APLF

Summary

APLF (aprataxin and PNKP like factor, HGNC:28724) is a protein-coding gene on chromosome 2p13.3, encoding Aprataxin and PNK-like factor (Q8IW19). Histone chaperone involved in single-strand and double-strand DNA break repair.

Enables several functions, including ADP-D-ribose modification-dependent protein binding activity; nuclease activity; and poly-ADP-D-ribose binding activity. Involved in DNA repair; DNA repair-dependent chromatin remodeling; and protein localization to chromatin. Located in nucleoplasm. Is active in site of double-strand break.

Source: NCBI Gene 200558 — RefSeq curated summary.

At a glance

• GWAS associations: 3
• Clinical variants (ClinVar): 89 total
• MANE Select transcript: NM_173545

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:28724
Approved symbol	APLF
Name	aprataxin and PNKP like factor
Location	2p13.3
Locus type	gene with protein product
Status	Approved
Aliases	MGC47799, Xip1, ZCCHH1
Ensembl gene	ENSG00000169621
Ensembl biotype	protein_coding
OMIM	611035
Entrez	200558

Gene structure

Transcript identifiers

Ensembl transcripts: 9 — 4 protein_coding, 3 protein_coding_CDS_not_defined, 2 nonsense_mediated_decay

ENST00000303795, ENST00000445692, ENST00000471727, ENST00000488585, ENST00000529851, ENST00000627740, ENST00000905978, ENST00000963710, ENST00000963711

RefSeq mRNA: 1 — MANE Select: NM_173545 NM_173545

CCDS: CCDS1888

Canonical transcript exons

ENST00000303795 — 10 exons

Exon	Start	End
ENSE00001305069	68502731	68502903
ENSE00001309418	68513548	68513680
ENSE00001321156	68490190	68490261
ENSE00001326939	68513080	68513227
ENSE00001757289	68467585	68467827
ENSE00003526042	68526061	68526242
ENSE00003543596	68567341	68567387
ENSE00003586373	68537872	68538227
ENSE00003619655	68545187	68545312
ENSE00003670255	68577820	68580162

Expression profiles

Bgee: expression breadth ubiquitous, 168 present calls, max score 89.97.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 4.5072 / max 69.9609, expressed in 1558 samples.

FANTOM5 promoters (2 alternative TSS)

Promoter ID	TPM avg	Samples expressed
20707	3.2514	1437
20708	1.2558	755

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
calcaneal tendon	UBERON:0003701	89.97	gold quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	81.88	gold quality
buccal mucosa cell	CL:0002336	81.17	silver quality
tendon	UBERON:0000043	79.32	gold quality
sperm	CL:0000019	78.46	silver quality
sural nerve	UBERON:0015488	75.85	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	75.42	gold quality
colonic epithelium	UBERON:0000397	75.29	gold quality
bone marrow cell	CL:0002092	75.15	gold quality
corpus callosum	UBERON:0002336	74.41	gold quality
left testis	UBERON:0004533	74.30	gold quality
right testis	UBERON:0004534	74.07	gold quality
stromal cell of endometrium	CL:0002255	74.04	gold quality
testis	UBERON:0000473	73.45	gold quality
skin of abdomen	UBERON:0001416	72.10	gold quality
cardiac muscle of right atrium	UBERON:0003379	71.64	gold quality
lower esophagus mucosa	UBERON:0035834	71.57	gold quality
left ventricle myocardium	UBERON:0006566	71.55	gold quality
epithelial cell of pancreas	CL:0000083	71.41	gold quality
skin of leg	UBERON:0001511	71.17	gold quality
muscle of leg	UBERON:0001383	70.30	gold quality
zone of skin	UBERON:0000014	69.96	gold quality
gastrocnemius	UBERON:0001388	69.73	gold quality
vagina	UBERON:0000996	69.58	gold quality
hindlimb stylopod muscle	UBERON:0004252	69.40	gold quality
smooth muscle tissue	UBERON:0001135	69.27	gold quality
esophagus mucosa	UBERON:0002469	68.98	gold quality
quadriceps femoris	UBERON:0001377	68.69	gold quality
tibial artery	UBERON:0007610	68.41	gold quality
popliteal artery	UBERON:0002250	68.39	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 0.

