. As a component of the tetrameric DNA polymerase delta complex (Pol-delta4), plays a role in high fidelity genome replication and repair. Within this complex, increases the rate of DNA synthesis and decreases fidelity by regulating POLD1 polymerase and proofreading 3’ to 5’ exonuclease activity. Pol-delta4 participates in Okazaki fragment processing, through both the short flap pathway, as well as a nick translation system. Under conditions of DNA replication stress, required for the repair of broken replication forks through break-induced replication (BIR), a mechanism that may induce segmental genomic duplications of up to 200 kb. Involved in Pol-delta4 translesion synthesis (TLS) of templates carrying O6-methylguanine or abasic sites. Its degradation in response to DNA damage is required for the inhibition of fork progression and cell survival.

Subunit / interactions. Component of the tetrameric DNA polymerase delta complex (Pol-delta4), which consists of POLD1/p125, POLD2/p50, POLD3/p66/p68 and POLD4/p12, with POLD1 bearing DNA polymerase and 3’ to 5’ proofreading exonuclease activities. Within this complex, directly interacts with POLD1 and POLD2. Directly interacts with PCNA, as do POLD1 and POLD3; this interaction stimulates Pol-delta4 polymerase activity. As POLD1 and POLD2, directly interacts with WRNIP1; this interaction stimulates DNA polymerase delta-mediated DNA synthesis, independently of the presence of PCNA. This stimulation may be due predominantly to an increase of initiation frequency and also to increased processivity. Upon genotoxic stress induced by DNA damaging agents or by replication stress, POLD4 is proteolytically degraded and Pol-delta4 is converted into a trimeric form of the complex (Pol-delta3) which has an increased proofreading activity. The DNA polymerase delta complex interacts with POLDIP2; this interaction is probably mediated through direct binding to POLD2.

Subcellular location. Nucleus.

Post-translational modifications. Ubiquitinated; undergoes ‘Lys-48’-linked ubiquitination in response to UV irradiation, leading to proteasomal degradation. This modification is partly mediated by RNF8 and by the DCX(DTL) E3 ubiquitin ligase complex (also called CRL4(CDT2)). Efficient degradation requires the presence of PCNA and is required for the inhibition of fork progression after DNA damage.

Induction. In response to DNA damage, genotoxic stress and replication stress, following UV irradiation, ionizing radiation, treatment with methyl methanesulfonate, hydroxyurea, or with aphidicolin, protein expression drops to undetectable levels, due to proteasomal degradation. This down-regulation is ATR-dependent.

Similarity. Belongs to the DNA polymerase delta subunit 4 family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9HCU8-1	1	yes
Q9HCU8-2	2

RefSeq proteins (2): NP_001243799, NP_066996* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR007218	DNA_pol_delta_4	Family

Pfam: PF04081

UniProt features (32 total): mutagenesis site 17, strand 4, helix 3, sequence variant 2, chain 1, region of interest 1, short sequence motif 1, compositionally biased region 1, turn 1, splice variant 1

Structure

Experimental structures (PDB)

7 structures.

PDB	Method	Resolution (Å)
6HVO	X-RAY DIFFRACTION	2.1
6TNY	ELECTRON MICROSCOPY	3.08
9EKB	ELECTRON MICROSCOPY	3.65
6TNZ	ELECTRON MICROSCOPY	4.05
6S1M	ELECTRON MICROSCOPY	4.27
6S1N	ELECTRON MICROSCOPY	4.86
6S1O	ELECTRON MICROSCOPY	8.1

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9HCU8-F1	85.73	0.63

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Mutagenesis-validated functional residues (17):

Position	Phenotype
4	no effect on ubiquitination. loss of ubiquitination, when associated with r-15, r-25, r-74 and r-89.
7	complete loss of pcna binding; when associated with 10-aa-11.
8	strongly increased stability following uv irradiation; when associated with a-9.
8	complete loss of pcna binding.
9	strongly increased stability following uv irradiation; when associated with a-8.
10–11	complete loss of pcna binding; when associated with a-7.
10	no effect on pcna binding, nor on degradation after uv irradiation; when associated with q-4. no effect on pcna binding,
15	decreased pcna binding. no effect on pcna binding, but normal degradation after uv irradiation; when associated with q-4
15	no effect on ubiquitination. loss of ubiquitination; when associated with r-4, r-25, r-74 and r-89.
16	increased stability following uv irradiation and no trough during s phase; when associated with a-15 and a-17.
17	increased stability following uv irradiation and no trough during s phase; when associated with a-15 and a-16.
25	no effect on ubiquitination. loss of ubiquitination; when associated with r-4, r-15, r-74 and r-89.
74	no effect on ubiquitination. loss of ubiquitination; when associated with r-4, r-15, r-25 and r-89.
89	no effect on ubiquitination. loss of ubiquitination; when associated with r-4, r-15, r-25 and r-74.
1–16	complete loss of pcna binding and of degradation after uv irradiation.
4	no effect on pcna binding.
4	no effect on pcna binding, nor on degradation after uv irradiation; when associated with y-10. no effect on pcna binding