Experiment	Marker?	Max mean expression
E-ANND-3	no	6.04

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): ATM

miRNA regulators (miRDB)

133 targeting APLF, 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-188-3P	100.00	68.76	1240
HSA-MIR-1252-5P	100.00	69.80	2774
HSA-LET-7A-3P	100.00	74.03	3932
HSA-LET-7B-3P	100.00	74.08	3913
HSA-LET-7F-1-3P	100.00	74.02	3928
HSA-MIR-98-3P	100.00	74.08	3907
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-33A-5P	99.99	68.62	1055
HSA-MIR-33B-5P	99.99	68.58	1062
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-4666A-3P	99.96	71.71	3434
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502
HSA-MIR-548AE-5P	99.94	71.23	3502
HSA-MIR-548AK	99.94	71.24	3488
HSA-MIR-548AM-5P	99.94	71.24	3488
HSA-MIR-548AP-5P	99.94	71.14	3489
HSA-MIR-548AQ-5P	99.94	71.34	3426

Literature-anchored findings (GeneRIF, showing 17)

• These data identify APLF as a novel component of the cellular response to DNA strand breaks in human cells. (PMID:17353262)
• PALF is novel human AP endonuclease with conserved zinc-finger-like motifs involved in DNA strand break responses. (PMID:17396150)
• APLF is an ATM target that is involved in nonhomologous end-joining and facilitates double-strand break repair, likely via interactions with Ku and XRCC4-DNA ligase IV. (PMID:18077224)
• interaction of poly(ADP-ribose) with a PBZ motif in two representative human proteins, APLF (aprataxin PNK-like factor) and CHFR (checkpoint protein with FHA and RING domains) (PMID:18172500)
• Study concludes that APLF can accumulate at sites of chromosomal damage via zinc finger-mediated binding to poly(ADP-ribose) and is a novel component of poly(ADP-ribose) signaling in mammalian cells. (PMID:18474613)
• The authors present solution structures of the two poly(ADP-ribose)-binding zinc finger modules of aprataxin and PNK-like factor (APLF), revealing a novel type of zinc finger. (PMID:20098424)
• APLF has a role in chromosomal DNA double-strand break repair. (PMID:21211721)
• The poly(ADP-ribose)-regulated protein APLF as a DNA-damage-specific histone chaperone. (PMID:21211722)
• only a positive association (OR=1.58, 95% CI 1.05-2.46, P=0.027) was obtained for XRCC1 (Arg280His (PMID:21414327)
• Polynucleotide kinase and aprataxin-like forkhead-associated protein (PALF) acts as both a single-stranded DNA endonuclease and a single-stranded DNA 3’ exonuclease and can participate in DNA end joining in a biochemical system. (PMID:21885877)
• APLF promotes the assembly and activity of multi-protein Ku-DNA complexes containing all of the Non-homologous end joining (NHEJ) factors required for DNA ligation. (PMID:23178593)
• These data suggest functional requirements for Ku and XRCC4 in APLF-dependent NHEJ and a unique role for Ku as a factor required to facilitate the nuclear retention of APLF. (PMID:23689425)
• characterization of the interaction of the APLF FHA domain with phosphorylated XRCC1 peptides (PMID:29059378)
• Data provided novel evidence for enrichment of APLF in breast tumors, which could regulate metastasis-associated epithelial-to-mesenchymal transition in invasive breast cancer. (PMID:29580241)
• The acidic domain of APLF is a histone chaperone that can bind both the histone H2A-H2B dimer and H3-H4 tetramer. (PMID:29905837)
• The crystal structures of the Ku-binding motifs (KBM) of the non-homologous end joining (NHEJ) proteins APLF (A-KBM) and XLF (X-KBM) bound to a Ku-DNA complex are discussed. (PMID:30291363)
• MIR888-dependent inhibition of APLF by E2F1 was demonstrated using overexpression and knockdown experiments, in combination with luciferase assays. (PMID:31287003)