Function

Pathways and Gene Ontology

Reactome pathways

17 pathways

ID	Pathway
R-HSA-110314	Recognition of DNA damage by PCNA-containing replication complex
R-HSA-174411	Polymerase switching on the C-strand of the telomere
R-HSA-174414	Processive synthesis on the C-strand of the telomere
R-HSA-174417	Telomere C-strand (Lagging Strand) Synthesis
R-HSA-174437	Removal of the Flap Intermediate from the C-strand
R-HSA-5358565	Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)
R-HSA-5358606	Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)
R-HSA-5651801	PCNA-Dependent Long Patch Base Excision Repair
R-HSA-5656169	Termination of translesion DNA synthesis
R-HSA-5685942	HDR through Homologous Recombination (HRR)
R-HSA-5696397	Gap-filling DNA repair synthesis and ligation in GG-NER
R-HSA-5696400	Dual Incision in GG-NER
R-HSA-6782135	Dual incision in TC-NER
R-HSA-6782210	Gap-filling DNA repair synthesis and ligation in TC-NER
R-HSA-69091	Polymerase switching
R-HSA-69166	Removal of the Flap Intermediate
R-HSA-69183	Processive synthesis on the lagging strand

MSigDB gene sets: 275 (showing top): REACTOME_DNA_REPLICATION, AP1_01, LFA1_Q6, ENK_UV_RESPONSE_KERATINOCYTE_UP, GCANCTGNY_MYOD_Q6, KAAB_HEART_ATRIUM_VS_VENTRICLE_UP, TGACCTY_ERR1_Q2, AP2_Q3, KAUFFMANN_DNA_REPAIR_GENES, GGGTGGRR_PAX4_03, chr11q13, CAGCTG_AP4_Q5, KEGG_HOMOLOGOUS_RECOMBINATION, GOCC_NUCLEAR_REPLICATION_FORK, MISSIAGLIA_REGULATED_BY_METHYLATION_UP

GO Biological Process (6): DNA synthesis involved in DNA repair (GO:0000731), positive regulation of endothelial cell proliferation (GO:0001938), DNA-templated DNA replication (GO:0006261), DNA replication (GO:0006260), DNA repair (GO:0006281), DNA damage response (GO:0006974)

GO Molecular Function (2): DNA-directed DNA polymerase activity (GO:0003887), protein binding (GO:0005515)

GO Cellular Component (3): nucleoplasm (GO:0005654), delta DNA polymerase complex (GO:0043625), nucleus (GO:0005634)

Reactome top-level categories

Rollup of top-13 pathways:

Category	Pathways
Telomere C-strand (Lagging Strand) Synthesis	2
Mismatch Repair	2
Global Genome Nucleotide Excision Repair (GG-NER)	2
Transcription-Coupled Nucleotide Excision Repair (TC-NER)	2
Lagging Strand Synthesis	2
DNA Damage Bypass	1
Extension of Telomeres	1
Processive synthesis on the C-strand of the telomere	1
Resolution of AP sites via the multiple-nucleotide patch replacement pathway	1
Translesion synthesis by Y family DNA polymerases bypasses lesions on DNA template	1
HDR through Homologous Recombination (HRR) or Single Strand Annealing (SSA)	1
Leading Strand Synthesis	1
Processive synthesis on the lagging strand	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
DNA biosynthetic process	2
DNA metabolic process	2
DNA repair	1
endothelial cell proliferation	1
regulation of endothelial cell proliferation	1
positive regulation of epithelial cell proliferation	1
DNA replication	1
DNA damage response	1
cellular response to stress	1
DNA polymerase activity	1
binding	1
nuclear lumen	1
cellular anatomical structure	1
DNA polymerase complex	1
nuclear replisome	1
nuclear protein-containing complex	1
intracellular membrane-bounded organelle	1

Protein interactions and networks

STRING

305 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
POLD4	POLD3	Q15054	989
POLD4	POLD1	P28340	980
POLD4	POLD2	P49005	927
POLD4	LIG1	P18858	671
POLD4	ANXA6	P08133	431
POLD4	SUMO2	P55855	427
POLD4	ATM	Q13315	350
POLD4	CFAP300	Q9BRQ4	328
POLD4	NHSL1	Q5SYE7	303
POLD4	DTL	Q9NZJ0	303
POLD4	FEN1	P39748	300
POLD4	MAD2L2	Q9UI95	288
POLD4	GINS3	Q9BRX5	286
POLD4	REV3L	O60673	258
POLD4	GINS4	Q9BRT9	253

IntAct

31 interactions, top by confidence:

A	B	Type	Score
POLD1	POLD2	psi-mi:“MI:0914”(association)	0.910
POLD1	POLD2	psi-mi:“MI:0915”(physical association)	0.910
POLD4	POLD1	psi-mi:“MI:0915”(physical association)	0.900
POLD4	POLD1	psi-mi:“MI:0407”(direct interaction)	0.900
POLD1	POLD4	psi-mi:“MI:0407”(direct interaction)	0.900
POLD4	POLD1	psi-mi:“MI:0914”(association)	0.900
POLD1	POLD4	psi-mi:“MI:0915”(physical association)	0.900
POLD2	POLD4	psi-mi:“MI:0915”(physical association)	0.790
POLD4	POLD2	psi-mi:“MI:0407”(direct interaction)	0.790
POLD2	POLD4	psi-mi:“MI:0407”(direct interaction)	0.790
POLD2	REV3L	psi-mi:“MI:0914”(association)	0.530
PCNA	POLD4	psi-mi:“MI:0915”(physical association)	0.520
POLD4	PCNA	psi-mi:“MI:0915”(physical association)	0.520
WRNIP1	POLD1	psi-mi:“MI:0914”(association)	0.500
POLD4	WRNIP1	psi-mi:“MI:0915”(physical association)	0.500
POLD4	POLD1	psi-mi:“MI:0915”(physical association)	0.400
POLD2	P4HA2	psi-mi:“MI:0914”(association)	0.350
POLD1	BAG2	psi-mi:“MI:0914”(association)	0.350
POLD3	ESYT2	psi-mi:“MI:0914”(association)	0.350
	POLD4	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (18): POLD4 (Affinity Capture-MS), POLD4 (Biochemical Activity), POLD4 (Biochemical Activity), PCNA (Reconstituted Complex), POLD4 (Affinity Capture-MS), POLD4 (Affinity Capture-MS), POLD4 (Affinity Capture-MS), POLD4 (Affinity Capture-MS), POLD4 (Co-fractionation), POLE (Reconstituted Complex), PCNA (Reconstituted Complex), PCNA (Far Western), POLD1 (Reconstituted Complex), POLD3 (Reconstituted Complex), POLD2 (Reconstituted Complex)

ESM2 similar proteins: A0A1B0GVZ6, A0A1W2PR82, A0A286YDK6, A2A9F4, A2VE02, A5D7I0, A6H7B4, A6NE82, A6NEV1, A6NJB7, A6NJI1, A6NJJ6, A6QP24, A6QPM6, A8MZG2, D3ZAQ5, D4AAA5, O94850, O95873, P0C7X2, P50617, P70339, Q0P5M0, Q2KIL8, Q2KIS6, Q3UN58, Q3ZCQ2, Q5JPB2, Q5M844, Q5VZ46, Q6AY88, Q6GQX2, Q6NZ36, Q6ZW13, Q76NI1, Q7TNS8, Q80TS7, Q86YN6, Q8C1M2, Q8K2F3

Diamond homologs: O59835, Q3T0X9, Q9CWP8, Q9HCU8

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
POLD4	“form complex”	“DNA polymerase delta”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

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

Top pathogenic / likely-pathogenic (0)

SpliceAI

847 predictions. Top by Δscore:

Variant	Effect	Δscore
11:67352890:T:A	donor_gain	1.0000
11:67353306:G:C	donor_gain	1.0000
11:67353348:C:A	donor_gain	1.0000
11:67352016:GAGA:G	acceptor_gain	0.9900
11:67352020:C:CC	acceptor_gain	0.9900
11:67352053:C:CT	acceptor_gain	0.9900
11:67352053:C:T	acceptor_gain	0.9900
11:67352833:T:C	acceptor_gain	0.9900
11:67353073:CTCCC:C	acceptor_gain	0.9900
11:67353075:CCC:C	acceptor_gain	0.9900
11:67353076:CC:C	acceptor_gain	0.9900
11:67353076:CCC:C	acceptor_gain	0.9900
11:67353077:CC:C	acceptor_gain	0.9900
11:67353078:C:CA	acceptor_loss	0.9900
11:67353078:C:CC	acceptor_gain	0.9900
11:67353079:TGCAA:T	acceptor_loss	0.9900
11:67353321:C:CA	donor_gain	0.9900
11:67353322:C:A	donor_gain	0.9900
11:67353347:T:TA	donor_gain	0.9900
11:67353351:T:TA	donor_gain	0.9900
11:67352015:AGAGA:A	acceptor_gain	0.9800
11:67352018:GA:G	acceptor_gain	0.9800
11:67352019:ACTGT:A	acceptor_loss	0.9800
11:67352020:C:A	acceptor_loss	0.9800
11:67352020:C:G	acceptor_loss	0.9800
11:67352021:T:A	acceptor_loss	0.9800
11:67352022:G:C	acceptor_gain	0.9800
11:67352054:A:T	acceptor_gain	0.9800
11:67352986:A:AC	donor_gain	0.9800
11:67352987:C:CC	donor_gain	0.9800