Cross-species orthologs

4 orthologs

Organism	Symbol	Gene ID
danio_rerio	aplf	ENSDARG00000096566
mus_musculus	Aplf	ENSMUSG00000030051
rattus_norvegicus	Aplf	ENSRNOG00000043059
drosophila_melanogaster	CG6171	FBGN0026737

Protein

Protein identifiers

Aprataxin and PNK-like factor — Q8IW19 (reviewed: Q8IW19)

Alternative names: Apurinic-apyrimidinic endonuclease APLF, PNK and APTX-like FHA domain-containing protein, XRCC1-interacting protein 1

All UniProt accessions (3): E9PRH6, Q8IW19, F8WET0

UniProt curated annotations — full annotation on UniProt →

Function. Histone chaperone involved in single-strand and double-strand DNA break repair. Recruited to sites of DNA damage through interaction with branched poly-ADP-ribose chains, a polymeric post-translational modification synthesized transiently at sites of chromosomal damage to accelerate DNA strand break repair reactions. Following recruitment to DNA damage sites, acts as a histone chaperone that mediates histone eviction during DNA repair and promotes recruitment of histone variant MACROH2A1. Also has a nuclease activity: displays apurinic-apyrimidinic (AP) endonuclease and 3’-5’ exonuclease activities in vitro. Also able to introduce nicks at hydroxyuracil and other types of pyrimidine base damage. Together with PARP3, promotes the retention of the LIG4-XRCC4 complex on chromatin and accelerate DNA ligation during non-homologous end-joining (NHEJ). Also acts as a negative regulator of cell pluripotency by promoting histone exchange. Required for the embryo implantation during the epithelial to mesenchymal transition in females.

Subunit / interactions. Interacts with LIG4. Interacts with PARP1. Interacts with XRCC4. Interacts (via KBM motif) with XRCC5 and XRCC6; promoting recruitment to DNA damage sites. Interacts with XRCC1. Interacts (via C-terminal disordered region) with histones; interacts with histone H2A, H2B and H3-H4.

Subcellular location. Nucleus. Chromosome. Cytoplasm. Cytosol.

Post-translational modifications. Poly-ADP-ribosylated. In addition to binding non covalently poly-ADP-ribose via its PBZ-type zinc fingers, the protein is also covalently poly-ADP-ribosylated by PARP1. Phosphorylated in an ATM-dependent manner upon double-strand DNA break.

Domain organisation. The PBZ-type zinc fingers (also named CYR) mediate non-covalent poly-ADP-ribose-binding. Specifically recognizes branched poly-ADP-ribose chains generated by PARP2. Poly-ADP-ribose-binding is dependent on the presence of zinc and promotes its recruitment to DNA damage sites. The KBM (Ku-binding motif) mediates interaction with XRCC5/Ku80 and XRCC6/Ku70 and recruitment to DNA damage sites. The FHA-like domain mediates interaction with XRCC1 and XRCC4. The NAP1L motif is required for the histone chaperone activity.

Similarity. Belongs to the APLF family.