AlphaMissense

683 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:67353019:A:C	F52L	0.993
11:67353019:A:T	F52L	0.993
11:67353021:A:G	F52L	0.993
11:67352785:G:T	R69S	0.985
11:67352999:C:T	G59E	0.984
11:67353017:T:A	D53V	0.984
11:67353020:A:C	F52C	0.984
11:67353020:A:G	F52S	0.984
11:67352015:A:G	W102R	0.976
11:67352015:A:T	W102R	0.976
11:67353016:G:C	D53E	0.973
11:67353016:G:T	D53E	0.973
11:67353017:T:G	D53A	0.973
11:67352772:G:T	A73D	0.971
11:67353018:C:G	D53H	0.971
11:67353000:C:G	G59R	0.967
11:67353000:C:T	G59R	0.967
11:67353017:T:C	D53G	0.967
11:67352782:A:G	W70R	0.966
11:67352782:A:T	W70R	0.966
11:67353000:C:A	G59W	0.965
11:67352775:C:G	R72P	0.964
11:67353018:C:T	D53N	0.963
11:67353014:A:G	L54P	0.960
11:67352013:C:A	W102C	0.957
11:67352013:C:G	W102C	0.957
11:67352999:C:A	G59V	0.957
11:67352992:G:C	C61W	0.956
11:67352751:G:T	P80H	0.955
11:67352794:G:C	R66G	0.953

dbSNP variants (sampled 300 via entrez): RS1001090983 (11:67353217 C>A,T), RS1001544985 (11:67353022 C>CT), RS1002167751 (11:67353693 G>T), RS1002259222 (11:67353108 T>C), RS1002357075 (11:67353737 G>A,C), RS1002637046 (11:67354910 C>T), RS1002711495 (11:67353556 G>A), RS1004276294 (11:67353735 G>A,C,T), RS1005104891 (11:67355294 A>C,G), RS1005707865 (11:67350731 C>T), RS1005952332 (11:67355219 G>A), RS1005985938 (11:67351949 G>A), RS1006878484 (11:67351075 C>G), RS1007237030 (11:67350826 T>C), RS1007618030 (11:67352605 A>C,G)

Disease associations

OMIM: gene MIM:611525 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST007293_14	Body fat distribution (arm fat ratio)	9.000000e-08
GCST007294_129	Body fat distribution (trunk fat ratio)	8.000000e-28
GCST007294_95	Body fat distribution (trunk fat ratio)	1.000000e-35
GCST007295_43	Body fat distribution (leg fat ratio)	1.000000e-25
GCST007295_76	Body fat distribution (leg fat ratio)	1.000000e-21

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004341	body fat distribution

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL2363042 (PROTEIN FAMILY), CHEMBL4742319 (PROTEIN-PROTEIN INTERACTION)

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

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Benzo(a)pyrene	affects expression, increases expression	4
Tretinoin	increases expression	3
Cyclosporine	decreases expression, decreases methylation, increases expression	3
Estradiol	decreases expression	2
Tetrachlorodibenzodioxin	increases expression	2
Aflatoxin B1	increases expression	2
Cadmium Chloride	decreases expression, increases abundance, increases expression	2
afuresertib	increases expression	1
dicrotophos	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	affects binding, decreases expression, increases activity	1
bisphenol A	decreases expression	1
beta-lapachone	increases expression	1
arsenite	affects binding, increases reaction	1
cobaltous chloride	decreases expression	1
tamibarotene	increases expression	1
di-n-butylphosphoric acid	affects expression	1
CPG-oligonucleotide	decreases expression	1
K 7174	increases expression	1
trans-10,cis-12-conjugated linoleic acid	increases expression	1
abrine	increases expression	1
Temozolomide	decreases expression	1
Arsenic Trioxide	increases expression	1
Acetaldehyde	decreases expression	1
Air Pollutants	increases abundance, affects expression	1
Arsenic	increases methylation	1
Azathioprine	increases expression	1
Cadmium	increases expression, increases abundance	1
Chlorpromazine	increases expression	1
Diazinon	increases methylation	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4713781	Binding	Protac activity at CRBN/POLD4 in human BxPC-3 cells assessed as POLD4 degradation incubated for 16 hrs by proteomic analysis	Discovery of a Napabucasin PROTAC as an Effective Degrader of the E3 Ligase ZFP91. — J Med Chem

Clinical trials (associated diseases)

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