RefSeq proteins (1): NP_775816* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR008984	SMAD_FHA_dom_sf	Homologous_superfamily
IPR019406	APLF_PBZ	Domain
IPR039253	APLF	Family
IPR041388	FHA_2	Domain

Pfam: PF10283, PF17913

UniProt features (63 total): mutagenesis site 16, strand 11, binding site 7, compositionally biased region 6, helix 4, sequence variant 3, region of interest 3, turn 3, zinc finger region 2, modified residue 2, short sequence motif 2, chain 1, domain 1, sequence conflict 1, coiled-coil region 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
5W7W	X-RAY DIFFRACTION	1.35
5E50	X-RAY DIFFRACTION	1.38
6TYZ	X-RAY DIFFRACTION	1.51
6TYW	X-RAY DIFFRACTION	1.7
5W7X	X-RAY DIFFRACTION	2
5W7Y	X-RAY DIFFRACTION	2.1
6YN1	X-RAY DIFFRACTION	2.35
6TYT	X-RAY DIFFRACTION	2.4
6ERF	X-RAY DIFFRACTION	3.01
2KQB	SOLUTION NMR
2KQC	SOLUTION NMR
2KQD	SOLUTION NMR
2KQE	SOLUTION NMR
2KUO	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q8IW19-F1	62.42	0.23

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 (7): 376; 381; 386; 387; 423; 428; 429

Post-translational modifications (2): 116, 149

Mutagenesis-validated functional residues (16):

Position	Phenotype
27	does not affect interaction with xrcc5 and xrcc6; decreased ability to promote non-homologous end-joining (nhej).
116	decreases phosphorylation by atm.
182–184	abolished interaction with xrcc5 and xrcc6.
182	reduced interaction with xrcc5 and xrcc6; impaired localization to the nucleus.
184	abolished interaction with xrcc5 and xrcc6; impaired localization to the nucleus.
189–191	abolished interaction with xrcc5 and xrcc6.
189	abolished interaction with xrcc5 and xrcc6; impaired localization to the nucleus; decreased ability to promote non-homol
190	reduced interaction with xrcc5 and xrcc6.
191	does not affect interaction with xrcc5 and xrcc6.
376	abolishes poly(adp-ribose)-binding and poly-adp-ribosylation by parp1; when associated with a-421 and a-427. does not af
379	abolishes poly(adp-ribose)-binding and poly-adp-ribosylation by parp1; when associated with a-385; a-421 and a-427. does
385	abolishes poly(adp-ribose)-binding and poly-adp-ribosylation by parp1; when associated with a-379; a-421 and a-427. does
421	abolishes poly(adp-ribose)-binding and poly-adp-ribosylation by parp1; when associated with a-379; a-385 and a-427. abol
427	abolishes poly(adp-ribose)-binding and poly-adp-ribosylation by parp1; when associated with a-379; a-385 and a-421. abol
477	impaired binding to histones and ability to mediate histone chaperone activity.
485	impaired binding to histones and ability to mediate histone chaperone activity.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 146 (showing top): GSE45365_CD8A_DC_VS_CD11B_DC_IFNAR_KO_MCMV_INFECTION_DN, GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_DN, GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_REGULATION_OF_DNA_RECOMBINATION, GOMF_ENDONUCLEASE_ACTIVITY, GOBP_B_CELL_ACTIVATION, GOMF_NUCLEASE_ACTIVITY, GOBP_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, GOBP_REGULATION_OF_DNA_REPAIR, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_B_CELL_MEDIATED_IMMUNITY, GOBP_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_REGULATION_OF_IMMUNOGLOBULIN_PRODUCTION, GOBP_REGULATION_OF_IMMUNE_RESPONSE, GOBP_PROTEIN_MATURATION

GO Biological Process (11): single strand break repair (GO:0000012), DNA repair (GO:0006281), double-strand break repair (GO:0006302), double-strand break repair via nonhomologous end joining (GO:0006303), DNA damage response (GO:0006974), embryo implantation (GO:0007566), regulation of epithelial to mesenchymal transition (GO:0010717), regulation of isotype switching (GO:0045191), protein localization to chromatin (GO:0071168), DNA repair-dependent chromatin remodeling (GO:0140861), protein folding (GO:0006457)

GO Molecular Function (13): nucleotide binding (GO:0000166), DNA-(apurinic or apyrimidinic site) endonuclease activity (GO:0003906), DNA endonuclease activity (GO:0004520), zinc ion binding (GO:0008270), 3’-5’ exonuclease activity (GO:0008408), histone binding (GO:0042393), protein folding chaperone (GO:0044183), poly-ADP-D-ribose binding (GO:0072572), histone chaperone activity (GO:0140713), ADP-D-ribose modification-dependent protein binding (GO:0160002), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872)

GO Cellular Component (7): nucleus (GO:0005634), nucleoplasm (GO:0005654), cytosol (GO:0005829), site of double-strand break (GO:0035861), site of DNA damage (GO:0090734), chromosome (GO:0005694), cytoplasm (GO:0005737)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
DNA repair	2
DNA damage response	2
DNA metabolic process	1
double-strand break repair	1
cellular response to stress	1
multicellular organism development	1
female pregnancy	1
reproductive process	1
epithelial to mesenchymal transition	1
regulation of cell differentiation	1
regulation of DNA recombination	1
regulation of immunoglobulin production	1
regulation of immunoglobulin mediated immune response	1
isotype switching	1
regulation of B cell activation	1
protein localization to chromosome	1
chromatin remodeling	1
cellular process	1
protein maturation	1
nucleoside phosphate binding	1
heterocyclic compound binding	1
DNA endonuclease activity	1
endonuclease activity	1
DNA nuclease activity	1
transition metal ion binding	1
exonuclease activity	1
protein binding	1
molecular_function	1
protein folding	1
carbohydrate derivative binding	1
histone binding	1
protein carrier activity	1
modification-dependent protein binding	1
binding	1
catalytic activity	1
cation binding	1
intracellular membrane-bounded organelle	1
nuclear lumen	1
cytoplasm	1

Protein interactions and networks

STRING

670 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
APLF	XRCC4	Q13426	997
APLF	XRCC1	P18887	995
APLF	APTX	Q7Z2E3	993
APLF	CHFR	Q96EP1	979
APLF	XRCC5	P13010	957
APLF	PARP3	Q9Y6F1	880
APLF	NHEJ1	Q9H9Q4	879
APLF	PNKP	Q96T60	868
APLF	LIG3	P49916	865
APLF	XRCC6	P12956	793
APLF	WRN	Q14191	722
APLF	PAXX	Q9BUH6	721
APLF	PRKDC	P78527	700
APLF	MACROH2A1	O75367	639
APLF	PARG	Q86W56	630

IntAct

51 interactions, top by confidence:

A	B	Type	Score
XRCC6	XRCC5	psi-mi:“MI:0914”(association)	0.970
APLF	XRCC1	psi-mi:“MI:0915”(physical association)	0.920
XRCC1	APLF	psi-mi:“MI:0915”(physical association)	0.920
XRCC1	APLF	psi-mi:“MI:0407”(direct interaction)	0.920
APLF	XRCC5	psi-mi:“MI:0407”(direct interaction)	0.900
APLF	XRCC5	psi-mi:“MI:0915”(physical association)	0.900
XRCC5	APLF	psi-mi:“MI:0915”(physical association)	0.900
APLF	XRCC4	psi-mi:“MI:0915”(physical association)	0.880
APLF	XRCC4	psi-mi:“MI:0407”(direct interaction)	0.880
XRCC4	APLF	psi-mi:“MI:0915”(physical association)	0.880
APLF	PARP1	psi-mi:“MI:0915”(physical association)	0.870
APLF	PARP1	psi-mi:“MI:0407”(direct interaction)	0.870
APLF	PARP1	psi-mi:“MI:0914”(association)	0.870
APLF	XRCC6	psi-mi:“MI:0915”(physical association)	0.830

BioGRID (110): APLF (Two-hybrid), APLF (Affinity Capture-MS), H2AFY2 (Affinity Capture-MS), H2AFY (Affinity Capture-MS), SUPT16H (Affinity Capture-MS), XRCC1 (Affinity Capture-MS), LIG3 (Affinity Capture-MS), PARP2 (Affinity Capture-MS), PARP1 (Affinity Capture-MS), XRCC6 (Affinity Capture-MS), HLTF (Affinity Capture-MS), XRCC5 (Affinity Capture-MS), HIST1H2BJ (Affinity Capture-MS), LIG4 (Affinity Capture-MS), HIST1H2AG (Affinity Capture-MS)

ESM2 similar proteins: A0A3Q2UEI8, A0JM80, A0JNH9, A6QNQ6, A8MT70, B1WC58, E7FAP1, F1R983, F6SNN2, P23497, P46100, P49452, Q09003, Q0IIM1, Q0P5X5, Q2M2Z5, Q3UHX0, Q4R731, Q5FBB7, Q5QJC4, Q5RD97, Q5REF4, Q5W0B1, Q5ZLE9, Q61687, Q62394, Q6GNV6, Q6KAQ7, Q6P0N0, Q6P9P0, Q6PJP8, Q76FK4, Q7YQM3, Q7YQM4, Q80WQ8, Q80XJ2, Q80YR6, Q8BRH4, Q8IW19, Q8IYH5

Diamond homologs: A0JNH9, A8JR14, Q8IW19, Q9D842

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
ATM	“up-regulates activity”	APLF	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 19 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
Nonhomologous End-Joining (NHEJ)	5	52.5×	8e-07
Dengue Virus-Host Interactions	7	20.0×	8e-07
Ub-specific processing proteases	6	19.9×	5e-06

GO biological processes:

GO term	Partners	Fold	FDR
double-strand break repair via nonhomologous end joining	6	140.4×	4e-10
base-excision repair	5	130.0×	1e-08
double-strand break repair	6	67.7×	1e-08

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	70
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

2629 predictions. Top by Δscore:

Variant	Effect	Δscore
2:68467824:GGGA:G	donor_gain	1.0000
2:68467825:G:GT	donor_gain	1.0000
2:68467825:GGA:G	donor_gain	1.0000
2:68467826:GAG:G	donor_gain	1.0000
2:68467828:G:GG	donor_gain	1.0000
2:68513075:TATA:T	acceptor_loss	1.0000
2:68513077:TA:T	acceptor_loss	1.0000
2:68513078:A:AG	acceptor_gain	1.0000
2:68513078:A:G	acceptor_loss	1.0000
2:68513079:G:GA	acceptor_gain	1.0000
2:68513079:GA:G	acceptor_gain	1.0000
2:68513079:GAAAC:G	acceptor_gain	1.0000
2:68513679:AGG:A	donor_loss	1.0000
2:68513680:GGTA:G	donor_loss	1.0000
2:68526051:T:G	acceptor_gain	1.0000
2:68526057:TAA:T	acceptor_loss	1.0000
2:68526059:AGG:A	acceptor_loss	1.0000
2:68526060:GG:G	acceptor_loss	1.0000
2:68526219:G:GT	donor_gain	1.0000
2:68526238:CCAAG:C	donor_loss	1.0000
2:68526239:CAAG:C	donor_loss	1.0000
2:68526240:AAGGT:A	donor_loss	1.0000
2:68526241:AG:A	donor_loss	1.0000
2:68526242:GG:G	donor_loss	1.0000
2:68526243:GT:G	donor_loss	1.0000
2:68526244:T:A	donor_loss	1.0000
2:68537866:TTACA:T	acceptor_loss	1.0000
2:68537867:TACA:T	acceptor_loss	1.0000
2:68537869:CA:C	acceptor_loss	1.0000
2:68537870:A:AG	acceptor_gain	1.0000

AlphaMissense

3390 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:68545187:G:C	R387S	0.995
2:68545187:G:T	R387S	0.995
2:68545287:T:C	C421R	0.995
2:68538227:G:C	R387T	0.993
2:68490220:G:C	A43P	0.992
2:68545218:C:G	H398D	0.992
2:68545220:T:A	H398Q	0.992
2:68545220:T:G	H398Q	0.992
2:68545287:T:A	C421S	0.992
2:68545288:G:C	C421S	0.992
2:68567341:G:C	R429S	0.992
2:68567341:G:T	R429S	0.992
2:68467808:G:A	G26D	0.991
2:68467810:C:A	R27S	0.991
2:68490221:C:A	A43D	0.991
2:68502828:T:C	F89S	0.989
2:68502834:T:C	L91S	0.989
2:68538202:T:C	C379R	0.989
2:68545202:T:A	H392Q	0.989
2:68545202:T:G	H392Q	0.989
2:68545305:T:C	C427R	0.989
2:68513623:T:A	W189R	0.988
2:68513623:T:C	W189R	0.988
2:68467813:G:A	G28R	0.987
2:68467813:G:C	G28R	0.987
2:68490227:T:C	L45P	0.987
2:68538227:G:T	R387M	0.987
2:68545312:G:C	R429T	0.987
2:68467811:G:C	R27P	0.986
2:68502855:T:C	F98S	0.986

dbSNP variants (sampled 300 via entrez): RS1000044288 (2:68493930 A>G,T), RS1000045105 (2:68572759 A>C), RS1000107075 (2:68579063 A>G), RS1000125900 (2:68468988 G>C), RS1000139647 (2:68578817 C>T), RS1000140897 (2:68519460 T>G), RS1000219240 (2:68498925 A>T), RS1000239324 (2:68560881 C>T), RS1000245607 (2:68554953 G>T), RS1000257347 (2:68519230 ATATAT>A,ATATATTATAT), RS1000279960 (2:68499211 C>G), RS1000361613 (2:68466883 A>C), RS1000365657 (2:68547895 A>G), RS1000392815 (2:68467045 G>A,C), RS1000400396 (2:68572650 A>G)

Disease associations

OMIM: gene MIM:611035 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

3 associations (top):

Study	Trait	p-value
GCST001341_19	Multiple sclerosis	2.000000e-07
GCST002830_15	Urate levels in lean individuals	1.000000e-06
GCST005042_4	Restless legs syndrome	1.000000e-58

EFO canonical traits (1, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs3213239	Efficacy	3	Platinum compounds	Non-Small Cell Lung Carcinoma

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs3213239	APLF, PINLYP, XRCC1	3	2.50	1	Platinum compounds

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
trichostatin A	affects expression, increases expression	2
sodium arsenite	decreases expression, increases abundance, increases expression	2
perfluorooctanoic acid	increases expression	2
perfluorooctane sulfonic acid	increases expression	2
Air Pollutants	decreases expression, increases abundance, increases expression	2
Arsenic	affects methylation, increases abundance, increases expression	2
Smoke	decreases expression, increases abundance	2
GSK-J4	decreases expression	1
triphenyl phosphate	affects expression	1
pirinixic acid	decreases expression, increases activity, affects binding	1
arsenite	decreases reaction, increases expression	1
acetochlor	affects response to substance	1
perfluoro-n-nonanoic acid	increases expression	1
perfluorohexanesulfonic acid	increases expression	1
clothianidin	increases expression	1
abrine	increases expression	1
jinfukang	affects cotreatment, increases expression	1
Sunitinib	increases expression	1
Fulvestrant	decreases reaction, increases expression	1
Cadmium	decreases reaction, increases expression, decreases expression	1
Cisplatin	affects cotreatment, increases expression	1
Coal	increases abundance, decreases expression	1
Doxorubicin	decreases expression	1
Estradiol	decreases expression	1
Ethyl Methanesulfonate	increases expression	1
Folic Acid	decreases expression	1
Malathion	decreases expression	1
Methyl Methanesulfonate	increases expression	1
Tretinoin	decreases expression	1
Valproic Acid	decreases methylation	1

Clinical trials (associated diseases)

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